As antibiotic pollutants cannot be incompletely removed by conventional wastewater treatment plants,ultraviolet(UV)based advanced oxidation processes(AOPs)such as UV/persulfate(UV/PS)and UV/chlorine are increasingly c...As antibiotic pollutants cannot be incompletely removed by conventional wastewater treatment plants,ultraviolet(UV)based advanced oxidation processes(AOPs)such as UV/persulfate(UV/PS)and UV/chlorine are increasingly concerned for the effective removal of antibiotics from wastewaters.However,the specific mechanisms involving degradation kinetics and transformation mechanisms are not well elucidated.Here we report a detailed examination of SO_(4)•−/Cl•-mediated degradation kinetics,products,and toxicities of sulfathiazole(ST),sarafloxacin(SAR),and lomefloxacin(LOM)in the two processes.Both SO_(4)•−/Cl•-mediated transformation kinetics were found to be dependent on pH(P<0.05),which was attributed to the disparate reactivities of their individual dissociated forms.Based on competition kinetic experiments and matrix calculations,the cationic forms(H_(2)ST^(+),H_(2)SAR^(+),and H_(2)LOM^(+))were more highly reactive towards SO_(4)•−in most cases,while the neutral forms(e.g.,HSAR^(0)and HLOM^(0))reacted the fastest with Cl•for the most of the antibiotics tested.Based on the identification of 31 key intermediates using tandem mass spectrometry,these reactions generated different products,of which the majority still retained the core chemical structure of the parent compounds.The corresponding diverse transformation pathways were proposed,involving S−N breaking,hydroxylation,defluorination,and chlorination reactions.Furthermore,the toxicity changes of their reaction solutions as well as the toxicity of each intermediate were evaluated by the vibrio fischeri and ECOSAR model,respectively.Many primary by-products were proven to be more toxic than the parent chemicals,raising the wider issue of extended potency for these compounds with regards to their ecotoxicity.These results have implications for assessing the degradative fate and risk of these chemicals during the AOPs.展开更多
With the acceleration of the global digital wave,enterprise procurement management is facing multiple challenges such as cost pressure,supply chain collaboration demand,and insufficient information ability.Based on dy...With the acceleration of the global digital wave,enterprise procurement management is facing multiple challenges such as cost pressure,supply chain collaboration demand,and insufficient information ability.Based on dynamic capability theory,resource-based view,and value chain theory,this paper constructs a four-level research framework of“driving factors-transformation paths-strategic actions-performance evaluation”.Firstly,through literature analysis and case review,it summarizes the internal and external driving factors such as external market competition pressure,supply chain coordination demand,policy and regulatory environment,as well as enterprise information foundation,organizational culture,and talent reserve,and analyzes their mechanism of action on procurement digital transformation.Secondly,the procurement digital transformation path is divided into two types:gradual upgrading and leap-forward reconstruction,and the strategic and tactical level strategies,such as top-level design,data governance,process remodeling,supplier collaboration platform construction,and intelligent decision support,are proposed.Thirdly,the implementation guarantee mechanism was designed from the four aspects of organization management,technology platform,talent culture,and risk control.Finally,the performance evaluation index system covering cost,cycle,quality,risk,and digital maturity was constructed,and the evaluation method and continuous improvement mechanism based on balanced scorecard and ROI/TCO analysis were proposed.The results show that the systematic strategy design and multi-dimensional guarantee can effectively improve the procurement efficiency of enterprises,reduce operating costs,enhance supply chain resilience,and provide theoretical and practical guidance for enterprises to achieve sustainable competitive advantage.展开更多
Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a str...Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a strain on the right side of the heart as it pumps blood through the lungs.PAH is characterized by changes in the structure of blood vessels and excessive cell growth.Untreated PAH leads to irreversible right-sided heart failure,often despite medical intervention.Patients experience a gradual decline in function until they are unable to perform daily activities.Advances in treatment have improved the prognosis for many PAH patients.Currently approved therapies target the prostacyclin,endothelin,nitric oxide,or phosphodiesterase pathways to slow the progression of the disease.To address the unmet need for effective PAH therapies,research efforts are focused on identifying new targets and developing therapies that specifically address the underlying disease mechanisms and restore vascular wall homeostasis.Among these,sotatercept,a fusion protein that targets the transforming growth factor-βsuperfamily signaling pathway,has emerged as a promising therapeutic option.In this review,we examine the available evidence from clinical trials to assess the potential of sotatercept as a treatment for PAH.展开更多
Astragali Radix(AR) and Notoginseng Radix et Rhizoma(NR) are frequently employed in cardiovascular disease treatment. However, the efficacy of the AR-NR medicine pair(AN) in improving cardiac remodeling and its underl...Astragali Radix(AR) and Notoginseng Radix et Rhizoma(NR) are frequently employed in cardiovascular disease treatment. However, the efficacy of the AR-NR medicine pair(AN) in improving cardiac remodeling and its underlying mechanism remains unclear. This study aimed to evaluate AN's cardioprotective effect and potential mechanism on cardiac remodeling using transverse aortic constriction(TAC) in mice and angiotensin II(Ang II)-induced neonatal rat cardiomyocytes(NRCMs) and fibroblasts in vitro. High-performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) characterized 23 main components of AN. AN significantly improved cardiac function in the TAC-induced mice. Furthermore, AN considerably reduced the serum levels of N-terminal pro-B-type natriuretic peptide(NT-pro BNP), cardiac troponin T(CTn-T), and interleukin-6(IL-6) and mitigated inflammatory cell infiltration. Post-AN treatment, TAC-induced heart size approached normal. AN decreased cardiomyocyte cross-sectional area and attenuated the upregulation of cardiac hypertrophy marker genes(ANP, BNP, and MYH7) in vivo and in vitro.Concurrently, AN alleviated collagen deposition in TAC-induced mice. AN also reduced the expression of fibrosis-related indicators(COL1A1 and COL3A1) and inhibited the activation of the transforming growth factor-β1(TGF-β1)/mothers against decapentaplegic homolog 3(Smad3) pathway. Thus, AN improved TAC-induced cardiac remodeling. Moreover, AN downregulated p-dynamin-related protein(Drp1)(Ser616) expression and upregulated mitogen 2(MFN-2) and optic atrophy 1(OPA1) expression in vivo and in vitro, thereby restoring mitochondrial fusion and fission balance. In conclusion, AN improves cardiac remodeling by regulating mitochondrial dynamic balance, providing experimental data for the rational application of Chinese medicine prescriptions with AN as the main component in clinical practice.展开更多
Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration vi...Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration via paracrine signaling;however,their clinical applications are limited by potential risks such as tumorigenesis and xenogeneic immune rejection,which are similar to the risks associated with other stem cell transplantations.The present study therefore focuses on small extracellular vesicles derived from hair follicle neural crest stem cells,which preserve the bioactive properties of the parent cells while avoiding the transplantation-associated risks.In vitro,small extracellular vesicles derived from hair follicle neural crest stem cells significantly enhanced the proliferation,migration,tube formation,and barrier function of perineurial cells,and subsequently upregulated the expression of tight junction proteins.Furthermore,in a rat model of sciatic nerve defects bridged with silicon tubes,treatment with small extracellular vesicles derived from hair follicle neural crest stem cells resulted in higher tight junction protein expression in perineurial cells,thus facilitating neural tissue regeneration.At 10 weeks post-surgery,rats treated with small extracellular vesicles derived from hair follicle neural crest stem cells exhibited improved nerve function recovery and reduced muscle atrophy.Transcriptomic and micro RNA analyses revealed that small extracellular vesicles derived from hair follicle neural crest stem cells deliver mi R-21-5p,which inhibits mothers against decapentaplegic homolog 7 expression,thereby activating the transforming growth factor-β/mothers against decapentaplegic homolog signaling pathway and upregulating hyaluronan synthase 2 expression,and further enhancing tight junction protein expression.Together,our findings indicate that small extracellular vesicles derived from hair follicle neural crest stem cells promote the proliferation,migration,and tight junction protein formation of perineurial cells.These results provide new insights into peripheral nerve regeneration from the perspective of perineurial cells,and present a novel approach for the clinical treatment of peripheral nerve defects.展开更多
Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a res...Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence.We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways.There are many trials underway with the aim of improving survival in oesophageal cancer.Currently,phase 2 and 3 trials are focused on MAP kinase inhibition,either through inhibition of growth factor receptors or signal transducer proteins.In order to avoid tumor resistance,it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas.This may be achievable in the future with the advent of gene signatures and a combinatorial approach.展开更多
Diclofenac(DCF), a widely used non-steroidal anti-inflammatory, reacted readily with birnessite under mild conditions, and the pseudo first order kinetic constants achieved 8.84 × 10^-2 hr^-1. Five products of DC...Diclofenac(DCF), a widely used non-steroidal anti-inflammatory, reacted readily with birnessite under mild conditions, and the pseudo first order kinetic constants achieved 8.84 × 10^-2 hr^-1. Five products of DCF including an iminoquinone product(2,5-iminoquinone-diclofenac) and four dimer products were observed and identified by tandem mass spectrometry during the reaction. Meanwhile, 2,5-iminoquinone-diclofenac was identified to be the major product, accounting for 83.09% of the transformed DCF. According to the results of spectroscopic Mn(III) trapping experiments and X-ray Photoelectron Spectroscopy, Mn(IV) contained in birnessite solid was consumed and mainly converted into Mn(III) during reaction process, which proved that the removal of DCF by birnessite was through oxidation. Based on the identified products of DCF and the changes of Mn valence state in birnessite solid, a tentative transformation pathway of DCF was proposed.展开更多
Isosbestic behavior has been traditionally deemed as a spectroscopic indicator of a chemical reaction,in which a reactant transforms directly to a product without intermediates.Room-temperature transformations of coll...Isosbestic behavior has been traditionally deemed as a spectroscopic indicator of a chemical reaction,in which a reactant transforms directly to a product without intermediates.Room-temperature transformations of colloidal semiconductor magic-size clusters(MSCs)from MSC-a to MSC-b display interrupted spectral shifts in optical absorption with or without isosbestic behavior.We demonstrate that a multicomponent model explains consistently the pathway.The model invokes precursor compounds(PCs)of MSCs as intermediates,with three key steps from MSC-a to PC-a(step 1),to PC-b(step 2),and to MSC-b(step 3).Monomer substitution assists step 2(PC-a to PC-b).Based on the experimental result and theoretical study,we conclude that when step 1 or 2 or 3 is rate-determining,isosbestic behavior can be ideally perfect or distorted or absent,respectively.Our study provides a deeper understanding of isosbestic behavior and of MSC transformations that are assisted by PC intermediates and monomer substitution.展开更多
Objective To investigate the effect and mechanism of Shuangshi Tonglin Capsules(SSTL)in the treatment of prostate fibrosis(PF).Methods Human prostate stromal cells(WPMY-1)were used for in vitro experiments to establis...Objective To investigate the effect and mechanism of Shuangshi Tonglin Capsules(SSTL)in the treatment of prostate fibrosis(PF).Methods Human prostate stromal cells(WPMY-1)were used for in vitro experiments to establish PF cell models induced with estradiol(E2).The cell proliferation,migration and clonogenic capacity were determined by cell counting kit-8,scratch assay,and crystal violet staining,respectively.Sprague-Dawley rats were used for in vivo experiments.The changes in histomorphology and organ index of rat prostate by SSTL were determined.Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin(HE)and Masson staining.Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23(FGF-23),E2 and prostate specific antigen(PSA).Mechanistically,changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats.Then the expressions of nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)and transforming growth factor-β1(TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro.Results In the efficacy study,SSTL significantly reduced the proliferation,migration,and clonogenic ability of cells,improved the morphology of the glandular tissue,significantly reduced the prostate index,reduced glandular fibrous tissue and collagen deposition,and resulted in a significant decrease in the levels of FGF-23,E2 and PSA(P<0.01 or P<0.05).In the mechanistic study,SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats(P<0.01 or P<0.05).SSTL significantly elevated the expressions of Nrf2,HO-1,NAD(P)H quinone oxidoreductase 1(NQO-1),and Smad7 proteins in both cells and rats,and significantly decreased the expressions of TGF-β1,collagen I,α-smooth muscle actin and Smad4 proteins(P<0.01 or P<0.05).SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats(P<0.01 or P<0.05).The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance.Conclusion SSTL was effective in improving PF in vivo and in vitro,and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.展开更多
Despite the widespread occurrence of phenols in anthropogenic and natural compounds, their fate in reactions with hypochlorous acid(HOCl), one of the most common water treatment disinfectants, remains incompletely und...Despite the widespread occurrence of phenols in anthropogenic and natural compounds, their fate in reactions with hypochlorous acid(HOCl), one of the most common water treatment disinfectants, remains incompletely understood. To close this knowledge gap, this study investigated the formation of disinfection by-products(DBPs) in the reaction of free chlorine with seven para-substituted phenols. Based on the chemical structures of the DBPs and the reaction mechanisms leading to their formation, the DBPs were categorized into four groups: chlorophenols, coupling products, substituent reaction products, and ring cleavage products. In contrast to previous studies that investigated the formation of earlystage chlorophenols, the primary focus of this study was on the elucidation of novel ring cleavage products, in particular α, β-unsaturated C-dialdehydes, and C-dicarboxylic acids, which, for the first time, were identified and quantified in this study. The molar yields of 2-butene-1,4-dial(BDA), one of the identified α, β-unsaturated C-dialdehydes, varied among the different phenolic compounds, reaching a maximum value of 10.4% for bisphenol S. Molar yields of 2-chloromaleic acid(Cl-MA), one of the identified C-dicarboxylic acids, reached a maximum value of 30.5% for 4-hydroxy-phenylacetic acid under given conditions. 2,4,6-trichlorophenol(TCP) was shown to be an important intermediate of the parent phenols and the C-ring cleavage products. Based on the temporal trends of α, β-unsaturated C-dialdehydes and C-dicarboxylic acids, their formation is likely attributable to two separate ring cleavage pathways. Based on the obtained results, an overall transformation pathway for the reaction of para-substituted phenols with free chlorine leading to the formation of novel Cring cleavage products was proposed.展开更多
To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a ex...To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting.RESULTSExpression of miR-34a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSIONmiR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.展开更多
AIM:To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ),Smad4 and transforming growth factor-beta (TGFβR) across a spectrum representing colorectal cancer (CR...AIM:To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ),Smad4 and transforming growth factor-beta (TGFβR) across a spectrum representing colorectal cancer (CRC) development.METHODS:Tissue microarrays were prepared from archival paraffin embedded tissue,including 51 colorectal carcinomas,25 tubular adenomas (TA) and 26 HPs,each with matched normal colonic epithelium.Immunohistochemistry was performed using antibodies against TIF1γ,Smad4 and TGFβ RⅡ.The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4).RESULTS:Overexpression of TIF1γ was detected in 5/26 (19%) HP;however,it was seen in a significantly higher proportion of neoplasms,15/25 (60%) TAs and 24/51 (47%) CRCs (P<0.05).Normal colonic mucosa,HP,and TAs showed strong Smad4 expression,while its expression was absent in 22/51 (43%) CRCs.Over-expression of TGFβ RⅡ was more commonly seen in neoplasms,13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P<0.05).Furthermore,there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value=0.35,P<0.05).The levels of TIF1γ overexpression were significantly higher in stage Ⅲ than in stage Ⅰ and Ⅱ CRC (P<0.05).CONCLUSION:The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis,is inversely related with Smad4 loss,and may be a prognostic indicator for poor outcome.展开更多
BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gast...BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gastric cancer remain unclear.AIM To evaluate the expression of PREX1 in gastric cancer and its significance in the development of gastric cancer,especially to evaluate the potential mechanism of PREX1 in gastric cancer.METHODS Bioinformatic analysis was performed in order to examine the expression of PREX1 in gastric cancer.The relationship between the survival rate of gastric cancer patients and PREX1 expression was assessed by Kaplan Meier portal.The Gene Set Enrichment Analysis and the correlation between PREX1 and transforming growth factor(TGF)β1 pathway-related mediators were evaluated by cBioPortal for Cancer Genomics.Western blotting and reverse transcriptase polymerase chain reaction assay were used to test the role of TGFβ1 on the expression of PREX1.Western blotting and dual-luciferase reporter system was used to evaluate the effect of PREX1 on the activation of TGFβ1 pathway.Wound healing and Transwell assay were used to assess the effect of PREX1 on the metastasis activity of gastric cancer cells.RESULTS PREX1 was overexpressed in the gastric tumors,and the expression levels were positively associated with the development of gastric cancer.Also,the high expression of PREX1 revealed poor prognosis,especially for those advanced and specific intestinal gastric cancer patients.PREX1 was closely involved in the positive regulation of cell adhesion and positively correlated with TGFβ1-related mediators.Furthermore,TGFβ1 could induce the expression of PREX1 at both the protein and mRNA level.Also,PREX1 could activate the TGFβ1 pathway.The induced PREX1 could increase the migration and invasion activity of gastric cancer cells.CONCLUSION PREX1 is overexpressed in gastric cancer,and the high level of PREX1 predicts poor prognosis.PREX1 is closely associated with TGFβsignaling and promotes the metastasis of gastric cancer cells.展开更多
AIM:To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis.METHODS:Male Sprague-Dawley rats underwent common bile duct ligation(BDL) for 14 d and were treated with Gardenia jasminoide...AIM:To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis.METHODS:Male Sprague-Dawley rats underwent common bile duct ligation(BDL) for 14 d and were treated with Gardenia jasminoides by gavage.The ef-fects of Gardenia jasminoides on liver fibrosis and the detailed molecular mechanisms were also assessed in human hepatic stellate cells(LX-2) in vitro.RESULTS:Treatment with Gardenia jasminoides decreased serum alanine aminotransferase(BDL vs BDL + 100 mg/kg Gardenia jasminoides,146.6 ± 15 U/L vs 77 ± 6.5 U/L,P = 0.0007) and aspartate aminotransferase(BDL vs BDL + 100 mg/kg Gardenia jasminoides,188 ± 35.2 U/L vs 128 ± 19 U/L,P = 0.005) as well as hydroxyproline(BDL vs BDL + 100 mg/kg Gardenia jasminoides,438 ± 40.2 μg/g vs 228 ± 10.3 μg/g liver tissue,P = 0.004) after BDL.Furthermore,Gardenia jasminoides significantly reduced liver mRNA and/or protein expression of transforming growth factor β1(TGF-β1),collagen type?Ⅰ?(Col?Ⅰ) and α-smooth muscle actin(α-SMA).Gardenia jasminoides significantly suppressed the upregulation of TGF-β1,Col?Ⅰand α-SMA in LX-2 exposed to recombinant TGF-β1.Moreover,Gardenia jasminoides inhibited TGF-β1-induced Smad2 phosphorylation in LX-2 cells.CONCLUSION:Gardenia jasminoides exerts antifibrotic effects in the liver fibrosis and may represent a novel antifibrotic agent.展开更多
BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 fin...BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.展开更多
Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pa...Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth-like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day （E） 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-β signalling pathway might play a role in this process.展开更多
Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,an...Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,and its dynamic changes are closely related to the proliferation of endothelial cells,the recruitment of pericytes to blood vessels,and functional differentiation during embryonic vascular development.The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells.Indeed,mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation.Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms,arteriovenous malformations,and cerebral atherosclerosis.In this review,we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis,and we discuss its relationship to functional dysregulation in cerebrovascular diseases.This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis,treatment,and prevention.展开更多
Nanoscale materials often undergo structural,morphological,or chemical changes,especially in solution processes,where heterogeneity and defects may significantly impact the transformation pathways.Liquid phase transmi...Nanoscale materials often undergo structural,morphological,or chemical changes,especially in solution processes,where heterogeneity and defects may significantly impact the transformation pathways.Liquid phase transmission electron microscopy(TEM),allowing us to track dynamic transformations of individual nanoparticles,has become a powerful platform to reveal nanoscale materials transformation pathways and address challenging issues that are hard to approach by other methods.With the development of modern liquid cells,implementing advanced imaging and image analysis methods,and strategically exploring diverse systems,significant advances have been made in liquid phase TEM,including improved high-resolution imaging through liquids at the atomic level and remarkable capabilities in handling complex systems and reactions.In the past more than a decade,we spent much effort in developing and applying liquid phase TEM to elucidate how atomic level heterogeneity and defects impact various physicochemical processes in liquids,such as growth,self-assembly of nanoparticles,etching/corrosion,electrodeposition of alkali metals,catalyst restructuring during reactions,and so on.This article provides a brief review of the liquid phase TEM study of nanoscale materials transformations,focusing on the growth of nanomaterials with distinct shape/hierarchical structures,such as one-dimensional(1D)growth by nanoparticle attachment,two-dimensional(2D)growth with nanoparticles as intermediates,core-shell structure ripening,solid-liquid interfaces including those in batteries and electrocatalysis,highlighting the impacts of heterogeneity and defects on broad nanoscale transformation pathways.展开更多
Agriculture is undergoing a pivotal transformation,shifting from a singular focus on food security to interdisciplinary research that encompasses food security,environmental protection and sustainable use of resources...Agriculture is undergoing a pivotal transformation,shifting from a singular focus on food security to interdisciplinary research that encompasses food security,environmental protection and sustainable use of resources.The growing global population and climate change exert the urgency to adopt sustainable practices that balance crop productivity and environmental stewardship.The merit of the approach of past agricultural research,typically centered on single processes and limited to specific disciplines and goals,is now a subject to debate.There is need for a multi-objective approach,an enhancement of the whole industry chain enhancement(involves service from the initial raw material stage to the final consumer)and a holistic approach for sustainable agricultural development.To address these challenges,this article presents an innovative agricultural system research approach.This approach integrates interdisciplinary research and advocates for a combined top-down and bottom-up strategy.The concept of innovative agriculture refers to redesigning systems through technological integration for large-scale application,ultimately aiming to enhance overall crop production,environmental sustainability and efficiency.The top-down approach sets yield targets and environmental thresholds at various scales,aligning with national objectives for food security,resource use efficiency and ecological sustainability.This method determines the necessary technical systems and integration methods.In contrast,the bottom-up approach based on Science and Technology Backyard,analyzes the factors that constrain high crop yields and efficiency,and develops systematic methods to achieve high yield and high efficiency.The integrated agricultural research approach can simultaneously address food security challenges,enhances resource use efficiency,and protect the environmental sustainability.This is essential for advancing sustainable agricultural practices in the face of increasing global demands and environmental concerns.展开更多
A recent UN Sustainable Development Goals(SDGs) analysis indicated a significant regression in the global SDG goal scores, particularly in SDG 2—Zero Hunger. The emissions of environmental pollution caused by meeting...A recent UN Sustainable Development Goals(SDGs) analysis indicated a significant regression in the global SDG goal scores, particularly in SDG 2—Zero Hunger. The emissions of environmental pollution caused by meeting food demands have prompted some countries to intensify their climate change mitigation efforts. These circumstances have introduced significant uncertainty to the future global sustainable food development. Additionally, a notable global challenge is the persistence of hidden hunger, primarily characterized by the insufficient consumption of high-quality animal protein. Addressing this issue would necessitate increased environmental costs to attain high-quality food security. The future food system presents a significant challenge in coordinating food security, food quality and environmental quality. This article presents a comprehensive review and proposes a three-step strategy for future agricultural development based on food security, quality, and environmental aspects. This is a novel food system transfer strategy, as it concurrently addresses both global food security and environmental thresholds. It involves the construction of an efficient food system that operates within the constraints of environmental limits. The objective is to align with global SDG indicators and to maintain natural resource consumption and pollutant emissions within planetary boundaries.展开更多
基金supported by the Key Research and Development Program of Shaanxi Province(No.2024SF-YBXM-567)the National Natural Science Foundation of China(Nos.21976045,22076112)the China Scholarship Council(CSC)Scholarship(No.202308610123).
文摘As antibiotic pollutants cannot be incompletely removed by conventional wastewater treatment plants,ultraviolet(UV)based advanced oxidation processes(AOPs)such as UV/persulfate(UV/PS)and UV/chlorine are increasingly concerned for the effective removal of antibiotics from wastewaters.However,the specific mechanisms involving degradation kinetics and transformation mechanisms are not well elucidated.Here we report a detailed examination of SO_(4)•−/Cl•-mediated degradation kinetics,products,and toxicities of sulfathiazole(ST),sarafloxacin(SAR),and lomefloxacin(LOM)in the two processes.Both SO_(4)•−/Cl•-mediated transformation kinetics were found to be dependent on pH(P<0.05),which was attributed to the disparate reactivities of their individual dissociated forms.Based on competition kinetic experiments and matrix calculations,the cationic forms(H_(2)ST^(+),H_(2)SAR^(+),and H_(2)LOM^(+))were more highly reactive towards SO_(4)•−in most cases,while the neutral forms(e.g.,HSAR^(0)and HLOM^(0))reacted the fastest with Cl•for the most of the antibiotics tested.Based on the identification of 31 key intermediates using tandem mass spectrometry,these reactions generated different products,of which the majority still retained the core chemical structure of the parent compounds.The corresponding diverse transformation pathways were proposed,involving S−N breaking,hydroxylation,defluorination,and chlorination reactions.Furthermore,the toxicity changes of their reaction solutions as well as the toxicity of each intermediate were evaluated by the vibrio fischeri and ECOSAR model,respectively.Many primary by-products were proven to be more toxic than the parent chemicals,raising the wider issue of extended potency for these compounds with regards to their ecotoxicity.These results have implications for assessing the degradative fate and risk of these chemicals during the AOPs.
文摘With the acceleration of the global digital wave,enterprise procurement management is facing multiple challenges such as cost pressure,supply chain collaboration demand,and insufficient information ability.Based on dynamic capability theory,resource-based view,and value chain theory,this paper constructs a four-level research framework of“driving factors-transformation paths-strategic actions-performance evaluation”.Firstly,through literature analysis and case review,it summarizes the internal and external driving factors such as external market competition pressure,supply chain coordination demand,policy and regulatory environment,as well as enterprise information foundation,organizational culture,and talent reserve,and analyzes their mechanism of action on procurement digital transformation.Secondly,the procurement digital transformation path is divided into two types:gradual upgrading and leap-forward reconstruction,and the strategic and tactical level strategies,such as top-level design,data governance,process remodeling,supplier collaboration platform construction,and intelligent decision support,are proposed.Thirdly,the implementation guarantee mechanism was designed from the four aspects of organization management,technology platform,talent culture,and risk control.Finally,the performance evaluation index system covering cost,cycle,quality,risk,and digital maturity was constructed,and the evaluation method and continuous improvement mechanism based on balanced scorecard and ROI/TCO analysis were proposed.The results show that the systematic strategy design and multi-dimensional guarantee can effectively improve the procurement efficiency of enterprises,reduce operating costs,enhance supply chain resilience,and provide theoretical and practical guidance for enterprises to achieve sustainable competitive advantage.
文摘Pulmonary arterial hypertension(PAH)is a progressive disease marked by degeneration of the lung’s blood vessels.As the disease progresses,the resistance to blood flow in the pulmonary arteries increases,putting a strain on the right side of the heart as it pumps blood through the lungs.PAH is characterized by changes in the structure of blood vessels and excessive cell growth.Untreated PAH leads to irreversible right-sided heart failure,often despite medical intervention.Patients experience a gradual decline in function until they are unable to perform daily activities.Advances in treatment have improved the prognosis for many PAH patients.Currently approved therapies target the prostacyclin,endothelin,nitric oxide,or phosphodiesterase pathways to slow the progression of the disease.To address the unmet need for effective PAH therapies,research efforts are focused on identifying new targets and developing therapies that specifically address the underlying disease mechanisms and restore vascular wall homeostasis.Among these,sotatercept,a fusion protein that targets the transforming growth factor-βsuperfamily signaling pathway,has emerged as a promising therapeutic option.In this review,we examine the available evidence from clinical trials to assess the potential of sotatercept as a treatment for PAH.
基金supported by the National Natural Science Foundation of China (Nos. 82274231 and 81973506)the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University, No.CMEMR2023-B12)+2 种基金the Fundamental Research Funds for the Central Universities (No. 2632023TD06)the Young Talent Support Project of Jiangsu Association for Science and Technology(No. TJ-2022-025)the Qinglan Project of Jiangsu Province。
文摘Astragali Radix(AR) and Notoginseng Radix et Rhizoma(NR) are frequently employed in cardiovascular disease treatment. However, the efficacy of the AR-NR medicine pair(AN) in improving cardiac remodeling and its underlying mechanism remains unclear. This study aimed to evaluate AN's cardioprotective effect and potential mechanism on cardiac remodeling using transverse aortic constriction(TAC) in mice and angiotensin II(Ang II)-induced neonatal rat cardiomyocytes(NRCMs) and fibroblasts in vitro. High-performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) characterized 23 main components of AN. AN significantly improved cardiac function in the TAC-induced mice. Furthermore, AN considerably reduced the serum levels of N-terminal pro-B-type natriuretic peptide(NT-pro BNP), cardiac troponin T(CTn-T), and interleukin-6(IL-6) and mitigated inflammatory cell infiltration. Post-AN treatment, TAC-induced heart size approached normal. AN decreased cardiomyocyte cross-sectional area and attenuated the upregulation of cardiac hypertrophy marker genes(ANP, BNP, and MYH7) in vivo and in vitro.Concurrently, AN alleviated collagen deposition in TAC-induced mice. AN also reduced the expression of fibrosis-related indicators(COL1A1 and COL3A1) and inhibited the activation of the transforming growth factor-β1(TGF-β1)/mothers against decapentaplegic homolog 3(Smad3) pathway. Thus, AN improved TAC-induced cardiac remodeling. Moreover, AN downregulated p-dynamin-related protein(Drp1)(Ser616) expression and upregulated mitogen 2(MFN-2) and optic atrophy 1(OPA1) expression in vivo and in vitro, thereby restoring mitochondrial fusion and fission balance. In conclusion, AN improves cardiac remodeling by regulating mitochondrial dynamic balance, providing experimental data for the rational application of Chinese medicine prescriptions with AN as the main component in clinical practice.
基金supported by the National Natural Science Foundation of China,No.81571211(to FL)the Natural Science Foundation of Shanghai,No.22ZR1476800(to CH)。
文摘Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration via paracrine signaling;however,their clinical applications are limited by potential risks such as tumorigenesis and xenogeneic immune rejection,which are similar to the risks associated with other stem cell transplantations.The present study therefore focuses on small extracellular vesicles derived from hair follicle neural crest stem cells,which preserve the bioactive properties of the parent cells while avoiding the transplantation-associated risks.In vitro,small extracellular vesicles derived from hair follicle neural crest stem cells significantly enhanced the proliferation,migration,tube formation,and barrier function of perineurial cells,and subsequently upregulated the expression of tight junction proteins.Furthermore,in a rat model of sciatic nerve defects bridged with silicon tubes,treatment with small extracellular vesicles derived from hair follicle neural crest stem cells resulted in higher tight junction protein expression in perineurial cells,thus facilitating neural tissue regeneration.At 10 weeks post-surgery,rats treated with small extracellular vesicles derived from hair follicle neural crest stem cells exhibited improved nerve function recovery and reduced muscle atrophy.Transcriptomic and micro RNA analyses revealed that small extracellular vesicles derived from hair follicle neural crest stem cells deliver mi R-21-5p,which inhibits mothers against decapentaplegic homolog 7 expression,thereby activating the transforming growth factor-β/mothers against decapentaplegic homolog signaling pathway and upregulating hyaluronan synthase 2 expression,and further enhancing tight junction protein expression.Together,our findings indicate that small extracellular vesicles derived from hair follicle neural crest stem cells promote the proliferation,migration,and tight junction protein formation of perineurial cells.These results provide new insights into peripheral nerve regeneration from the perspective of perineurial cells,and present a novel approach for the clinical treatment of peripheral nerve defects.
基金Supported by UK National Institute of Health Research/Cancer Research Network (UK NIHR/UKCRN) and Research and Development Department of Wrightington Wigan and Leigh NHS Foundation Trust (to Ang YS)R Keld WrightingtonWigan and Leigh NHS Foundation Trust Cancer Therapy Fund(to Keld RR,in part)
文摘Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence.We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways.There are many trials underway with the aim of improving survival in oesophageal cancer.Currently,phase 2 and 3 trials are focused on MAP kinase inhibition,either through inhibition of growth factor receptors or signal transducer proteins.In order to avoid tumor resistance,it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas.This may be achievable in the future with the advent of gene signatures and a combinatorial approach.
基金supported by the National Program of Control and Treatment of Water Pollution (No. 2018ZX07109-004)the project from the China Geological Survey (No. DD20190323)the Agricultural Science and Technology Innovation Program of China。
文摘Diclofenac(DCF), a widely used non-steroidal anti-inflammatory, reacted readily with birnessite under mild conditions, and the pseudo first order kinetic constants achieved 8.84 × 10^-2 hr^-1. Five products of DCF including an iminoquinone product(2,5-iminoquinone-diclofenac) and four dimer products were observed and identified by tandem mass spectrometry during the reaction. Meanwhile, 2,5-iminoquinone-diclofenac was identified to be the major product, accounting for 83.09% of the transformed DCF. According to the results of spectroscopic Mn(III) trapping experiments and X-ray Photoelectron Spectroscopy, Mn(IV) contained in birnessite solid was consumed and mainly converted into Mn(III) during reaction process, which proved that the removal of DCF by birnessite was through oxidation. Based on the identified products of DCF and the changes of Mn valence state in birnessite solid, a tentative transformation pathway of DCF was proposed.
基金the National Key Research and Development Program of China(No.2024YFA1210001)the National Natural Science Foundation of China(No.22275126)+1 种基金the Natural Science Foundation of Sichuan Province(No.2023NSFSC0634)the Open Project of Key State Laboratory for Supramolecular Structures and Materials of Jilin University(No.SKLSSM 202522).
文摘Isosbestic behavior has been traditionally deemed as a spectroscopic indicator of a chemical reaction,in which a reactant transforms directly to a product without intermediates.Room-temperature transformations of colloidal semiconductor magic-size clusters(MSCs)from MSC-a to MSC-b display interrupted spectral shifts in optical absorption with or without isosbestic behavior.We demonstrate that a multicomponent model explains consistently the pathway.The model invokes precursor compounds(PCs)of MSCs as intermediates,with three key steps from MSC-a to PC-a(step 1),to PC-b(step 2),and to MSC-b(step 3).Monomer substitution assists step 2(PC-a to PC-b).Based on the experimental result and theoretical study,we conclude that when step 1 or 2 or 3 is rate-determining,isosbestic behavior can be ideally perfect or distorted or absent,respectively.Our study provides a deeper understanding of isosbestic behavior and of MSC transformations that are assisted by PC intermediates and monomer substitution.
基金Supported by the Shaanxi Provincial Enterprises and Institutes Joint Key Projects(No.2023-LL-QY-39)Shaanxi Provincial Key Research and Development Project(No.2022SF-435)。
文摘Objective To investigate the effect and mechanism of Shuangshi Tonglin Capsules(SSTL)in the treatment of prostate fibrosis(PF).Methods Human prostate stromal cells(WPMY-1)were used for in vitro experiments to establish PF cell models induced with estradiol(E2).The cell proliferation,migration and clonogenic capacity were determined by cell counting kit-8,scratch assay,and crystal violet staining,respectively.Sprague-Dawley rats were used for in vivo experiments.The changes in histomorphology and organ index of rat prostate by SSTL were determined.Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin(HE)and Masson staining.Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23(FGF-23),E2 and prostate specific antigen(PSA).Mechanistically,changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats.Then the expressions of nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)and transforming growth factor-β1(TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro.Results In the efficacy study,SSTL significantly reduced the proliferation,migration,and clonogenic ability of cells,improved the morphology of the glandular tissue,significantly reduced the prostate index,reduced glandular fibrous tissue and collagen deposition,and resulted in a significant decrease in the levels of FGF-23,E2 and PSA(P<0.01 or P<0.05).In the mechanistic study,SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats(P<0.01 or P<0.05).SSTL significantly elevated the expressions of Nrf2,HO-1,NAD(P)H quinone oxidoreductase 1(NQO-1),and Smad7 proteins in both cells and rats,and significantly decreased the expressions of TGF-β1,collagen I,α-smooth muscle actin and Smad4 proteins(P<0.01 or P<0.05).SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats(P<0.01 or P<0.05).The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance.Conclusion SSTL was effective in improving PF in vivo and in vitro,and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.
基金supported by internal funding from Johns Hopkins University。
文摘Despite the widespread occurrence of phenols in anthropogenic and natural compounds, their fate in reactions with hypochlorous acid(HOCl), one of the most common water treatment disinfectants, remains incompletely understood. To close this knowledge gap, this study investigated the formation of disinfection by-products(DBPs) in the reaction of free chlorine with seven para-substituted phenols. Based on the chemical structures of the DBPs and the reaction mechanisms leading to their formation, the DBPs were categorized into four groups: chlorophenols, coupling products, substituent reaction products, and ring cleavage products. In contrast to previous studies that investigated the formation of earlystage chlorophenols, the primary focus of this study was on the elucidation of novel ring cleavage products, in particular α, β-unsaturated C-dialdehydes, and C-dicarboxylic acids, which, for the first time, were identified and quantified in this study. The molar yields of 2-butene-1,4-dial(BDA), one of the identified α, β-unsaturated C-dialdehydes, varied among the different phenolic compounds, reaching a maximum value of 10.4% for bisphenol S. Molar yields of 2-chloromaleic acid(Cl-MA), one of the identified C-dicarboxylic acids, reached a maximum value of 30.5% for 4-hydroxy-phenylacetic acid under given conditions. 2,4,6-trichlorophenol(TCP) was shown to be an important intermediate of the parent phenols and the C-ring cleavage products. Based on the temporal trends of α, β-unsaturated C-dialdehydes and C-dicarboxylic acids, their formation is likely attributable to two separate ring cleavage pathways. Based on the obtained results, an overall transformation pathway for the reaction of para-substituted phenols with free chlorine leading to the formation of novel Cring cleavage products was proposed.
基金Supported by Science Foundation of Education Department of Heilongjiang Province,China,no.12541430
文摘To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting.RESULTSExpression of miR-34a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSIONmiR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.
基金Supported by Department of Pathology Research Fund,NYU School of Medicine,New York,NY 10016,United States
文摘AIM:To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ),Smad4 and transforming growth factor-beta (TGFβR) across a spectrum representing colorectal cancer (CRC) development.METHODS:Tissue microarrays were prepared from archival paraffin embedded tissue,including 51 colorectal carcinomas,25 tubular adenomas (TA) and 26 HPs,each with matched normal colonic epithelium.Immunohistochemistry was performed using antibodies against TIF1γ,Smad4 and TGFβ RⅡ.The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4).RESULTS:Overexpression of TIF1γ was detected in 5/26 (19%) HP;however,it was seen in a significantly higher proportion of neoplasms,15/25 (60%) TAs and 24/51 (47%) CRCs (P<0.05).Normal colonic mucosa,HP,and TAs showed strong Smad4 expression,while its expression was absent in 22/51 (43%) CRCs.Over-expression of TGFβ RⅡ was more commonly seen in neoplasms,13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P<0.05).Furthermore,there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value=0.35,P<0.05).The levels of TIF1γ overexpression were significantly higher in stage Ⅲ than in stage Ⅰ and Ⅱ CRC (P<0.05).CONCLUSION:The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis,is inversely related with Smad4 loss,and may be a prognostic indicator for poor outcome.
文摘BACKGROUND Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1(PREX1)was reported to be overexpressed in some cancers and involved in cancer development,but its expression and significance in gastric cancer remain unclear.AIM To evaluate the expression of PREX1 in gastric cancer and its significance in the development of gastric cancer,especially to evaluate the potential mechanism of PREX1 in gastric cancer.METHODS Bioinformatic analysis was performed in order to examine the expression of PREX1 in gastric cancer.The relationship between the survival rate of gastric cancer patients and PREX1 expression was assessed by Kaplan Meier portal.The Gene Set Enrichment Analysis and the correlation between PREX1 and transforming growth factor(TGF)β1 pathway-related mediators were evaluated by cBioPortal for Cancer Genomics.Western blotting and reverse transcriptase polymerase chain reaction assay were used to test the role of TGFβ1 on the expression of PREX1.Western blotting and dual-luciferase reporter system was used to evaluate the effect of PREX1 on the activation of TGFβ1 pathway.Wound healing and Transwell assay were used to assess the effect of PREX1 on the metastasis activity of gastric cancer cells.RESULTS PREX1 was overexpressed in the gastric tumors,and the expression levels were positively associated with the development of gastric cancer.Also,the high expression of PREX1 revealed poor prognosis,especially for those advanced and specific intestinal gastric cancer patients.PREX1 was closely involved in the positive regulation of cell adhesion and positively correlated with TGFβ1-related mediators.Furthermore,TGFβ1 could induce the expression of PREX1 at both the protein and mRNA level.Also,PREX1 could activate the TGFβ1 pathway.The induced PREX1 could increase the migration and invasion activity of gastric cancer cells.CONCLUSION PREX1 is overexpressed in gastric cancer,and the high level of PREX1 predicts poor prognosis.PREX1 is closely associated with TGFβsignaling and promotes the metastasis of gastric cancer cells.
基金Supported by The Natural Science Foundation of China,No.81170450 to Lu MQ and No.81200308 to Lan TThe PhD Start-up Fund of Natural Science Foundation of Guangdong Province,China,No.S2012040008026The New Star of Science and Technology Foundation of Zhu Jiang in Guangzhou City
文摘AIM:To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis.METHODS:Male Sprague-Dawley rats underwent common bile duct ligation(BDL) for 14 d and were treated with Gardenia jasminoides by gavage.The ef-fects of Gardenia jasminoides on liver fibrosis and the detailed molecular mechanisms were also assessed in human hepatic stellate cells(LX-2) in vitro.RESULTS:Treatment with Gardenia jasminoides decreased serum alanine aminotransferase(BDL vs BDL + 100 mg/kg Gardenia jasminoides,146.6 ± 15 U/L vs 77 ± 6.5 U/L,P = 0.0007) and aspartate aminotransferase(BDL vs BDL + 100 mg/kg Gardenia jasminoides,188 ± 35.2 U/L vs 128 ± 19 U/L,P = 0.005) as well as hydroxyproline(BDL vs BDL + 100 mg/kg Gardenia jasminoides,438 ± 40.2 μg/g vs 228 ± 10.3 μg/g liver tissue,P = 0.004) after BDL.Furthermore,Gardenia jasminoides significantly reduced liver mRNA and/or protein expression of transforming growth factor β1(TGF-β1),collagen type?Ⅰ?(Col?Ⅰ) and α-smooth muscle actin(α-SMA).Gardenia jasminoides significantly suppressed the upregulation of TGF-β1,Col?Ⅰand α-SMA in LX-2 exposed to recombinant TGF-β1.Moreover,Gardenia jasminoides inhibited TGF-β1-induced Smad2 phosphorylation in LX-2 cells.CONCLUSION:Gardenia jasminoides exerts antifibrotic effects in the liver fibrosis and may represent a novel antifibrotic agent.
基金Supported by the Special Research Project for Capital Health Development,No.2022-2-2174the Beijing Municipal Science and Technology Commission,No.Z191100007619037.
文摘BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
基金supported by NSFC grant 81371136 to Xue-Dong Zhou, NSFC grant 81470711 to Li-Wei Zheng and grant 2015TD0011 to Ling Ye
文摘Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth-like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day （E） 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-β signalling pathway might play a role in this process.
基金supported by the National Natural Science Foundation of China,No.81801175(to CLT)the Fundamental Research Funds for the Central Universities of China,No.WK9110000044(to CLT)+2 种基金China Scholarship Council,No.201706270155(to CLT)the China Postdoctoral Science Foundation,No.2019M662179(to CLT)the Anhui Province Postdoctoral Science Foundation of China,No.2019B324(to CLT)
文摘Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,and its dynamic changes are closely related to the proliferation of endothelial cells,the recruitment of pericytes to blood vessels,and functional differentiation during embryonic vascular development.The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells.Indeed,mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation.Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms,arteriovenous malformations,and cerebral atherosclerosis.In this review,we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis,and we discuss its relationship to functional dysregulation in cerebrovascular diseases.This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis,treatment,and prevention.
基金supported by the U.S.Department of Energy,Office of Science,Office of Basic Energy Sciences(BES),Materials Sciences and Engineering Division under Contract No.DE-AC02-05-CH11231 within the in-situ TEM program(KC22ZH)supported by the U.S.Department of Energy under Contract No.DE-AC02-05CH11231the Kwanjeong Study Abroad Scholarship from the KEF(Kwanjeong Educational Foundation)(KEF-2019).
文摘Nanoscale materials often undergo structural,morphological,or chemical changes,especially in solution processes,where heterogeneity and defects may significantly impact the transformation pathways.Liquid phase transmission electron microscopy(TEM),allowing us to track dynamic transformations of individual nanoparticles,has become a powerful platform to reveal nanoscale materials transformation pathways and address challenging issues that are hard to approach by other methods.With the development of modern liquid cells,implementing advanced imaging and image analysis methods,and strategically exploring diverse systems,significant advances have been made in liquid phase TEM,including improved high-resolution imaging through liquids at the atomic level and remarkable capabilities in handling complex systems and reactions.In the past more than a decade,we spent much effort in developing and applying liquid phase TEM to elucidate how atomic level heterogeneity and defects impact various physicochemical processes in liquids,such as growth,self-assembly of nanoparticles,etching/corrosion,electrodeposition of alkali metals,catalyst restructuring during reactions,and so on.This article provides a brief review of the liquid phase TEM study of nanoscale materials transformations,focusing on the growth of nanomaterials with distinct shape/hierarchical structures,such as one-dimensional(1D)growth by nanoparticle attachment,two-dimensional(2D)growth with nanoparticles as intermediates,core-shell structure ripening,solid-liquid interfaces including those in batteries and electrocatalysis,highlighting the impacts of heterogeneity and defects on broad nanoscale transformation pathways.
文摘Agriculture is undergoing a pivotal transformation,shifting from a singular focus on food security to interdisciplinary research that encompasses food security,environmental protection and sustainable use of resources.The growing global population and climate change exert the urgency to adopt sustainable practices that balance crop productivity and environmental stewardship.The merit of the approach of past agricultural research,typically centered on single processes and limited to specific disciplines and goals,is now a subject to debate.There is need for a multi-objective approach,an enhancement of the whole industry chain enhancement(involves service from the initial raw material stage to the final consumer)and a holistic approach for sustainable agricultural development.To address these challenges,this article presents an innovative agricultural system research approach.This approach integrates interdisciplinary research and advocates for a combined top-down and bottom-up strategy.The concept of innovative agriculture refers to redesigning systems through technological integration for large-scale application,ultimately aiming to enhance overall crop production,environmental sustainability and efficiency.The top-down approach sets yield targets and environmental thresholds at various scales,aligning with national objectives for food security,resource use efficiency and ecological sustainability.This method determines the necessary technical systems and integration methods.In contrast,the bottom-up approach based on Science and Technology Backyard,analyzes the factors that constrain high crop yields and efficiency,and develops systematic methods to achieve high yield and high efficiency.The integrated agricultural research approach can simultaneously address food security challenges,enhances resource use efficiency,and protect the environmental sustainability.This is essential for advancing sustainable agricultural practices in the face of increasing global demands and environmental concerns.
文摘A recent UN Sustainable Development Goals(SDGs) analysis indicated a significant regression in the global SDG goal scores, particularly in SDG 2—Zero Hunger. The emissions of environmental pollution caused by meeting food demands have prompted some countries to intensify their climate change mitigation efforts. These circumstances have introduced significant uncertainty to the future global sustainable food development. Additionally, a notable global challenge is the persistence of hidden hunger, primarily characterized by the insufficient consumption of high-quality animal protein. Addressing this issue would necessitate increased environmental costs to attain high-quality food security. The future food system presents a significant challenge in coordinating food security, food quality and environmental quality. This article presents a comprehensive review and proposes a three-step strategy for future agricultural development based on food security, quality, and environmental aspects. This is a novel food system transfer strategy, as it concurrently addresses both global food security and environmental thresholds. It involves the construction of an efficient food system that operates within the constraints of environmental limits. The objective is to align with global SDG indicators and to maintain natural resource consumption and pollutant emissions within planetary boundaries.
