The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystallin...The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystalline mineralogy,geochemistry,and Re-Os and U-Pb geochronology in the Dahu,Qinnan,and Yangzhaiyu deposits.The Xiaoqinling Orogen comprises an E-W-trending fold and thrust system with repeated structural reactivation and the Mo or Au orebodies in these deposits are dominantly controlled by E-W-trending and NW-SE-trending shear zones.Molybdenum mineralization related to K-feldspar alteration comprises early molybdenite,pyrite,rutile,and monazite within gray quartz veins plus late molybdenite and pyrite within white quartz veins in the Dahu and Qinnan Au-Mo deposits.Early and late Au mineralization events have similar mineral assemblages of pyrite,native gold±Au-Ag-Te minerals,rutile,and monazite associated with quartz-sericite alteration at Yangzhaiyu.The early dissem-inated molybdenite is characterized by rhombohedral polytype and oscillatory Re zoning,in contrast to the late molybdenite with a coexistence of rhombohedral and hexagonal polytypes and irregularly distributed Re.The early molybdenite has a Re-Os isochron age of 222.5±1.3 Ma,compatible with a monazite U-Pb age of 224±6.1 Ma,whereas late molybdenite provides a Re-Os isochron age of 185.0±12 Ma,with the implication that the 3R-polytype molybdenite with oscillatory Re zoning is more suitable for high-precision dating.The early and late Au mineralization have a pyrite Re-Os age of 202.0±5.9 Ma and U-Pb age of 124.0±1.3 Ma,respectively.In accordance with its complex geodynamic setting,geological and geochronological studies record a complicated 100-million-year mineralization history with multiple magmatic-hydrothermal Mo and orogenic Au mineralization events that formed within a structural framework of multiply reactivated shear zones.展开更多
Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators...Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation.We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression.Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology,including reduced process complexity and an immature gene expression profile.Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state,marked by elevated levels of HOPX and GFAP,resembling human astrocytes.Mechanistically,Olig1 and Olig2 bind directly to the Bmp7 enhancer,repressing its expression to promote astrocyte maturation.Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants,confirming the critical role of BMP7 signaling in this process.These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation,with potential implications for understanding glial dysfunction in neurological diseases.展开更多
Background Energy deficiency is a leading cause of the high pre-weaning mortality of neonatal piglets in the swine industry.Thus,optimal energy metabolism is of crucial importance for improving the survivability of ne...Background Energy deficiency is a leading cause of the high pre-weaning mortality of neonatal piglets in the swine industry.Thus,optimal energy metabolism is of crucial importance for improving the survivability of neonatal piglets.The effective utilization of milk fat as primary energy is indispensably required.Methods Pregnant sows(n=27)were randomly assigned into 3 treatments.Each treatment received a standard diet(3,265 kcal ME/kg)supplemented with either 0,0.25%or 0.5%clofibrate(w/w)from d 107 of gestation to d 7 of lacta-tion.The effects of maternal clofibrate on their milk fatty acid(FA)and performance of the piglets were evaluated.The evaluations were performed via measuring sow productive performance,milk FA composition,and hepatic FA oxida-tion of the piglets at birth and d 1,7,14 and 19 after birth.Results Maternal supplementation of clofibrate had no effect on reproductive performance of the sows at farrowing and weaning(P>0.05).However,the mortality at weaning was reduced for piglets from sows with 0.25%of clofi-brate,and the average weekly(and daily)gain was higher in piglets from sows that received clofibrate than sows without clofibrate in the first week(P<0.0001).Maternal clofibrate increased percentage of milk C12:0 and C14:0 FAs but decreased C18:2 and n-6 polyunsaturated FAs.Maternal clofibrate also increased plasma ketone body levels and hepatic FA oxidation measured at the first day of birth,but the increase was not detected in piglets on d 7,14 or 19.Clofibrate was not detected in milk collected from the clofibrate-treated sows.The percentage of FA oxidation decreased,and the percentage of FA esterification increased with increasing in postnatal age.Supplemental carni-tine increased FA oxidation regardless of succinate dehydrogenase inhibition,and the increase had no effect on FA esterification.Conclusions Maternal supplementation of clofibrate during late gestation and early lactation increases hepatic FA oxidative metabolism at birth and improves growth performance of newborn piglets.Maternal clofibrate transfer to suckling piglets via milk was not detected.Carnitine availability is critical for piglets to maintain a high FA oxidation rate during the suckling period.展开更多
Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic i...Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.展开更多
Aqueous zinc-ion batteries(AZIBs)hold great promise for next-generation energy storage but face challenges such as Zn dendrite growth,side reactions,and limited performance at low temperatures.Here,we propose an elect...Aqueous zinc-ion batteries(AZIBs)hold great promise for next-generation energy storage but face challenges such as Zn dendrite growth,side reactions,and limited performance at low temperatures.Here,we propose an electrolyte design strategy that reconstructs the hydrogenbond network through the synergistic effect of glycerol(GL)and methylsulfonamide(MSA),enabling the formation of a(100)-oriented Zn anode.This design significantly broadens the operating current and temperature windows of AZIBs.As a result,Zn||Zn symmetric cells exhibit remarkable cycling stability,achieving 4,000 h at 1 mA cm^(-2)and 600 h at 40 mA cm^(-2)(both at 1 mAh cm^(-2)capacity);even at-20℃,Zn||Zn symmetric cells deliver ultra-stable cycling for over 5,400 h.Furthermore,Zn||VO_(2)full cells retain 77.3%of their capacity after 2,000 cycles at 30°C with a current density of 0.5 A g^(-1)and 85.4%capacity retention after 2,000 cycles at-20°C and 0.25 A g^(-1).These results demonstrate a robust pathway for enhancing the practicality and low-temperature adaptability of AZIBs.展开更多
Orogenic disseminated and Carlin gold deposits share much similarity in alteration and mineralization.The disseminated orogenic Zhenyuan Au deposit along the Ailaoshan shear zone,southeastern Tibet,was selected to cla...Orogenic disseminated and Carlin gold deposits share much similarity in alteration and mineralization.The disseminated orogenic Zhenyuan Au deposit along the Ailaoshan shear zone,southeastern Tibet,was selected to clarify their difference.The alteration and mineralization from the different lithologies,including meta-quartz sandstone,carbonaceous slate,meta-(ultra)mafic rock,quartz porphyry and lamprophyre were researched.According to the mineral assemblage and replacement relationship in all types of host rocks,two reactions show general control on gold deposition:(1) replacement of earlier magnetite by pyrite and carbonaceous material;(2) alteration of biotite and phlogopite phenocrysts in quartz porphyry and lamprophyre into dolomite/ankerite and sericite.Despite the lamprophyre is volumetrically minor and much less fractured than other host rocks,it contains a large portion of Au reserve,indicating that the chemically active lithology has played a more important role in gold precipitation compared to structure.LA-ICP-MS analysis shows that Au mainly occurs as invisible gold in fine-grained pyrite disseminated in the host rocks,with Au content reaching to 258.95 ppm.The diagenetic core of pyrite in meta-quartz sandstone enriched in Co,Ni,Mo,Ag and Hg is wrapped by hydrothermal pyrite enriched in Cu,As,Sb,Au,Tl,Pb and Bi.Different host rock lithology has much impact on the alteration and mineralization features.Carbonate and sericite in altered lamprophyre show they have higher Mg than those developed in other of host rocks denoting that the carbonate and sericite incorporated Mg from phlogopite phenocrysts in the primary lamprophyre during alteration.The ore fluid activated the diagenetic pyrite in meta-quartz sandstone leading the hydrothermal pyrite enriched in Cu,Mo,Ag,Sb,Te,Hg,Tl,Pb and Bi,but the hydrothermal pyrite in meta-(ultra)mafic rock is enriched in Co and Ni as the meta-(ultra)mafic rock host rock contain high content of Co and Ni.However,Au and As shear similar range in both types of host rocks indicating that these two elements most likely come from the deep source fluid rather than the host rocks.It was shown in the disseminated orogenic gold deposit that similar hydrothermal alteration with mineral assemblage of carbonate (mainly dolomite and ankerite),sericite,pyrite and arsenopyrite develops in all types of host rocks.This is different from the Nevada Carlin type,in which alteration is mainly dissolution and silicification of carbonate host rock.On the other hand,Au mainly occur as invisible gold in both disseminated orogenic and Carlin gold deposits.展开更多
Objective： The novel fully automated immunohistochemistry （IHC） assay-Ventana anaplastic lymphoma kinase （ALK）-DSF3 for screening ALK rearrangements has been approved by China＇s Food and Drug Administration in 2...Objective： The novel fully automated immunohistochemistry （IHC） assay-Ventana anaplastic lymphoma kinase （ALK）-DSF3 for screening ALK rearrangements has been approved by China＇s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK （＋） and ALK （-） lung adenocarcinoma.Methods： A total of 1,504 consecutive surgical lung adenocareinoma eases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with dinieopathologieal characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK （＋） patients were followed-up, and targeted therapy of ALKinhibitors was adopted and observed in patients with stage IV according to the NCCN guideline.Results： ALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group （P〈0.05）.Mucinous adenocarcinoma （28.2%） was determined to be predominant in ALK （＋） cases, followed by the solid type （11.7%）, specific type （6.8%）, papillary type （5.6%）, acinar type （5.5%）, and lepidic type （3.1%）, and the differences were statistically significant （χ2=42.01 1, P〈0.05）. ALK （＋） adenocarcinoma with lymph node metastasis （10.8%） were significantly higher than that without lymph node metastasis （4.5%） （g2=19.809, P〈0.05）; and ALK （＋） in phase Ⅳ （20%） was significantly higher than phaseⅢ （12.9%）, phase Ⅱ （4.2%）, phase Ⅰ （4.5%）, and phase 0 （0） （g2=36.068, P〈0.05）. Multivariate logistic regression disclosed that patient age, AJCC staging, and histological mucinous subtype were correlated with ALK positive staining （OR=0.959, 1.578, 5.036, respectively）. Sixty eight patients had followed-up results, five patients out of which primarily diagnosed or progressed into Stage IV benefited well from targeted therapy with Crizotinib.Conclusions： The ALK fusion protein was seen in 6.6% Chinese NSCLC patients, and mosdy seen in younger, clinically higher staging, mueinous and solid predominant adenoearcinoma. Clinical trials in patients of Stage Ⅳ eonfirmed that ALK-DSF3 Ventana IHC is serviceable in screening ALK-positive candidates for molecular targeted therapy.展开更多
BACKGROUND Owing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis(PALM) and evaluation of therapeutic ef...BACKGROUND Owing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis(PALM) and evaluation of therapeutic effects in gastric cancer, which leads to inevitable false-positive findings in imaging. Patients with clinical PALM may have entirely different pathological stages(stage IV or not), which require completely different treatment strategies. There is no consensus on whether surgical intervention should be implemented for this group of patients. In particular, the value of D2 gastrectomy in a multidisciplinary treatment(MDT)approach for advanced gastric cancer with clinical PALM remains unknown.AIM To investigate the value of D2 gastrectomy in a MDT approach for gastric cancer patients with clinical PALM.METHODS In this real-world study, clinico-pathological data of all gastric cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Sciences between 2011 and 2016 were reviewed to identify those with clinically enlarged PALM. All the clinico-pathological data were prospectively documented in the patient medical record. For all the gastric cancer patients with advanced stage disease,especially those with suspicious distant metastasis, the treatment methods were determined by a multidisciplinary team.RESULTS In total, 48 of 7077 primary gastric cancer patients were diagnosed as having clinical PALM without other distant metastases. All 48 patients received chemotherapy as the initial treatment. Complete or partial response was observed in 39.6%(19/48) of patients in overall and 52.1%(25/48) of patients in the primary tumor. Complete response of PALM was observed in 50.0%(24/48)of patients. After chemotherapy, 45.8%(22/48) of patients received D2 gastrectomy, and 12.5%(6/48) of patients received additional radiotherapy. The postoperative major complication rate and mortality were 27.3%(6/22) and 4.5%(1/22), respectively. The median overall survival and progression-free survival of all the patients were 18.9 and 12.1 mo, respectively. The median overall survival of patients who underwent surgical resection or not was 50.7 and 12.8 mo,respectively. The 3-year and 5-year survival rates were 56.8% and 47.3%,respectively, for patients who underwent D2 resection. Limited PALM and complete response of PALM after chemotherapy were identified as favorable factors for D2 gastrectomy.CONCLUSION For gastric cancer patients with radiologically suspicious PALM that responds well to chemotherapy, D2 gastrectomy could be a safe and effective treatment and should be adopted in a MDT approach for gastric cancer with clinical PALM.展开更多
Chronic stress models, established in adult Sprague-Dawley rats through a 14-day subcutaneous injection of 40 mg/kg corticosterone, once per day, were given a daily oral feeding of 50 mg/kg baicalin. The study was an ...Chronic stress models, established in adult Sprague-Dawley rats through a 14-day subcutaneous injection of 40 mg/kg corticosterone, once per day, were given a daily oral feeding of 50 mg/kg baicalin. The study was an attempt to observe the effect of baicalin on neurogenesis in chronically stressed rats. Results showed that subcutaneous injection of corticosterone significantly decreased the total number of doublecortin-positive neurons in the hippocampus. The reduced cell number caused by corticosterone was mainly due to the decrease of class II doublecortin-positive neurons, but the class I doublecortin-positive neurons were unaffected. Baicalin treatment increased the number of both class I and class II doublecortin-positive neurons. In addition, doublecortin-positive neurons showed less complexity in dendritic morphology after corticosterone injection, and this change was totally reversed by baicalin treatment. These findings suggest that baicalin exhibits a beneficial effect on adult neurogenesis.展开更多
The gold deposits in the Youjiang basin,totaling>25 Moz gold,have traditionally been thought to be of Carlin-type,particularly those with extensional structural geometries in the northern basin dominated by platfor...The gold deposits in the Youjiang basin,totaling>25 Moz gold,have traditionally been thought to be of Carlin-type,particularly those with extensional structural geometries in the northern basin dominated by platform sedimentary sequences.However,the structural geometries,mineralization styles and alteration types for the Jinya,Gaolong and Nakuang gold deposits in the south-central part of the basin are remarkably similar to those of unequivocal orogenic gold deposits.Structural studies show that gold mineralization in the three gold deposits was controlled by tight“locked-up”anticlines with NW−SE-to E−W-trending and/or concomitant thrusts and/or shear zones,which resulted from NE−SW-to N–S-trending compression or transpression following the Early Triassic closure of the Paleo-Tethyan Ocean.Alteration zones in these deposits are dominated by silicification(quartz),sericitization,sulfidation and carbonation.Zoned pyrites in these deposits comprise Au-poor cores and invisible Au-bearing rims with minor external free gold.Euhedral to subhedral auriferous arsenopyrites also contribute to the gold budget.These features indicate that the three gold deposits are sediment-hosted orogenic gold deposits that contrast markedly with the Carlin-type gold deposits in the northern part of the Youjiang basin in terms of structural geometry and timing,mineralization style and nature of associated alteration.Although additional reliable ages using robust methodologies are still required,the older isotopic ages of the gold deposits in the south-central Youjiang basin are also consistent with earlier formation during transpression that predated extension during orogenic collapse,the period of formation of the Carlin-type gold deposits in the northern Youjiang basin.展开更多
Enzymatic glycosylation catalyzed by glycosyltransferases (GTs) has great potential in creating diverse novel and bioactive glycosides. Herein, three new GTs (UGT84 A33, UGT71 AE1 and UGT90 A14) from Carthamus tinctor...Enzymatic glycosylation catalyzed by glycosyltransferases (GTs) has great potential in creating diverse novel and bioactive glycosides. Herein, three new GTs (UGT84 A33, UGT71 AE1 and UGT90 A14) from Carthamus tinctorius exhibited robust catalytic promiscuity to benzylisoquinoline alkaloids, and were used as enzymatic tools in glycosylation of bioactive benzylisoquinoline alkaloids. Seven novel benzylisoquinoline alkaloids O-glycosides were synthesized with high efficiency. These studies indicate the significant potential of promiscuous GTs in synthesis of benzylisoquinoline alkaloids glycosides for drug discovery.展开更多
The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, bu...The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, but it requires significant trust between users and providers. To alleviate privacy concerns, the most commonly used strategy is to anonymize sensitive data. Unfortunately, studies have shown that anonymization is insufficient to protect against reidentification attacks. Recently, privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data. We present the PICOTEES framework, a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants (https://birthdefectlab.cn:3000/). PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology, which can protect the privacy of the user's query information, backend models, and data, as well as the final results. We demonstrate the utility and performance of PICOTEES by exploring a bioinformatics dataset. The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China, dominated by the Chinese Han population (>99.9%). Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.展开更多
Background Ochratoxin A(OTA)is a mycotoxin widely present in raw food and feed materials and is mainly pro-duced by Aspergillus ochraceus and Penicillium verrucosum.Our previous study showed that OTA principally induc...Background Ochratoxin A(OTA)is a mycotoxin widely present in raw food and feed materials and is mainly pro-duced by Aspergillus ochraceus and Penicillium verrucosum.Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder,especially Bacteroides plebeius(B.plebeius)overgrowth.However,whether OTA or B.plebeius alteration leads to abnormal tryptophan-related metabolism in the intestine and liver is largely unknown.This study aimed to elucidate the metabolic changes in the intestine and liver induced by OTA and the tryptophan-related metabolic pathway in the liver.Materials and methods A total of 30 healthy 1-day-old male Cherry Valley ducks were randomly divided into 2 groups.The control group was given 0.1 mol/L NaHCO3 solution,and the OTA group was given 235μg/kg body weight OTA for 14 consecutive days.Tryptophan metabolites were determined by intestinal chyme metabolomics and liver tryptophan-targeted metabolomics.AMPK-related signaling pathway factors were analyzed by Western blot-ting and mRNA expression.Results Metabolomic analysis of the intestinal chyme showed that OTA treatment resulted in a decrease in intesti-nal nicotinuric acid levels,the downstream product of tryptophan metabolism,which were significantly negatively correlated with B.plebeius abundance.In contrast,OTA induced a significant increase in indole-3-acetamide levels,which were positively correlated with B.plebeius abundance.Simultaneously,OTA decreased the levels of ATP,NAD+and dipeptidase in the liver.Liver tryptophan metabolomics analysis showed that OTA inhibited the kynurenine metabolic pathway and reduced the levels of kynurenine,anthranilic acid and nicotinic acid.Moreover,OTA increased the phosphorylation of AMPK protein and decreased the phosphorylation of mTOR protein.Conclusion OTA decreased the level of nicotinuric acid in the intestinal tract,which was negatively correlated with B.plebeius abundance.The abnormal metabolism of tryptophan led to a deficiency of NAD+and ATP in the liver,which in turn activated the AMPK signaling pathway.Our results provide new insights into the toxic mechanism of OTA,and tryptophan metabolism might be a target for prevention and treatment.展开更多
BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of actio...BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma(GC)cell apoptosis and chemosensitivity to cisplatin.METHODS The GC cell lines AGS,HGC-27,and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltet-razolium bromide assays for cell apoptosis and viability determination.Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins(Bax,Bid,Bad,and Fas),DNA repair-associated proteins(Rad51 and MDM2),and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin(PI3K/AKT/mTOR)and p38-mitogen-activated protein kinase(MAPK)axis proteins.Additionally,the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo.RESULTS Deltonin treatment weakened viability,enhanced apoptosis,and dampened DNA repair in GC cell lines in a dose-dependent pattern.Furthermore,deltonin mitigated PI3K,AKT,mTOR,and p38-MAPK phosphorylation.HS-173,an inhibitor of PI3K,attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation.Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis.CONCLUSION Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.展开更多
基金supported by the National Key Research and Development Project of China(2020YFA0714802)the National Natural Science Foundation of China(42330809)the 111 Project of the Ministry of Science and Technology(BP0719021).
文摘The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystalline mineralogy,geochemistry,and Re-Os and U-Pb geochronology in the Dahu,Qinnan,and Yangzhaiyu deposits.The Xiaoqinling Orogen comprises an E-W-trending fold and thrust system with repeated structural reactivation and the Mo or Au orebodies in these deposits are dominantly controlled by E-W-trending and NW-SE-trending shear zones.Molybdenum mineralization related to K-feldspar alteration comprises early molybdenite,pyrite,rutile,and monazite within gray quartz veins plus late molybdenite and pyrite within white quartz veins in the Dahu and Qinnan Au-Mo deposits.Early and late Au mineralization events have similar mineral assemblages of pyrite,native gold±Au-Ag-Te minerals,rutile,and monazite associated with quartz-sericite alteration at Yangzhaiyu.The early dissem-inated molybdenite is characterized by rhombohedral polytype and oscillatory Re zoning,in contrast to the late molybdenite with a coexistence of rhombohedral and hexagonal polytypes and irregularly distributed Re.The early molybdenite has a Re-Os isochron age of 222.5±1.3 Ma,compatible with a monazite U-Pb age of 224±6.1 Ma,whereas late molybdenite provides a Re-Os isochron age of 185.0±12 Ma,with the implication that the 3R-polytype molybdenite with oscillatory Re zoning is more suitable for high-precision dating.The early and late Au mineralization have a pyrite Re-Os age of 202.0±5.9 Ma and U-Pb age of 124.0±1.3 Ma,respectively.In accordance with its complex geodynamic setting,geological and geochronological studies record a complicated 100-million-year mineralization history with multiple magmatic-hydrothermal Mo and orogenic Au mineralization events that formed within a structural framework of multiply reactivated shear zones.
基金supported by the National Natural Science Foundation of China(82271197,81974175,31820103006,32070971,32200792,32200776).
文摘Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation.We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression.Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology,including reduced process complexity and an immature gene expression profile.Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state,marked by elevated levels of HOPX and GFAP,resembling human astrocytes.Mechanistically,Olig1 and Olig2 bind directly to the Bmp7 enhancer,repressing its expression to promote astrocyte maturation.Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants,confirming the critical role of BMP7 signaling in this process.These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation,with potential implications for understanding glial dysfunction in neurological diseases.
基金Animal Nutrition,Growth and Lactation(grant no.2015–67015-23245/project accession no.1005855)Animal Health and Production and Animal Products(grant no.2023–67015-39663/1030033)from the USDA National Institute of Food and AgricultureNorth Carolina Agricultural Research Hatch projects 1016618 and 02780.
文摘Background Energy deficiency is a leading cause of the high pre-weaning mortality of neonatal piglets in the swine industry.Thus,optimal energy metabolism is of crucial importance for improving the survivability of neonatal piglets.The effective utilization of milk fat as primary energy is indispensably required.Methods Pregnant sows(n=27)were randomly assigned into 3 treatments.Each treatment received a standard diet(3,265 kcal ME/kg)supplemented with either 0,0.25%or 0.5%clofibrate(w/w)from d 107 of gestation to d 7 of lacta-tion.The effects of maternal clofibrate on their milk fatty acid(FA)and performance of the piglets were evaluated.The evaluations were performed via measuring sow productive performance,milk FA composition,and hepatic FA oxida-tion of the piglets at birth and d 1,7,14 and 19 after birth.Results Maternal supplementation of clofibrate had no effect on reproductive performance of the sows at farrowing and weaning(P>0.05).However,the mortality at weaning was reduced for piglets from sows with 0.25%of clofi-brate,and the average weekly(and daily)gain was higher in piglets from sows that received clofibrate than sows without clofibrate in the first week(P<0.0001).Maternal clofibrate increased percentage of milk C12:0 and C14:0 FAs but decreased C18:2 and n-6 polyunsaturated FAs.Maternal clofibrate also increased plasma ketone body levels and hepatic FA oxidation measured at the first day of birth,but the increase was not detected in piglets on d 7,14 or 19.Clofibrate was not detected in milk collected from the clofibrate-treated sows.The percentage of FA oxidation decreased,and the percentage of FA esterification increased with increasing in postnatal age.Supplemental carni-tine increased FA oxidation regardless of succinate dehydrogenase inhibition,and the increase had no effect on FA esterification.Conclusions Maternal supplementation of clofibrate during late gestation and early lactation increases hepatic FA oxidative metabolism at birth and improves growth performance of newborn piglets.Maternal clofibrate transfer to suckling piglets via milk was not detected.Carnitine availability is critical for piglets to maintain a high FA oxidation rate during the suckling period.
基金supported in part by the National Natural Science Foundation of China,Nos.81927804(to GL),82260456(to LY),U21A20479(to LY)Science and Technology Planning Project of Shenzhen,No.JCYJ20230807140559047(to LY)+3 种基金Key-Area Research and Development Program of Guangdong Province,No.2020B0909020004(to GL)Guangdong Basic and Applied Research Foundation,No.2023A1515011478(to LY)the Science and Technology Program of Guangdong Province,No.2022A0505090007(to GL)Ministry of Science and Technology,Shenzhen,No.QN2022032013L(to LY)。
文摘Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.
基金financially supported by Guangdong Major Project of Basic Research(No.2023B0303000002)Shenzhen Fundamental Research Programs(No.JCYJ20241202125404007)+1 种基金Shenzhen Key Laboratory of Advanced Energy Storage(No.ZDSYS20220401141000001)National Natural Science Foundation of China(No.52263016,22265007)。
文摘Aqueous zinc-ion batteries(AZIBs)hold great promise for next-generation energy storage but face challenges such as Zn dendrite growth,side reactions,and limited performance at low temperatures.Here,we propose an electrolyte design strategy that reconstructs the hydrogenbond network through the synergistic effect of glycerol(GL)and methylsulfonamide(MSA),enabling the formation of a(100)-oriented Zn anode.This design significantly broadens the operating current and temperature windows of AZIBs.As a result,Zn||Zn symmetric cells exhibit remarkable cycling stability,achieving 4,000 h at 1 mA cm^(-2)and 600 h at 40 mA cm^(-2)(both at 1 mAh cm^(-2)capacity);even at-20℃,Zn||Zn symmetric cells deliver ultra-stable cycling for over 5,400 h.Furthermore,Zn||VO_(2)full cells retain 77.3%of their capacity after 2,000 cycles at 30°C with a current density of 0.5 A g^(-1)and 85.4%capacity retention after 2,000 cycles at-20°C and 0.25 A g^(-1).These results demonstrate a robust pathway for enhancing the practicality and low-temperature adaptability of AZIBs.
基金jointly supported by the National Key Research and Development Project of China (Grant No.2016YFC0600307)the National Key Basic Research Development Program (973 Program+1 种基金 Grant No.2015CB452606)the fundamental research funds of university teachers(No.53200959708 and No.2-9-2018-126)
文摘Orogenic disseminated and Carlin gold deposits share much similarity in alteration and mineralization.The disseminated orogenic Zhenyuan Au deposit along the Ailaoshan shear zone,southeastern Tibet,was selected to clarify their difference.The alteration and mineralization from the different lithologies,including meta-quartz sandstone,carbonaceous slate,meta-(ultra)mafic rock,quartz porphyry and lamprophyre were researched.According to the mineral assemblage and replacement relationship in all types of host rocks,two reactions show general control on gold deposition:(1) replacement of earlier magnetite by pyrite and carbonaceous material;(2) alteration of biotite and phlogopite phenocrysts in quartz porphyry and lamprophyre into dolomite/ankerite and sericite.Despite the lamprophyre is volumetrically minor and much less fractured than other host rocks,it contains a large portion of Au reserve,indicating that the chemically active lithology has played a more important role in gold precipitation compared to structure.LA-ICP-MS analysis shows that Au mainly occurs as invisible gold in fine-grained pyrite disseminated in the host rocks,with Au content reaching to 258.95 ppm.The diagenetic core of pyrite in meta-quartz sandstone enriched in Co,Ni,Mo,Ag and Hg is wrapped by hydrothermal pyrite enriched in Cu,As,Sb,Au,Tl,Pb and Bi.Different host rock lithology has much impact on the alteration and mineralization features.Carbonate and sericite in altered lamprophyre show they have higher Mg than those developed in other of host rocks denoting that the carbonate and sericite incorporated Mg from phlogopite phenocrysts in the primary lamprophyre during alteration.The ore fluid activated the diagenetic pyrite in meta-quartz sandstone leading the hydrothermal pyrite enriched in Cu,Mo,Ag,Sb,Te,Hg,Tl,Pb and Bi,but the hydrothermal pyrite in meta-(ultra)mafic rock is enriched in Co and Ni as the meta-(ultra)mafic rock host rock contain high content of Co and Ni.However,Au and As shear similar range in both types of host rocks indicating that these two elements most likely come from the deep source fluid rather than the host rocks.It was shown in the disseminated orogenic gold deposit that similar hydrothermal alteration with mineral assemblage of carbonate (mainly dolomite and ankerite),sericite,pyrite and arsenopyrite develops in all types of host rocks.This is different from the Nevada Carlin type,in which alteration is mainly dissolution and silicification of carbonate host rock.On the other hand,Au mainly occur as invisible gold in both disseminated orogenic and Carlin gold deposits.
基金supported by the PUMC Youth Fundthe Fundamental Research Funds for the Central Universities (3332015060)
文摘Objective： The novel fully automated immunohistochemistry （IHC） assay-Ventana anaplastic lymphoma kinase （ALK）-DSF3 for screening ALK rearrangements has been approved by China＇s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK （＋） and ALK （-） lung adenocarcinoma.Methods： A total of 1,504 consecutive surgical lung adenocareinoma eases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with dinieopathologieal characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK （＋） patients were followed-up, and targeted therapy of ALKinhibitors was adopted and observed in patients with stage IV according to the NCCN guideline.Results： ALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group （P〈0.05）.Mucinous adenocarcinoma （28.2%） was determined to be predominant in ALK （＋） cases, followed by the solid type （11.7%）, specific type （6.8%）, papillary type （5.6%）, acinar type （5.5%）, and lepidic type （3.1%）, and the differences were statistically significant （χ2=42.01 1, P〈0.05）. ALK （＋） adenocarcinoma with lymph node metastasis （10.8%） were significantly higher than that without lymph node metastasis （4.5%） （g2=19.809, P〈0.05）; and ALK （＋） in phase Ⅳ （20%） was significantly higher than phaseⅢ （12.9%）, phase Ⅱ （4.2%）, phase Ⅰ （4.5%）, and phase 0 （0） （g2=36.068, P〈0.05）. Multivariate logistic regression disclosed that patient age, AJCC staging, and histological mucinous subtype were correlated with ALK positive staining （OR=0.959, 1.578, 5.036, respectively）. Sixty eight patients had followed-up results, five patients out of which primarily diagnosed or progressed into Stage IV benefited well from targeted therapy with Crizotinib.Conclusions： The ALK fusion protein was seen in 6.6% Chinese NSCLC patients, and mosdy seen in younger, clinically higher staging, mueinous and solid predominant adenoearcinoma. Clinical trials in patients of Stage Ⅳ eonfirmed that ALK-DSF3 Ventana IHC is serviceable in screening ALK-positive candidates for molecular targeted therapy.
基金Supported by the CAMS Initiative for Innovative Medicine,No.2016-I2M-1-007
文摘BACKGROUND Owing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis(PALM) and evaluation of therapeutic effects in gastric cancer, which leads to inevitable false-positive findings in imaging. Patients with clinical PALM may have entirely different pathological stages(stage IV or not), which require completely different treatment strategies. There is no consensus on whether surgical intervention should be implemented for this group of patients. In particular, the value of D2 gastrectomy in a multidisciplinary treatment(MDT)approach for advanced gastric cancer with clinical PALM remains unknown.AIM To investigate the value of D2 gastrectomy in a MDT approach for gastric cancer patients with clinical PALM.METHODS In this real-world study, clinico-pathological data of all gastric cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Sciences between 2011 and 2016 were reviewed to identify those with clinically enlarged PALM. All the clinico-pathological data were prospectively documented in the patient medical record. For all the gastric cancer patients with advanced stage disease,especially those with suspicious distant metastasis, the treatment methods were determined by a multidisciplinary team.RESULTS In total, 48 of 7077 primary gastric cancer patients were diagnosed as having clinical PALM without other distant metastases. All 48 patients received chemotherapy as the initial treatment. Complete or partial response was observed in 39.6%(19/48) of patients in overall and 52.1%(25/48) of patients in the primary tumor. Complete response of PALM was observed in 50.0%(24/48)of patients. After chemotherapy, 45.8%(22/48) of patients received D2 gastrectomy, and 12.5%(6/48) of patients received additional radiotherapy. The postoperative major complication rate and mortality were 27.3%(6/22) and 4.5%(1/22), respectively. The median overall survival and progression-free survival of all the patients were 18.9 and 12.1 mo, respectively. The median overall survival of patients who underwent surgical resection or not was 50.7 and 12.8 mo,respectively. The 3-year and 5-year survival rates were 56.8% and 47.3%,respectively, for patients who underwent D2 resection. Limited PALM and complete response of PALM after chemotherapy were identified as favorable factors for D2 gastrectomy.CONCLUSION For gastric cancer patients with radiologically suspicious PALM that responds well to chemotherapy, D2 gastrectomy could be a safe and effective treatment and should be adopted in a MDT approach for gastric cancer with clinical PALM.
基金supported by the National Natural Science Foundation of China,No. 81070994the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education of the People’s Republic of China,No. 2009/8
文摘Chronic stress models, established in adult Sprague-Dawley rats through a 14-day subcutaneous injection of 40 mg/kg corticosterone, once per day, were given a daily oral feeding of 50 mg/kg baicalin. The study was an attempt to observe the effect of baicalin on neurogenesis in chronically stressed rats. Results showed that subcutaneous injection of corticosterone significantly decreased the total number of doublecortin-positive neurons in the hippocampus. The reduced cell number caused by corticosterone was mainly due to the decrease of class II doublecortin-positive neurons, but the class I doublecortin-positive neurons were unaffected. Baicalin treatment increased the number of both class I and class II doublecortin-positive neurons. In addition, doublecortin-positive neurons showed less complexity in dendritic morphology after corticosterone injection, and this change was totally reversed by baicalin treatment. These findings suggest that baicalin exhibits a beneficial effect on adult neurogenesis.
基金supported by the National Key Research and Development Project of China(2016YFC0600307)the National Key Basic Research Development Program(973 Program+3 种基金2015CB452606)the Chinese Post-doctoral Innovative Talent Support Program(BX20180280)the China Postdoctoral Science Foundation(2018M641428)the 111 Project of the Ministry of Science and Technology(BP0719021).
文摘The gold deposits in the Youjiang basin,totaling>25 Moz gold,have traditionally been thought to be of Carlin-type,particularly those with extensional structural geometries in the northern basin dominated by platform sedimentary sequences.However,the structural geometries,mineralization styles and alteration types for the Jinya,Gaolong and Nakuang gold deposits in the south-central part of the basin are remarkably similar to those of unequivocal orogenic gold deposits.Structural studies show that gold mineralization in the three gold deposits was controlled by tight“locked-up”anticlines with NW−SE-to E−W-trending and/or concomitant thrusts and/or shear zones,which resulted from NE−SW-to N–S-trending compression or transpression following the Early Triassic closure of the Paleo-Tethyan Ocean.Alteration zones in these deposits are dominated by silicification(quartz),sericitization,sulfidation and carbonation.Zoned pyrites in these deposits comprise Au-poor cores and invisible Au-bearing rims with minor external free gold.Euhedral to subhedral auriferous arsenopyrites also contribute to the gold budget.These features indicate that the three gold deposits are sediment-hosted orogenic gold deposits that contrast markedly with the Carlin-type gold deposits in the northern part of the Youjiang basin in terms of structural geometry and timing,mineralization style and nature of associated alteration.Although additional reliable ages using robust methodologies are still required,the older isotopic ages of the gold deposits in the south-central Youjiang basin are also consistent with earlier formation during transpression that predated extension during orogenic collapse,the period of formation of the Carlin-type gold deposits in the northern Youjiang basin.
基金financially supported by the National Natural Science Foundation of China (No. 81573317)CAMS Innovation Fund for Medical Sciences(Nos. CIFMS-2016-I2M-3-012 and CIFMS-2016-I2M-2-002)
文摘Enzymatic glycosylation catalyzed by glycosyltransferases (GTs) has great potential in creating diverse novel and bioactive glycosides. Herein, three new GTs (UGT84 A33, UGT71 AE1 and UGT90 A14) from Carthamus tinctorius exhibited robust catalytic promiscuity to benzylisoquinoline alkaloids, and were used as enzymatic tools in glycosylation of bioactive benzylisoquinoline alkaloids. Seven novel benzylisoquinoline alkaloids O-glycosides were synthesized with high efficiency. These studies indicate the significant potential of promiscuous GTs in synthesis of benzylisoquinoline alkaloids glycosides for drug discovery.
基金funded by the Shanghai Hospital Development Center(SHDC2020CR6028-002 to W.Zhou)National Key R&D Program of China(2020YFC2006402 to Y.Lu)+7 种基金National Key R&D Program of China(2022ZD0116003 to X.Dong)the Science and Technology Commission of Shanghai(22002400700 to S.Wu)Shanghai Municipal Science and Technology Major Project(20Z11900600 to W.Zhou)National Key Research and Development Program(2018YFC0116903 to W.Zhou)Major Research Projects for Young and Middle-aged People of Fujian Province(2021ZQNZD017 to Y.Lu)supported by Key Lab Information Network Security,Ministry of Public Security(to H.Zheng and S.Wang)“Pioneer”and”Leading Goose”R&D Program of Zhejiang(No.2022C01126 to Q.Sun and S.Wang)National Key R&D Program of China(2021YFC2500802 and 2021YFC2500806 to H.Zheng and S.Wang).
文摘The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, but it requires significant trust between users and providers. To alleviate privacy concerns, the most commonly used strategy is to anonymize sensitive data. Unfortunately, studies have shown that anonymization is insufficient to protect against reidentification attacks. Recently, privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data. We present the PICOTEES framework, a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants (https://birthdefectlab.cn:3000/). PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology, which can protect the privacy of the user's query information, backend models, and data, as well as the final results. We demonstrate the utility and performance of PICOTEES by exploring a bioinformatics dataset. The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China, dominated by the Chinese Han population (>99.9%). Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.
基金Guangdong Province Natural Science Funds for Distinguished Young Scholar(2022B1515020016)the National Science Fund for Outstanding Young Scholars(32222080)+5 种基金National Key Research Program(2021YFD1300404)National Science Fund Project of China(32072751)Guangdong Basic and Applied Basic Research Foundation(2022B1515130003)China Agriculture Research System(CARS-42-15)Modern Agricultural Industrial Technology System Innovation Team of Guangdong Province(2022KJ137)Natural Science Foundation of Guangdong Province(2019B1515210012).
文摘Background Ochratoxin A(OTA)is a mycotoxin widely present in raw food and feed materials and is mainly pro-duced by Aspergillus ochraceus and Penicillium verrucosum.Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder,especially Bacteroides plebeius(B.plebeius)overgrowth.However,whether OTA or B.plebeius alteration leads to abnormal tryptophan-related metabolism in the intestine and liver is largely unknown.This study aimed to elucidate the metabolic changes in the intestine and liver induced by OTA and the tryptophan-related metabolic pathway in the liver.Materials and methods A total of 30 healthy 1-day-old male Cherry Valley ducks were randomly divided into 2 groups.The control group was given 0.1 mol/L NaHCO3 solution,and the OTA group was given 235μg/kg body weight OTA for 14 consecutive days.Tryptophan metabolites were determined by intestinal chyme metabolomics and liver tryptophan-targeted metabolomics.AMPK-related signaling pathway factors were analyzed by Western blot-ting and mRNA expression.Results Metabolomic analysis of the intestinal chyme showed that OTA treatment resulted in a decrease in intesti-nal nicotinuric acid levels,the downstream product of tryptophan metabolism,which were significantly negatively correlated with B.plebeius abundance.In contrast,OTA induced a significant increase in indole-3-acetamide levels,which were positively correlated with B.plebeius abundance.Simultaneously,OTA decreased the levels of ATP,NAD+and dipeptidase in the liver.Liver tryptophan metabolomics analysis showed that OTA inhibited the kynurenine metabolic pathway and reduced the levels of kynurenine,anthranilic acid and nicotinic acid.Moreover,OTA increased the phosphorylation of AMPK protein and decreased the phosphorylation of mTOR protein.Conclusion OTA decreased the level of nicotinuric acid in the intestinal tract,which was negatively correlated with B.plebeius abundance.The abnormal metabolism of tryptophan led to a deficiency of NAD+and ATP in the liver,which in turn activated the AMPK signaling pathway.Our results provide new insights into the toxic mechanism of OTA,and tryptophan metabolism might be a target for prevention and treatment.
文摘BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma(GC)cell apoptosis and chemosensitivity to cisplatin.METHODS The GC cell lines AGS,HGC-27,and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltet-razolium bromide assays for cell apoptosis and viability determination.Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins(Bax,Bid,Bad,and Fas),DNA repair-associated proteins(Rad51 and MDM2),and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin(PI3K/AKT/mTOR)and p38-mitogen-activated protein kinase(MAPK)axis proteins.Additionally,the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo.RESULTS Deltonin treatment weakened viability,enhanced apoptosis,and dampened DNA repair in GC cell lines in a dose-dependent pattern.Furthermore,deltonin mitigated PI3K,AKT,mTOR,and p38-MAPK phosphorylation.HS-173,an inhibitor of PI3K,attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation.Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis.CONCLUSION Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.
