Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca2+ Homeostasis Regulation and Pancreas Autodigestion Inhibition.

Severe acute pancreatitis (AP) is a life-threatening pancreatic inflammatory disease with a high mortality rate (∼40%). Existing pharmaceutical therapies in development or in clinical trials showed insufficient treatment efficacy due to their single molecular therapeutic target, poor water solubility, short half-life, limited pancreas-targeting specificity, etc. Herein, acid-responsive hollow mesoporous Prussian blue nanoparticles wrapped with neutrophil membranes and surface modified with the N,N-dimethyl-1,3-propanediamine moiety were developed for codelivering membrane-permeable calcium chelator BAPTA-AM (BA) and trypsin activity inhibitor gabexate mesylate (Ga). In the AP mouse model, the formulation exhibited efficient recruitment at the inflammatory endothelium, trans-endothelial migration, and precise acinar cell targeting, resulting in rapid pancreatic localization and higher accumulation. A single low dose of the formulation (BA: 200 µg kg-1, Ga: 0.75 mg kg-1) significantly reduced pancreas function indicators to close to normal levels at 24 h, effectively restored the cell redox status, reduced apoptotic cell proportion, and blocked the systemic inflammatory amplified cascade, resulting in a dramatic increase in the survival rate from 58.3 to even 100%. Mechanistically, the formulation inhibited endoplasmic reticulum stress (IRE1/XBP1 and ATF4/CHOP axis) and restored impaired autophagy (Beclin-1/p62/LC3 axis), thereby preserving dying acinar cells and restoring the cellular "health status". This formulation provides an upstream therapeutic strategy with clinical translation prospects for AP management through synergistic ion homeostasis regulation and pancreatic autodigestion inhibition.

The associations among athlete gratitude, athlete engagement, athlete burnout: A cross-lagged study in China.

The purpose of this study is to explore the causal relationship among athlete gratitude, athlete engagement, athlete burnout by cross-lag analysis of longitudinal associations. Two questionnaire surveys were conducted on 352 Chinese athletes with an interval of 1 year using gratitude questionnaire, athlete engagement questionnaire and athlete burnout questionnaire. The analysis yielded four main findings. (1) The overall level of athlete gratitude and athlete engagement was high in China. Chinese athletes at master level had higher levels of gratitude and athlete engagement than athletes at I and II grades. (2) Athlete gratitude is a significant negative predictor of athlete burnout, and also a significant positive predictor of athlete engagement. (3) Athlete engagement and athlete burnout are mutually causal and can be mutually predicted. (4) Athlete gratitude indirectly affects athlete burnout through athlete engagement, and also indirectly affects athlete engagement through athlete burnout. The results of the current study demonstrated the important value of gratitude in the growth process of athletes, and clarified the mechanism of gratitude affecting athlete engagement and athlete burnout. These findings have important implications for athlete development by raising athlete gratitude, motivating athlete engagement levels and relieve athlete burnout.

Crystal engineering of ferrocene-based charge-transfer complexes for NIR-II photothermal therapy and ferroptosis.

Organic charge-transfer complexes (CTCs) can function as versatile second near-infrared (NIR-II) theranostic platforms to tackle complicated solid tumors, while the structure-property relationship is still an unanswered problem. To uncover the effect of molecular stacking modes on photophysical and biochemical properties, herein, five ferrocene derivatives were synthesized as electron donors and co-assembled with electron-deficient F4TCNQ to form the corresponding CTCs. The crystalline and photophysical results showed that only herringbone-aligned CTCs (named anion-radical salts, ARS NPs) possess good NIR-II absorption ability and a photothermal effect for short π-π distances (<3.24 Å) and strong π-electron delocalization in the 1D F4TCNQ anion chain. More importantly, the ARS NPs simultaneously possess ·OH generation and thiol (Cys, GSH) depletion abilities to perturb cellular redox homeostasis for ROS/LPO accumulation and enhanced ferroptosis. In vitro experiments, FcNEt-F4 NPs, and typical ARS NPs, show outstanding antitumor efficiency for the synergistic effect of NIR-II photothermal therapy and ferroptosis, which provides a new paradigm to develop versatile CTCs for anti-tumor application.

Association between Urban Built Environments and Moderate-to-Vigorous Physical Activity of Adolescents: A Cross-Lagged Study in Shanghai, China.

The aim of this study was to determine the relationship between the built environment and moderate-to-vigorous physical activity (MVPA) among adolescents aged 14−16 years. This study used a cross-lagged panel analysis to investigate the relationship between the urban built environment and adolescents' MVPA in Shanghai, China. A total of 517 adolescents (275 boys and 242 girls) aged 14−17 years were recruited in Shanghai, China. Geographic information system technology was used to collect data on the built environment variables of the residential areas assessed. ActiGraphGT3X+ was used to monitor the physical activity of the adolescents at two time points (T1 and T2) spanning 2 years. The correlations between the T1 and T2 built environment variables were significant (r = 0.54−0.65, p < 0.05), and the T2 built environment was significantly better than the T1 built environment. The correlation between the T1 and T2 MVPA was significant (r = 0.28−0.56, p < 0.05), and the T2 weekend MVPA was higher than the T1 weekend MVPA. The T1 built environment could not predict the T2 weekday MVPA (ß = 0.17, p > 0.05), but it positively predicted the T2 weekend MVPA (ß = 0.24, p < 0.05). In conclusion, the urban built environment significantly affected weekend MVPA among adolescents.

γ-Fe2 O3 Loading Mitoxantrone and Glucose Oxidase for pH-Responsive Chemo/Chemodynamic/Photothermal Synergistic Cancer Therapy.

Traditional cancer therapy is limited by poor prognosis and risk of recurrence. Emerging therapies offer alternatives to these problems. In addition, synergistic therapy can combine the advantages of multiple therapies to eliminate cancer cells while attenuating damage to normal tissues. Herein, a theranostic nanoplatform based on the chemotherapeutic drug mitoxantrone (MTO) and glucose oxidase (GOx) co-loaded γ-Fe2 O3 nanoparticles (MTO-GOx@γ-Fe2 O3 NPs) is designed and prepared to realize photoacoustic imaging-guided chemo/chemodynamic/photothermal (CT/CDT/PTT) synergistic cancer therapy. With a particle size of about 86.2 nm, the synthesized MTO-GOx@γ-Fe2 O3 NPs can selectively accumulate at tumor sites by enhanced permeability and retention (EPR) effects. After entering cancer cells by endocytosis, MTO-GOx@γ-Fe2 O3 NPs decompose into Fe3+ ions and release cargo because of their pH-responsive characteristic. As a Food and Drug Administration (FDA)-approved chemotherapy drug, MTO shows strong DNA disruption ability and satisfying photothermal conversion ability under laser irradiation for photothermal therapy. Simultaneously, GOx catalyzes the decomposition of glucose and generates hydrogen peroxide (H2 O2 ) to enhance the chemodynamic therapy efficiency. In vitro and in vivo experiments reveal that MTO-GOx@γ-Fe2 O3 NPs possess a significant synergistic therapeutic effect in cancer treatment.

Structural effect of NIR-II absorbing charge transfer complexes and its application on cysteine-depletion mediated ferroptosis and phototherapy.

Second near-infrared (NIR-II) absorbing organic photothermal agents (PTAs) usually suffer from laborious and time-consuming synthesis; therefore, it is of importance to develop a simple and easy-to-handle method for the preparation of NIR-II PTAs. Charge-transfer complexes (CTCs) can be easily used to construct NIR-II absorbing PTAs, although the relationship between their molecular structure and photophysical properties is yet to be uncovered. Herein, three kinds of electron donors with different substitutions (chloroethyl, ethyl, and methyl) were synthesized and assembled with electron-deficient F4TCNQ to afford corresponding CTC nanoparticles (Cl-F4, Et-F4, and Me-F4 NPs). The large energy gap (>0.61 eV) between HOMO of the donor and LUMO of the acceptor made the CTCs exhibit high charge transfer (>0.93) and dramatic differences in photophysical properties. Additionally, Et-F4 NPs possess the highest NIR-II absorption ability and best photothermal effect because of different packing modes (mass extinction coefficient of 11.0 L g-1 cm-1 and photothermal conversion efficiency of 40.2% at 1060 nm). The mixed stacking mode formed strong charge-transfer absorption bands, indicating that the photophysical properties of CTCs can be tailored by changing the molecular structure and aggregate behaviors. Furthermore, Et-F4 NPs with cyano groups could specifically react with cysteine to block the intracellular biosynthesis of GSH and result in ROS accumulation and ferroptosis. Et-F4 NPs possess outstanding antitumor efficacy for the combined actions of NIR-II triggered photothermal killing effect and ferroptosis in vivo.

Association between Weight Status and Physical Fitness in Chinese Mainland Children and Adolescents: A Cross-Sectional Study.

Background: The increasing prevalence of obesity among children and adolescents is a major public health challenge worldwide. This study examined the relationship between physical fitness and BMI spanning the range from underweight to obese among Chinese mainland children and adolescents. Methods: Participants were 22,681 children and adolescents (11,300 boys and 11,381 girls) aged 10-18 years from the Chinese mainland. Weight status was classified as underweight, normal weight, overweight, and obese using WHO 2007 standards. Physical fitness parameters such as cardiorespiratory fitness (VO2max), lower body explosive strength (standing broad jump), upper body explosive strength (handgrip strength), abdominal muscular endurance (sit-ups in 30 s), flexibility (sit-and-reach), and agility (repeat bestride (20 s)) were assessed. Results: There was a significant association between weight status categories and physical fitness in all age groups and sex (plinear < 0.001, pquadratic < 0.001). Underweight adolescents performed better in lower limb strength, flexibility, agility, and cardiorespiratory fitness than their obese peers, but worse in upper limb strength. Underweight boys aged 10-11 and 12-13 years and girls aged 10-11 years showed significantly (p < 0.05) high odds of meeting a low physical fitness index. Obese adolescents have high odds of meeting a low physical fitness index with age. Conclusion: The present study showed a nonlinear relationship between weight status and physical fitness. Children and adolescents who were classified as underweight or obese had poorer physical fitness than their normal-weight peers.

Hoxa5 Promotes Adipose Differentiation via Increasing DNA Methylation Level and Inhibiting PKA/HSL Signal Pathway in Mice.

BACKGROUND/AIMS: Impaired adipogenesis may be the underlying cause in the development of obesity and type II diabetes. Mechanistically, the family of Homeobox transcription factors is implicated in the regulation of adipocyte fate. Hoxa5 is highly expressed in adipocytes, and its mRNA expression is decreased during differentiation. However, the function of Hoxa5 in adipose tissue has been poorly understood. The aim of this study is to unveil the role of Hoxa5 on adipocyte differentiation and its underlying mechanisms. METHODS: Quantitative real-time PCR (qPCR) and western blot were performed to determine Hoxa5 expression in primary adipocytes and in adipose tissues from mice. Lipid accumulation was evaluated by bodipy staining. Dual luciferase assay was applied to explore the transcription factor of Hoxa5 and the transcriptional target gene modulated by Hoxa5. All measurements were performed at least for three times at least. RESULTS: A significant reduction of Hoxa5 expression was observed in adipose tissue of High Fat Diet (HFD) induced obesity mice. We determined Hoxa5 increased adipocytes differentiation and mitochondrial biogenesis in adipocytes in vitro. CEBPß was determined a transcription factor of Hoxa5 and inhibited methylation level of Hoxa5 by combining on the promoter of Hoxa5. Importantly, we found Fabp4, a known positive regulator of adipocytes differentiation, was transcriptional activation by Hoxa5. In addition, Hoxa5 promotes adipocytes differentiation by inhibiting PKA/HSL pathway. CONCLUSION: Our study demonstrated the promoting role of Hoxa5 in adipocytes differentiation and therefore bringing a new therapeutic mean to the treatment of obesity and type II diabetes.

ColXV promotes adipocyte differentiation via inhibiting DNA methylation and cAMP/PKA pathway in mice.

Extracellular matrix (ECM), as an essential component of adipose tissue, not only provides mechanical support for adipocyte growth, but also participates in ECM-adipocyte communication via various secreted proteins, including highly enriched collagens. Collagen XV (ColXV) is a secreted non-fibrillar collagen within ECM Basement Membrane (BM) zones and well recognized as a tumor suppressor. However, the role of ColXV in adipose tissue is still unknown. In this study, high fat diet (HFD) fed mice were used as obese model, in which we deeply investigated the interaction between ColXV and adipocyte differentiation or adipose metabolism. We found great elevated ColXV expression and positive effect of ColXV on lipid deposition during adipocyte differentiation or obesity both in vitro and in vivo. cAMP response element binding protein (CREB) is a cellular transcription factor that can inhibit adipogenesis and promote lipolysis. Here we proposed ColXV as a newly discovered downstream gene of CREB. We further proved that CREB can repress adipocyte differentiation and enhance lipolysis by negatively regulating ColXV transcription. Mechanistic studies showed ColXV enhanced adipocyte differentiation and lipid deposition through reducing its DNA methylation and repressing the cAMP/PKA signaling pathway. Collectively, our study identified ColXV as a novel downstream gene for CREB and could promote adipocyte differentiation, inhibit lipolysis through repressing cAMP/PKA signaling pathway and positively regulating adipogenic markers expressions by repressing the activity of maintenance methyltransferase Dnmt1. Our data discovered a novel role of ColXV in adipocyte differentiation and provide insight into obesity and related metabolic diseases.

αMSH inhibits adipose inflammation via reducing FoxOs transcription and blocking Akt/JNK pathway in mice.

Alpha melanocyte stimulating hormone (αMSH) abates inflammation in multiple tissues, while Forkhead box proteins O (FoxOs) stimulate inflammatory cascade. However, the relationship between αMSH and FoxOs in adipose inflammation remains unclear. In this study, we used LPS-induced inflammation model, attempted to interpret the function of αMSH in inflammation and the interactions with FoxOs. Results indicated that upon inflammatory situation, the secretion of αMSH and the expression of its receptor MC5R were greatly decreased, but FoxOs expressions were elevated. After the treatment with αMSH, LPS-induced adipose inflammation together with FoxOs expressions was significantly reduced. Conversely, when Foxo1, Foxo3a or Foxo4 overexpressed in αMSH treated inflammatory mouse model, all the anti-inflammatory impacts of αMSH were found disappeared. We further studied the mechanisms by which αMSH exerts its anti-inflammatory impacts and how FoxOs reverse αMSH's function. Foxo4 was found as a negative regulator for MC5R transcription in αMSH inhibited inflammation. Moreover, a negative role was found of αMSH in regulating both Akt and JNK signal pathways by observing the enhanced the anti-inflammatory impacts of pathway-specific inhibitors with αMSH treatment. Our findings demonstrate αMSH plays a key role in the prevention of adipose inflammation and inflammatory diseases by down-regulating Akt/JNK signal pathway and negatively interacting with FoxOs, which brings up αMSH as a novel candidate factor in the adipose anti-inflammation process in obesity.

Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-κB/GSDMD signal in mice adipose tissue.

Pyroptosis is a proinflammatory form of cell death that is associated with pathogenesis of many chronic inflammatory diseases. Melatonin is substantially reported to possess anti-inflammatory properties by inhibiting inflammasome activation. However, the effects of melatonin on inflammasome-induced pyroptosis in adipocytes remain elusive. Here, we demonstrated that melatonin alleviated lipopolysaccharides (LPS)-induced inflammation and NLRP3 inflammasome formation in mice adipose tissue. The NLRP3 inflammasome-mediated pyroptosis was also inhibited by melatonin in adipocytes. Further analysis revealed that gasdermin D (GSDMD), the key executioner of pyroptosis, was the target for melatonin inhibition of adipocyte pyroptosis. Importantly, we determined that nuclear factor κB (NF-κB) signal was required for the GSDMD-mediated pyroptosis in adipocytes. We also confirmed that melatonin alleviated adipocyte pyroptosis by transcriptional suppression of GSDMD. Moreover, GSDMD physically interacted with interferon regulatory factor 7 (IRF7) and subsequently formed a complex to promote adipocyte pyroptosis. Melatonin also attenuated NLRP3 inflammasome activation and pyroptosis, which was induced by LPS or obesity. In summary, our results demonstrate that melatonin alleviates inflammasome-induced pyroptosis by blocking NF-κB/GSDMD signal in mice adipose tissue. Our data reveal a novel function of melatonin on adipocyte pyroptosis, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory response.

Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue.

Sirtuin 1 (Sirt1) promotes adaptive thermogenesis by controlling the acetylation status of enzymes and transcriptional factors in interscapular brown adipose tissue (iBAT). However, the effects of Sirt1 on endoplasmic reticulum (ER) stress and apoptosis of iBAT remain elusive. In this study, the mRNA levels of Sirt1 and thermogenesis genes were reduced but the genes related with ER stress were elevated in iBAT of high-fat diet (HFD)-induced obese mice. Moreover, ER stress further inhibited mRNA level of Sirt1 and triggered brown adipocyte apoptosis in vitro and in vivo. Further analysis revealed that Sirt1 overexpression alleviated ER stress-induced brown adipocyte apoptosis by inhibiting Smad3 and ATF4. In addition, Smad3 bound to ATF4 promoter region and positively transcriptional regulation of ATF4. Our data also confirmed that Sirt1 reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by directly interacting with ATF4. Furthermore, Sirt1 attenuated tunicamycin-induced cold intolerance and elevating thermogenesis by inhibiting ER stress and apoptosis in iBAT. In summary, our data collectively revealed Sirt1 reduced ER stress and apoptosis of brown adipocyte in vivo and in vitro by inhibiting Smad3/ATF4 signal. These data reveal a novel mechanism that links Sirt1 to brown adipocyte apoptosis.

(1)H NMR-based metabonomics revealed protective effect of Naodesheng bioactive extract on ischemic stroke rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Stroke is a leading cause of death and disability in the world. However, current therapies are limited. Naodesheng, a widely used traditional Chinese medicine prescription, has shown a good clinical curative effect on ischemic stroke. Also, Naodesheng has been suggested to have neuroprotective effect on focal cerebral ischemia rats, but the underlying molecular mechanism remains unclear. AIM OF THE STUDY: The present study was designed to evaluate the effect of Naodesheng bioactive extract on the metabolic changes in brain tissue, plasma and urine induced by cerebral ischemia perfusion injury, and explore the possible metabolic mechanisms by using a (1)H NMR-based metabonomics approach. MATERIALS AND METHODS: A middle cerebral artery occlusion rat model was established and confirmed by the experiments of neurobehavioral abnormality evaluation, brain tissue TTC staining and pathological examination. The metabolic changes in brain tissue, plasma and urine were then assessed by a (1)H NMR technique combined with multivariate statistical analysis method. RESULTS: These NMR data showed that cerebral ischemia reperfusion induced great metabolic disorders in brain tissue, plasma and urine metabolisms. However, Naodesheng bioactive extract could reverse most of the imbalanced metabolites. Meanwhile, it was found that both the medium and high dosages of Naodesheng bioactive extract were more effective on the metabolic changes than the low dosage, consistent with histopathological assessments. CONCLUSIONS: These results revealed that Naodesheng had protective effect on ischemic stroke rats and the underlying mechanisms involved multiple metabolic pathways, including energy metabolism, amino acid metabolism, oxidative stress and inflammatory injury. The present study could provide evidence that metabonomics revealed its capacity to evaluate the holistic efficacy of traditional Chinese medicine and explore the underlying mechanisms.

Purification of coenzyme Q10 from fermentation extract: high-speed counter-current chromatography versus silica gel column chromatography.

High-speed counter-current chromatography (HSCCC) is applied to the purification of coenzyme Q(10) (CoQ(10)) for the first time. CoQ(10) was obtained from a fermentation broth extract. A non-aqueous two-phase solvent system composed of heptane-acetonitrile-dichloromethane (12:7:3.5, v/v/v) was selected by analytical HSCCC and used for purification of CoQ(10) from 500 mg of the crude extract. The separation yielded 130 mg of CoQ(10) at an HPLC purity of over 99%. The overall results of the present studies show the advantages of HSCCC over an alternative of silica gel chromatography followed by recrystallization. These advantages extend to higher purity (97.8% versus 93.3%), recovery (88% versus 74.3%) and yield (26.4% versus 23.4%). An effort to avoid the toxic, expensive solvent CH(2)Cl(2) was unsuccessful, but at least its percentage is low in the solvent system.