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Mei Cong,1,* Houjun Pang,1,2,* Guangxing Xie,1 Feifei Li,3 Chunxiao Li,3 Hao Sun,3 Shaoyou Yang,1 Weidong Zhao3 1School of Pharmacy, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2Department of Pharmacy, Dazhou Women and Children’s Hospital, Dazhou, People’s Republic of China; 3Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weidong Zhao, Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China, Tel +86 0373 3029977, Fax +86 0373 3029977, Email 141051@xxmu.edu.cnPurpose: Molecular targeted therapy is one of the most pivotal strategies in the treatment of non-small cell lung cancer, yet its curative effect is severely compromised by the poor aqueous solubility, low bioavailability and inadequate tumor accumulation of targeted agents. To enhance the efficacy of targeted agents, we demonstrate a novel self-assemble amphiphilic molecule based on erlotinib as an effective nanodrug for anti-cancer treatment.Methods: An amphiphilic molecule composed of hydrophobic erlotinib and hydrophilic biotin block was synthesized and characterized by nuclear magnetic resonance (NMR) as well as high-resolution mass spectrometry (HRMS). Then, nanoassemblies of the amphiphilic molecules are formulated by using nanoprecipitation method. Subsequently, the size, morphology, cell uptake, the anticancer activity and in vivo distribution of the newly constructed erlotinib nanodrug were systematically assessed by some methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), flow cytometry, in vivo imaging system etc.Results: We developed a novel nanoformulation of erlotinib, which possesses a high drug loading of 45%. With the features of well-defined structure and small size, the obtained nanodrug could be effectively accumulated in tumor sites and rapidly internalized by cancer cells. Finally, the erlotinib-based nanoformulation showed considerably better anticancer activity compared to free erlotinib both in vitro and in vivo. Moreover, the nanodrug displayed great tolerability.Conclusion: Combining the advantageous features of both nanotechnology and self-assemble, this novel erlotinib nanomedicine constitutes a promising therapeutic candidate for cancer treatment. This study also underlines the potential use of amphiphilic molecule for improving drug efficacy as well as reducing drug toxicity, which could become a general strategy for the preparation of nanodrugs of active agents.Keywords: erlotinib, amphiphilic molecule, self-assembling, drug self-delivery system, non-small cell lung cancer

Weidong Zhao,1,2,* Shaoyou Yang,3,* Chunxiao Li,1,2 Feifei Li,1,2 Houjun Pang,3 Guangling Xu,1,2 Yuxin Wang,3 Mei Cong3 1Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China; 2Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China; 3School of Pharmacy, Xinxiang Medical University, Xinxiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei Cong, School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China, Tel +86 0373 3029879, Fax + 86 0373 3029879, Email 151051@xxmu.edu.cnPurpose: Gemcitabine is the first line and the gold standard drug for pancreatic cancer. However, the anticancer efficacy is severely limited by its instability and poor cellular uptake. To enhance the clinical efficacy of gemcitabine, we constructed a novel nanodrug delivery system based on amphiphilic dendrimers and aliphatic gemcitabine prodrug.Methods: An aliphatic gemcitabine prodrug and a small amphiphilic dendrimer were synthesized and characterized by high resolution mass spectrometry (HRMS) as well as nuclear magnetic resonance (NMR). Then the aliphatic gemcitabine prodrug was encapsulated into the small amphiphilic dendrimer by film dispersion method, resulting in a novel nanodrug delivery system. Subsequently, the size, morphology, drug loading, stability, drug release profiles, cell uptake, toxicity, the anticancer activity and in vivo distribution of the new developed gemcitabine delivery system were systematically evaluated by different technical methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), ultraviolet spectrophotometer, flow cytometry, in vivo imaging system etc.Results: We developed a novel nanodrug delivery system of gemcitabine using amphiphilic dendrimer. This dendrimer-based gemcitabine nanoformulation reported here possess a high drug loading of 33%. With the features of small size, stable formulation and pH-responsive drug release, the obtained gemcitabine nanoformulation could effectively accumulate in tumor site and rapid uptake in cells. Finally, the gemcitabine nanoformulation displayed more potent anticancer activity compared to free gemcitabine both in vitro and in vivo. Moreover, the nanodrug displayed greatly reduced adverse effects and satisfactory biocompatibility.Conclusion: Benefiting the advantageous features of both amphiphilic dendrimers and nanotechnology-based drug delivery, this gemcitabine nanosystem constitutes a promising therapeutic candidate for pancreatic cancer treatment. This study also underlines the potential use of self-assembling amphiphilic dendrimer-based nanotechnology for improving drug efficacy as well as reducing drug toxicity.Graphical Abstract: Keywords: gemcitabine, amphiphilic dendrimer, self-assembling, pancreatic cancer, anticancer candidate

Meng Si,1,* Yanni Xia,1,* Menglin Cong,1,* Dandan Wang,2 Yong Hou,1 Hecheng Ma1 1Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 2Jinan Center hospital affiliated to Shandong University, Shandong University, Jinan, 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hecheng Ma, Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China, Tel +86-531-82166551, Email yopo2007@qq.comPurpose: Osteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity.Methods: A novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice.Results: The PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity.Conclusion: The combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.Keywords: hydrogels, localized delivery, synergistic therapy, combination therapy, osteosarcoma

Hailun Xie,1– 3,* Guotian Ruan,1– 3,* Qi Zhang,1– 3,* Yizhong Ge,1– 3 Mengmeng Song,1– 3 Xi Zhang,1– 3 Xiaoyue Liu,1– 3 Shiqi Lin,1– 3 Xiaowei Zhang,1– 3 Xiangrui Li,1– 3 Kangping Zhang,1– 3 Ming Yang,1– 3 Meng Tang,1– 3 Minghua Cong,4 Hanping Shi1– 3 1Department of Gastrointestinal Surgery/Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 2Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, 100038, People’s Republic of China; 3Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, 100038, People’s Republic of China; 4Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hanping Shi, Department of Gastrointestinal Surgery/Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China, Email shihp@ccmu.edu.cnPurpose: The nutritional risk index (NRI) and handgrip strength (HGS) are useful indicators of nutritional and physical status, respectively, both of them can predict the prognosis of many cancers; however, the predictive accuracy of a single indicator is unsatisfactory. Whether the combination of NRI and HGS could enhance the stratification of the prognosis of patients with cancer cachexia.Patients and Methods: The study population was randomly divided into training and validation cohorts. We combined NRI and HGS and constructed the NRI–HGS score. Restricted cubic splines were used to assess the associations between NRI, HGS, and all-cause mortality. The Kaplan–Meier method was used to calculate the survival probability of the patients. The Cox proportional hazards risk model was used to analyze survival and prognostic factors.Results: Low NRI and low HGS were independent predictors of poor prognosis in patients with cancer cachexia. The NRI–HGS score showed a better prognostic stratification than either NRI or HGS. The co-occurrence of low NRI and low HGS was associated with an approximately 1.8-fold increased risk of mortality. The NRI–HGS score could effectively distinguish patients with a poor prognosis at different pathological stages. Furthermore, we constructed a novel prognostic nomogram based on NRI and HGS. The concordance index and calibration plot confirmed that the nomogram had good prognostic accuracy. The area under the receiver operating characteristic curve of the nomogram reached > 0.8, which was much higher than that of the traditional tumor–node–metastasis staging system. The nomogram provided better prognostic stratification for patients with cancer cachexia.Conclusion: Low NRI and low HGS are independent prognostic indicators in cancer cachexia. The combination of NRI and HGS improve prognostic stratification for patients with cancer cachexia. Our study suggests combining nutritional and physical status in future cachexia research.Keywords: nutritional risk index, handgrip strength, cancer cachexia, prognostic

Lei Zhang,1,* Fengjun He,1,* Lina Gao,1 Minghui Cong,1 Juan Sun,2 Jialu Xu,2 Yutong Wang,2 Yang Hu,1 Sajid Asghar,3 Lihong Hu,1,2 Hongzhi Qiao1,2,4 1Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 3Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan; 4Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongzhi Qiao; Lihong HuSchool of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, People’s Republic of ChinaEmail qiaohz@njucm.edu.cn; lhhu@njucm.edu.cnBackground: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants.Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model.Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects.Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.Keywords: exosome, exosome-like nanovesicles, Asparagus cochinchinensis, engineering exosome, antitumor

Abstract Adolescents experience numerous changes, both psychologically and physically, and they are also the age group with a high prevalence of mental problems that need counseling help. The study aims to assess the difficulties and the needs for psychological support, factors affecting the need to use psychological services among adolescents. A cross-sectional study was conducted on 672 high school students in Thu Duc City, Vietnam. The results showed that there was a statistically significant difference between grades 10–12 in student’s difficulties (DS) and a statistically significant difference in needs for psychological services (NPS, RPS). Additionally, there was a statistically significant difference in academic performance for DS. The findings also implied that RPS was predicted by a DS, NPS, and factors affecting the need to use psychological services (FA), in which NPS and DS were mediators in the relationship between FA and RPS. The study significantly contributes to research practices and the theoretical framework that the parliament and the government use to make counselors mandatory in schools. Meanwhile, the study suggested that school counselors, educators, and teachers must appropriately evaluate students' counseling needs and psychological difficulties; this is essential to providing support and interventions when students deal with challenges promptly.

Abstract Background Emotional Intelligence is a noteworthy concept in the academic environment due to its theoretical significance and practical implications. The objectives of this research were to investigate (1) the correlation between academic stress, attitudes toward seeking professional psychological help and emotional intelligence, and (2) the mediating role of emotional intelligence. Methods An online questionnaire was administered to a convenience sample of 908 Vietnamese secondary school students. Three scales were employed to gather demographic variables and self-reported data, including The Wong and Law Emotional Intelligence Scale, The Educational Stress Scale for Adolescents, and Attitudes Toward Seeking Professional Psychological Help. Results The findings indicated substantial differences across many variables, such as gender, grade, and academic performance ranking. The investigation identified significant relationships, including the emotional intelligence of others’ emotion appraisal positively affects self-expectation, while self-emotion appraisal negatively influences self-expectation. The use of emotion was positively associated with the openness to seeking professional help. Moderation analyses revealed age moderating others’ emotion appraisal and despondency, self-emotion appraisal, and openness to seeking professional help. Conclusion Emotional intelligence exerts a substantial influence on both academic stress levels and attitudes toward seeking professional psychological assistance. The results are analysed using the guidelines for conducting mixed-methods research. Workshops and awareness sessions for educators and students on emotional intelligence can be conducted with the cooperation of all parties concerned because of the endorsement of all stakeholders.

ABSTRACTAortic aneurysm/dissection (AAD) poses a life-threatening cardiovascular emergency with complex mechanisms and a notably high mortality rate. Zebrafish (Danio rerio) serve as valuable models for AAD due to the conservation of their three-layered arterial structure and genome with that of humans. However, the existing studies have predominantly focused on larval zebrafish, leaving a gap in our understanding of adult zebrafish. In this study, we utilized β-Aminopropionic Nitrile (BAPN) impregnation to induce AAD in both larval and adult zebrafish. Following induction, larval zebrafish exhibited a 28% widening of the dorsal aortic diameter (p

Abstract There is a relative scarcity of large-scale population studies investigating the relationship between the insulin resistance index of homeostasis model assessment (HOMA-IR) and vascular damage. Therefore, we assessed the association between HOMA-IR and vascular damage in adults aged 18 years and older in China. A total of 17,985 research subjects were included. Vascular damage markers and relevant laboratory tests were measured. HOMA-IR was calculated as (fasting insulin * fasting blood glucose)/22.5. Vascular damage included arteriosclerosis (ba-PWV > 1800 cm/s), peripheral artery disease (ABI 30 mg/g). The relationship between HOMA-IR and vascular damage was analyzed using the RCS. The restricted cubic spline (RCS) analysis suggested that HOMA-IR was nonlinearly associated with arteriosclerosis (P for no-liner

Land reclamation in mining areas is an inevitable measure to accelerate the restoration of biodiversity, promote the transformation and development of mining areas, and realize the transformation of carbon sources into carbon sinks. There are few studies focused on the quantitative assessment of carbon sink capacity and biodiversity restoration of artificial ecosystems and their synergistic effects in reclaimed lands. The dumps in Heidaigou open-pit mining area of Jungar Banner was taken as the research area, and the carbon sinks of vegetation and soil of the reclaimed land were calculated by combining the sample plot survey and remote sensing data. Grey correlation analysis was carried out for each region under different restoration modes to assess the synergy between the biodiversity maintenance function and carbon sequestration capacity of artificial ecosystems of reclaimed land. The results showed that: ①The area proportions of extremely important, highly important, important, average and unimportant biodiversity in the research area were 2.28%, 8.29%, 15.67%, 25.27% and 48.50% respectively. In the artificial ecosystem of reclaimed land, the biodiversity index of trees + shrubs + herbs was higher than other vegetation restoration models, which was mainly located in the inner dump, the middle of the north dump, and the middle and south of the east side dump. The important value of biodiversity maintenance function of forest land in artificial ecosystem was higher than other land use types, and most of them were located on slope or platform edge. ②The top 9 regions in terms of vegetation carbon sink were in trees + shrubs + hers restoration mode, and the average carbon sink of this vegetation restoration model (32.224 g/(m2·a)) was higher than that of other vegetation restoration models. The average soil carbon sink of tree + herbaceous vegetation restoration mode was the highest (18.164 g/(m2·a)), followed by tree + shrub + herbaceous restoration mode (16.909 g/(m2·a)). The vegetation carbon sink (5.897 g/(m2·a)) and soil carbon sink (6.237 g/(m2·a)) under the herbaceous vegetation restoration model (mainly located in the east and north dumps) were the lowest among all restoration models. The carbon sink capacity of reclaimed land was in the trend of forest ecosystem > farmland ecosystem > grassland ecosystem. ③The grey correlation index between vegetation and soil carbon sink and the assessment results of biodiversity maintenance were 0.735 and 0.710, respectively, showing a significant correlation. The vegetation carbon sink increased with the species richness index and diversity index. The increased altitude and the reclamation period led to the greater soil carbon sink.

Abstract To date, earlier diagnosis of Alzheimer’s disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aβ) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aβ plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aβ plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aβ plaque formation.

In this work, ginsenoside CK was confirmed as an EGFR tyrosine kinase inhibitor, with an IC50 value of 32.58 ± 0.09 μM. Molecular docking showed that ginsenoside CK could fit into EGFR binding pocket, thereby acting as a ligand for EGFR. Ginsenoside CK inhibited proliferation of A549 cells as well as induced its apoptosis via downregulating anti-apoptotic factors and upregulating apoptosis induction factors. Ginsenoside CK alone and combined with gefitinib inhibited the tumor progression of A549 lung cancer xenografts in BALB/c nude mice. ELISA assay showed that ginsenoside CK combined with gefitinib alleviated the inflammatory response by suppressing the release of pro-inflammatory cytokines, indicating better inhibitory effects than ginsenoside CK or gefitinib alone. This work further confirmed that ginsenoside CK regulated the EGFR/MAPK/ERK signaling both in vitro and in vivo. In conclusion, ginsenoside CK can exhibit the anti-lung cancer effect via acting as an EGFR tyrosine kinase inhibitor.

Fine particulate matter (PM2.5) may disrupt women's reproductive hormones, posing potential reproductive risks. However, the exact compositions of PM2.5 responsible for these effects remain unclear. Our investigation explored the long-term impacts of PM2.5 constituents on reproductive hormones, based on a large longitudinal assisted reproductive cohort study in Anhui, China. We included 24,396 reproductive hormone samples from 19,845 women attending assisted reproductive technologies (ART) between 2014 and 2020. Using high-resolution gridded data (1-km resolution), we calculated the residence-specified PM2.5 constituents during the year before the month of hormone testing. Relationships between PM2.5 constituents [organic matter (OM), chloride (Cl-), sulfate (SO42-), ammonium (NH4+), black carbon, and nitrate] and reproductive hormones were investigated using the linear mixed model with subject-specific intercepts. The constituent-proportion model and the constituent-residual model were also constructed. Additionally, cubic spline analysis was used to examine the potential non-linear exposure-response relationship. We found that per interquartile range (IQR) increment in OM was associated with a 5.31 % (3.74 %, 6.89 %) increase in estradiol, and per IQR increment in Cl- and NH4+ were associated with 13.56 % (7.63 %, 19.82 %) and 9.07 % (4.35 %, 14.01 %) increases in luteinizing hormone. Conversely, per IQR increment in OM and Cl- were associated with −7.27 % (-9.34 %, −5.16 %) and −8.52 % (-10.99 %, −5.98 %) decreases in progesterone, and per IQR increment in SO42- was associated with a −9.15 % (-10.31 %, −7.98 %) decrease in testosterone. These associations were held in both proportional and residual models. Moreover, exposure-response curves for estradiol and progesterone with PM2.5 constituents exhibited approximately U-shaped. These results suggested that specific PM2.5 constituents might disrupt reproductive hormone homeostasis in women attending ART, providing new evidence for formulating PM2.5 pollution reduction strategies that could benefit women's reproductive health.

Abstract Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S‐nitrosylation of gephyrin (SNO‐gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO‐gephyrin is significantly increased in the BLA of high‐anxiety rats and a downregulation of SNO‐gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO‐gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABAAR γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic‐like effects of physical exercise. This study reveals a key role of downregulating SNO‐gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post‐translational modifications in the brain after exercise.

3-methyl-4-nitrophenol (PNMC), a degradation product of organophosphorus insecticides and a byproduct of fuel combustion, exerting endocrine-disrupting effects. However, its impact on the meiotic process of oocytes remains unclear. In the present study, we investigated the effects of PNMC on meiotic maturation of mouse oocytes in vitro and related mechanisms. Morphologically, PNMC-exposure affected germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Proteomic analysis suggested that PNMC-exposure altered oocyte protein expression that are associated with cytoskeleton, mitochondrial function and oxidative stress. Further studies demonstrated that PNMC-exposure disrupted spindle assembly and chromosome alignment, caused sustained activation of spindle assembly checkpoint (SAC), and arrested meiosis in oocytes. Specifically, PNMC-exposure interfered with the function of microtubule organizing centers (MTOCs) by significantly reducing phosphorylated mitogen activated protein kinase (p-MAPK) expression and disrupting the localization of Pericentrin and p-Aurora A, leading to spindle assembly failure. Besides, PNMC-exposure also increased α-tubulin acetylation, decreased microtubule stability. Moreover, PNMC-exposure impaired mitochondrial function, evidenced by abnormal mitochondrial distribution, decreased mitochondrial membrane potential and ATP levels, release of Cytochrome C into the cytoplasm, and elevated ROS levels. As a result, exposure to PNMC caused DNA damage and early apoptosis in oocytes. Fortunately, melatonin was able to promote oocyte maturation by removing the excessive ROS and enhancing mitochondrial function. These results highlight the adverse effects of PNMC on meiotic maturation, and underscore the protective role of melatonin against PNMC-induced damage.

The current study investigates the microstructure and properties of laser welding involving Hastelloy C-276 and 304 stainless steel with filler wire, which is closely related to nuclear reactor pump can end sealing. The experimental results indicate the presence of an unmixed zone (UZ) and a small amount of Mo-rich secondary phase in weld seam, and microstructure of UZ is composed of austenite and ferrite phases. Laser welding enhances the ratio of low-angle misorientation and the uniformity of elements macro-distribution. The end sealing property of nuclear reactor pump can is characterized by anti-peel property of weld joints. The welded joint has local fracture and through fracture in the test of anti-peel property. The weld with local fracture exhibits superior anti-peel property. The joint crack starts at the bottom of the UZ. The anti-peel property of the welded joint is 239.6 ± 4.7 N/mm and mainly related to the weld penetration. The corrosion property of welded joints is determined by the elements of the weld, and the welded joints showcasing a better integral corrosion property than that of 304 base metals. Laser welding Ni-based alloy/austenitic stainless steel with filler wire has significant technical advantages for end sealing of nuclear reactor pump can.

Abstract Background Little is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy. Methods Patients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding. Results Among 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events. Conclusions This study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH. Trial registration ISRCTN65203415.

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.

Abstract Background Coronary inflammation plays crucial role in type 2 diabetes mellitus (T2DM) induced cardiovascular complications. Both glucose-lowering drug interventions (GLDIS) and glycemic control (GC) status potentially correlate coronary inflammation, as indicated by changes in pericoronary adipose tissue (PCAT) attenuation, and thus influence cardiovascular risk. This study evaluated the impact of GLDIS and GC status on PCAT attenuation in T2DM patients. Methods This retrospective study collected clinical data and coronary computed tomography angiography (CCTA) images of 1,342 patients, including 547 T2DM patients and 795 non-T2DM patients in two tertiary hospitals. T2DM patients were subgroup based on two criteria: (1) GC status: well: HbA1c 9%; (2) GLDIS and non-GLDIS. PCAT attenuations of the left anterior descending artery (LAD-PCAT), left circumflex artery (LCX-PCAT), and right coronary artery (RCA-PCAT) were measured. Propensity matching (PSM) was used to cross compare PCAT attenuation of non-T2DM and all subgroups of T2DM patients. Linear regressions were conducted to evaluate the impact of GC status and GLDIS on PCAT attenuation in T2DM patients. Results Significant differences were observed in RCA-PCAT and LCX-PCAT between poor GC-T2DM and non-T2DM patients (LCX: − 68.75 ± 7.59 HU vs. – 71.93 ± 7.25 HU, p = 0.008; RCA: − 74.37 ± 8.44 HU vs. − 77.2 ± 7.42 HU, p = 0.026). Higher PCAT attenuation was observed in LAD-PCAT, LCX-PCAT, and RCA-PCAT in non-GLDIS T2DM patients compared with GLDIS T2DM patients (LAD: − 78.11 ± 8.01 HU vs. − 75.04 ± 8.26 HU, p = 0.022; LCX: − 71.10 ± 8.13 HU vs. − 68.31 ± 7.90 HU, p = 0.037; RCA: − 78.17 ± 8.64 HU vs. − 73.35 ± 9.32 HU, p = 0.001). In the linear regression, other than sex and duration of diabetes, both metformin and acarbose were found to be significantly associated with lower LAD-PCAT (metformin: β coefficient = − 2.476, p=0.021; acarbose: β coefficient = − 1.841, p = 0.031). Conclusion Inadequate diabetes management, including poor GC and lack of GLDIS, may be associated with increased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA, leading to increased cardiovascular risk. This finding could help healthcare providers identify T2DM patients with increased cardiovascular risk, develop improved cardiovascular management programs, and reduce subsequent cardiovascular related mortality.

Abstract Key message The forest canopy gaps, formed by natural or anthropogenic factors, have been found to reduce soil carbon content and increase nutrient availability. The magnitudes of these effects have been observed to increase with gap age and size, and are largely influenced by changes in temperature, precipitation, and solar radiation. Context Local studies have illustrated the influence of canopy gaps on the spatial heterogeneity of soil carbon and nutrients, playing a pivotal role in driving forest regeneration and succession. Nevertheless, it remains largely unknown whether the response of soil carbon and nutrient content to gap formation is consistent across forest ecosystems at global scale. Aims The aim of this paper is to assess the homogeneity of the observed responses of soil carbon and nutrients following gap formation among a wide array of forest ecosystems and climatic regions. Methods We performed a meta-analysis synthesizing 2127 pairwise observations from 52 published articles to quantify the changes in in soil physical, chemical, and microbial variables resulting from gap creation in natural forests and plantations spanning tropical to boreal regions. Results Canopy gaps resulted in significant decrease of soil organic carbon (C org) and microbial carbon (C mic). The concentrations of ammonium (NH4 +), nitrate (NO3 −), and available phosphorus (available P) increased following gap creation. These changes mainly occurred in the growing season and in the mineral soil layer, becoming more pronounced with increasing gap age and size. The change in C org was negatively regulated by mean annual precipitation, and was associated with the changes in Nt and N mic . The change in NH4 + was positively regulated by mean annual temperature, and was associated with the changes in available P and oxidoreductases (Ox-EEAs). The model explaining the change in soil carbon content exhibited a higher explanatory power than the one accounting for changes in soil nutrient availability. Conclusion The results indicated that forest canopy gaps resulted in a reduction in soil carbon content and an increase in nutrient availability. These findings contribute to a better understanding of the role of small-scale disturbances as drivers of forest ecosystem succession.

Background: Depression in high school students is a common mental health problem and requires evaluation for early intervention. The study was carried out to determine the prevalence of depression symptoms and associated characteristics among high school students in Ho Chi Minh City, Vietnam. Methods: This cross-sectional study enrolled participants between February 2022 and June 2022. The instrument utilized was a questionnaire of socioeconomic-demographic variables, educational characteristics, and the self-reported depression scale obtained from the Centre for Epidemiological Studies-Depression (CES-D). Results: 384 high school students (165 males and 219 females) were questioned. The CES-D had a mean score of 17.3, with 57.6% of participants reporting depressed symptoms. The frequency was 63.3% among male students (OR = 1.84, 95% CI = 1.19-2.83, p = .005). Multiple logistic regression revealed that adolescents with poor health, weak friendships, limited participation in school activities, family problems, financial worries, and negative educational environments were significantly more likely to experience depressive symptoms (odds ratios ranging from 1.60 to 9.97, confidence intervals spanning 1.03 to 78.05, and p-values from

Introduction: Sodium zirconium cyclosilicate (SZC) is a nonabsorbed cation-exchanger approved in China for the treatment of hyperkalemia [HK; serum potassium (sK+) levels >5.0 mmol/L]. This is the first real-world study aimed to assess the effectiveness, safety, and treatment patterns of SZC in Chinese patients with HK. Here we present the results of the first interim analysis.Methods: This multicenter, prospective, cohort study included patients aged ≥18 years with documented HK within 1-year before study enrollment day. These patients were followed up for 6 months from the enrollment day after initiating SZC treatment. The treatment was categorized into correction phase (FAS-P1) and maintenance phase (FAS-P2 new and ongoing users). Subgroup analysis was performed in patients on hemodialysis (FAS-H). The primary objective was evaluation of safety profile of SZC; secondary objectives included assessment of treatment patterns of SZC and its effectiveness.Results: Of 421 screened patients, 193, 354, and 162 patients were enrolled in the FAS-P1, FAS-P2, and FAS-H groups, respectively. sK+ levels were reduced significantly from 5.9 mmol/L to 5.0 mmol/L after the correction phase. For the maintenance phase, the mean sK+ levels were maintained at 5.2 mmol/L and 5.0 mmol/L in the FAS-P2 new and ongoing user, respectively, and 5.3 mmol/L in the FAS-H subgroup. A considerable proportion of patients showed normokalemia after 48 h of SZC treatment (FAS-P1:51.3%) which was maintained up to 6 months in the maintenance phase (FAS-P2:44%). SZC was well-tolerated.Conclusion: SZC was effective and safe for the treatment of HK in real-world clinical practice in China.

ABSTRACT Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical–protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

With the proposal of ''Carbon peaking and carbon neutrality'', Adiabatic Compressed Air Energy Storage (A-CAES) has emerged as a significant component within China's energy storage infrastructure. But its thermodynamic efficiency and economical return need yet to be raised. The present paper proposed a modified system coupling with thermal power plant to utilize the excess compression heat. Utilizing advanced transient modeling software, an A-CAES plant is modeled and validated. The operation performance of the coupled system is compared with non-coupled system, which shows that the system efficiency is raised from 54.8 % to 76.7 % and the investment return rate is improved from 9.18 % to 10.43 %.

Background: Older patients with cancer have a higher risk for malnutrition and impaired quality of life (QoL). The present study aimed to investigate the relationship between malnutrition diagnosed according to the Global Leadership Initiative Malnutrition (GLIM) criteria and QoL across various tumor types, and to evaluate the combined prognostic value of malnutrition and QoL in predicting survival among older patients with cancer. Methods: This multicenter, observational cohort study included 5310 older patients with cancer and 2184 with malnutrition (moderate stage, n = 1023; severe stage, n = 1161). An empirical cumulative distribution curve was performed to illustrate the correlation between malnutrition and QoL. The primary objective was to investigate the association between malnutrition and QoL using logistic regression analysis. Survival analyses were performed to assess the combined prognostic value of malnutrition and QoL. Results: The median age of the patients (66.9% male, 33.1% female) was 70 years (interquartile range [IQR] 67–74 years) years. The median QoL score was highest in patients without malnutrition (91.88 [IQR 84.44–97.44]), followed by those with moderate (86.15 [IQR 76.18–93.85) and severe (82.31 [IQR 69.87–91.11]) malnutrition. Logistics regression revealed that the risk for developing impaired QoL increased 1.98 (95% confidence interval [CI] 1.64–2.38; P < 0.001) and 2.33 (95% CI 1.93–2.81; P < 0.001) times in patients with moderate and severe malnutrition, respectively. Kaplan–Meier curves showed that QoL in combination with GLIM criteria demonstrated a significant discriminative performance for survival and served as an independent prognostic factor among older patients with cancer, especially for lung and gastric cancers. Conclusions: Malnutrition diagnosed according to the GLIM criteria was a predictor of impaired QoL. Additionally, the combination of QoL and malnutrition demonstrated utility for predicting survival outcomes in older patients with cancer.

Given the physiological function and anatomical location of the reproductive tract, studying the upper reproductive tract microbiota may be essential for studying male infertility and other male diseases. This study aimed to characterize the microbiota of the upper reproductive tract male rats and investigate whether specific microbial compositions are associated with sperm parameters. 16S rRNA gene sequencing was used to characterize the microbial composition in the testis, epididymis, seminal vesicles, vas deferens and prostate tissues of the rats. The results showed significant enrichment of Methyloperoxococcus spp. in testicular tissues, Jeotgalicoccus spp. in epididymal tissues. Spearman's correlation analysis revealed that the abundance of several bacterial genera in epididymal, testicular, and seminal vesicle gland tissues correlated with several sperm activity parameters. Our findings provide detailed information on characterizing the upper reproductive tract microbiome in male rats, as well as a potentially crucial link between the reproductive system microbiota and sperm quality.

Sirtuin 5 (Sirt5), a member of the Sirtuin family, is involved in various intracellular biological processes. However, the function of Sirt5 in oocyte maturation has not been clearly elucidated. In this study, we observed that Sirt5 was persistently expressed during the meiotic division of mouse oocytes, with a notable decline in expression in aging oocytes. Sirt5 inhibition led to the failure of the first polar body extrusion and induced cell cycle arrest, indicative of unsuccessful oocyte maturation. Furthermore, Sirt5 inhibition was associated with the extrusion of abnormally large polar bodies, suggesting disrupted asymmetric oocyte division. Mechanistically, the inhibition of Sirt5 resulted in aberrant spindle assembly and disordered chromosome alignment in oocytes. Moreover, Sirt5 inhibition caused the spindle to be centrally located in the oocyte without migrating to the cortical region, consequently preventing the formation of the actin cap. Further investigation revealed that Sirt5 inhibition notably diminished the expression of phosphorylated cofilin and profilin1, while increasing cytoplasmic F-actin levels. These findings suggest that Sirt5 inhibition during oocyte maturation adversely affects spindle assembly and chromosome alignment and disrupts actin dynamics impairing spindle migration and contributing to the failure of symmetric oocyte division and maturation.

The treatment of diabetic wounds is a major challenge faced by the medical system, and there is a growing interest in developing innovative therapies to accelerate wound healing. Regenerative medicine with cells has shown promising potential in skin repair, with the regenerative properties primarily attributed to the paracrine effects of secreted products, including exosomes. Compared to cell-based approaches, using exosomes as a cell-free therapy for chronic wounds has several advantages. Exosomes can regulate intercellular communication by releasing their contents, including mRNA, miRNA, lipids, and proteins, which further promote wound healing. Exosomes are well explored in biomedical application owing to their advantages such as their biocompatibility and low immunogenicity. However, the common method of exosome administration is through injection, but due to their rapid clearance rate in the body, maintaining the necessary therapeutic concentration around the wound is challenging. Therefore, it is necessary to develop a new biocompatible scaffold as a carrier for extracellular vesicles, allowing them to sustain the therapeutic concentration at chronic non-healing wound sites and continuously promote wound healing. Engineered exosomes are kinds of exosomes modified with internal treated molecules, surface decoration or delivered through engineered platform. In addition, some researchers have further processed and modified exosomes, known as engineered exosomes, with internal treated molecules, surface decoration, or delivery through engineered platforms. Compared to regular exosomes, engineered exosomes have greater advantages in promoting wound healing. In this review, we summarize the molecular mechanisms of exosomes from different sources with varying modifications in wound healing. Advantages and limitations of different engineered exosomes for chronic wound repair were also discussed. Finally, we highlight the challenges and future development directions for translating our knowledge of engineered exosomes into clinical practice.