Gastric cancer is one of the most prevalent cancers worldwide,and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20%of the total cases.Currently,trastuzumab+chemotherapy is the...Gastric cancer is one of the most prevalent cancers worldwide,and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20%of the total cases.Currently,trastuzumab+chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer,and the combination has exhibited definite efficacy in HER2-targeted therapy.However,the emergence of drug resistance during treatment considerably reduces its effectiveness;thus,it is imperative to investigate the potential mechanisms underlying resistance.In the present review article,we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases,aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.展开更多
Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid drople...Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.展开更多
Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatmen...Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.展开更多
Coastal zones are active reactors of continental material including that transported by rivers via a series of microbiota-mediated reactions. Nevertheless, current knowledge of the ecology and functioning of the micro...Coastal zones are active reactors of continental material including that transported by rivers via a series of microbiota-mediated reactions. Nevertheless, current knowledge of the ecology and functioning of the microbiota in coastal areas affected by large riverine inputs remains insufficient on a global scale. Here, an investigation on sediment microbial composition, including taxonomy and metabolic network, as well as their relationship with major benthic reaction substrates, namely carbon, nitrogen, sulphur and phosphorus, was conducted in the continental shelf affected by the spread of the Changjiang River plume. Surface sediment samples(48 samples)were collected during March 2018, obtaining a mean Operational Taxonomic Units(OTUs) number of 3 341.Proteobacteria, Acidobacteria and Actinobacteria were abundant phyla in the studied sediments. Bray-Curtis distance analysis classified the 48 samples into 4 clusters(MG1 to MG4) at the phylum-level. MG1 and MG2 are found near the river mouth, receiving substantial land-derived particles from the Changjiang River runoff.Particle-attached microbes may be settled in these regions and influenced the observed sediment microbial diversity and biomass, e.g., increased Crenarchaeota relative abundance. The relative enrichment of these two groups in heterotrophic microbes further suggests a reliance of benthic microbiota on substrates with terrestrial origin, particularly specialized on processing sulphur-rich substrates. Regions MG3 and MG4 are located in the outer margin of the area affected by the Changjiang River plume, mainly fed by settling pelagic particles from phytoplankton. Compared to MG1 and MG2, a significant increase in the abundance of Thaumarcheota(phylumlevel) and Nitrosopumilus(genus-level) was found in MG3, suggesting nitrogen-related transformations as the key reactions to sustain microbial metabolism in this region. Coupled with the identified variations in the taxonomic composition, significant differences in the keystone taxa between MG1/MG2 and MG3/MG4 were identified via OTU co-occurrence analyses. A higher abundance of Actinobacteria, Thaumarchaeota and Acidobacteria in MG3 and MG4 reinforced the identified spatial variability in benthic metabolism and highlighted the significance of substrate inputs on the sediment microbial structure and biogeography.展开更多
Medicarpin is an important bioactive compound with multiple medicinal activities,including anti-tumor,anti-osteoporosis,and anti-bacterial effects.Medicarpin is associated with pterocarpans derived from medicinal plan...Medicarpin is an important bioactive compound with multiple medicinal activities,including anti-tumor,anti-osteoporosis,and anti-bacterial effects.Medicarpin is associated with pterocarpans derived from medicinal plants,such as Sophora japonica,Glycyrrhiza uralensis Fisch.,and Glycyrrhiza glabra L.However,these medicinal plants contain only low amounts of medicarpin.Moreover,the planting area for medicarpin-producing plants is limited;consequently,the current medicarpin supply cannot meet the high demands of medicinal markets.In this study,eight key genes involved in medicarpin biosynthesis were identified using comparative transcriptome and bioinformatic analyses.In vitro and in vivo enzymatic reaction confirmed the catalytic functions of candidate enzymes responsible for the biosynthesis of medicarpin and medicarpin intermediates.Further engineering of these genes in Saccharomyces cerevisiae achieved the heterologous biosynthesis of medicarpin using liquiritigenin as a substrate,with a final medicarpin yield of 0.82±0.18 mg/L.By increasing the gene copy numbers of vestitone reductase(VR)and pterocarpan synthase(PTS),the final medicarpin yield was increased to 2.05±0.72 mg/L.This study provides a solid foundation for the economic and sustainable production of medicarpin through a synthetic biology strategy.展开更多
Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell ...Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell proliferation,migration,and invasion by regulating chromatin morphology and gene expression,and is closely related to the development of non-small cell lung cancer(NSCLC).1 However,the underlying mechanism of LSD1 on cell proliferation and migration remains unclear.展开更多
S-phase kinase-associated protein 2(Skp2)is a well-characterized oncoprotein localized mainly in the nucleus and cytoplasm.It is an integral component of SCFskp2 E3 ubiquitin ligase complex which confers substrate sel...S-phase kinase-associated protein 2(Skp2)is a well-characterized oncoprotein localized mainly in the nucleus and cytoplasm.It is an integral component of SCFskp2 E3 ubiquitin ligase complex which confers substrate selectivity to the ligase by specifically targeting a distinct set of proteins destined for proteasomal degradation such as p21,p27,cyclin E,and c-Myc.1 Skp2 is crucial in a multitude of cellular processes including cell cycle,cell proliferation,apoptosis,differentiation,and survival.However,despite its immense and well-established role in ubiquitin-proteasome system-mediated protein turnover,much is unknown about the function of Skp2 independent of the ubiquitination pathway.Previously,Skp2 has been reported to regulate RhoA gene transcription and the p300 signaling pathway in an E3 ligase-independent manner.2Moreover,Skp2 also acts as a cofactor for c-Myc-regulated gene expression.展开更多
Artificial sweeteners(AS)have been widely applied in the food industry as sugar substitutes with reduced calorie content but high sweetening power[1].The consumption of sugar-sweetened beverages is associated with the...Artificial sweeteners(AS)have been widely applied in the food industry as sugar substitutes with reduced calorie content but high sweetening power[1].The consumption of sugar-sweetened beverages is associated with the incidence of obesity and type 2 diabetes[2,3].Non-caloric AS(NCAS)have been recommended for weight management and as a treatment strategy for type 2 diabetes[4].While AS are generally considered safe with acceptable daily intake by regulatory agencies(e.g.,European Food Safety Authority,US Food and Drug Administration),mounting epidemiological evidence shows that the consumption of AS is associated with the risk of cardiometabolic disease[2,3,5].展开更多
Fungi are widely distributed in the environment,and some are beneficial to medicine,industry,agriculture,and food.For example,Penicillium chrysogenum,Acremonium chrysogenum,and Aspergillus terreus can synthesizeβ-lac...Fungi are widely distributed in the environment,and some are beneficial to medicine,industry,agriculture,and food.For example,Penicillium chrysogenum,Acremonium chrysogenum,and Aspergillus terreus can synthesizeβ-lactams,which can be used as drugs[1];Aspergillus niger and Trichoderma reesei are well-known industrial enzyme producers[2].展开更多
Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently r...Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently required.Jiyuan oridonin A(JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical application.Here,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer cells.Subsequently,we discovered for the first time that a2 induced ferroptosis.Importantly,compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2.Furthermore,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition.Moreover,a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric canc er cell line-derived xenograft mice models.Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2,and GPX4 downregulation indicated the sensitivity of tumors to a2.Finally,a2 exhibited well pharmacokinetic characteristic s.Overall,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.展开更多
Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. ...Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.展开更多
Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Neverth...Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.展开更多
N6-Methyladenosine(m^(6)A) is the most abundant internal modification in eukaryotic mRNA,playing critical role in various bioprocesses. Like other epigenetic modifications, m^(6)A modification can be catalyzed by the ...N6-Methyladenosine(m^(6)A) is the most abundant internal modification in eukaryotic mRNA,playing critical role in various bioprocesses. Like other epigenetic modifications, m^(6)A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m^(6)A demethylases have been reported, fat mass and obesity-associated protein(FTO)and alkylation protein AlkB homolog 5(ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.展开更多
Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cl...Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cluster bomb” oral drug delivery system (DOX@PFeL@L100) with core-shell structure to overcome the complex absorption barriers. The inner core termed as “bomb” that contains a lot of ultra-small diameter Fe_(3)O_(4) nanoparticles (DOX@PFeL NPs) loaded with doxorubicin (DOX) and modified with l-valine, which can efficiently penetrate the epithelial cells via PePT1 receptor mediated endocytosis. The outer shell of this “cluster bomb” is a layer of pH-sensitive polymer (Eudragit®L100) that can be served as a pH-responsive switch and effectively control the “bomb” release in the intestinal microenvironment to improve the antitumor efficiency by the Fenton like reaction of DOX and Fe^(2+)/Fe^(3+). This study demonstrates that the “cluster comb” oral drug delivery system can sequentially overcome the multiple biological barriers, providing a safe and effective approach for tumor therapy.展开更多
Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous stud...Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.展开更多
Photothermal therapy(PTT)-induced immune response has attracted much attention,however,which cannot work at full capacity.In this study,the simvastatin(SV)adjuvant is loaded into gold nanocages(AuNCs)to develop a simp...Photothermal therapy(PTT)-induced immune response has attracted much attention,however,which cannot work at full capacity.In this study,the simvastatin(SV)adjuvant is loaded into gold nanocages(AuNCs)to develop a simple drug delivery system,which can efficiently utilize the tumor-associated antigens(TAAs)for improving immune responses.AuNCs/SV-mediated PTT treatment enhances tumor cells damage and promotes the release of TAAs which are immediately captured by Au NCs/SV to form AuNCs/SV/TAAs recombinant nanoparticle.Impressively,AuNCs/SV/TAAs can accumulate in lymph nodes effectively due to the suitable size of~55 nm and hyperthermia-induced vasodilative effect.And the codelivery of antigen and adjuvant is beneficial to stimulating the maturation of dendritic cells for further activating T cells.In a word,the recombinant strategy could make full use of TAAs to produce an individual powerful immunotherapy.展开更多
An efficient metal-free intramolecular hydroarylation reaction of alkynes is described here.A series of aryl and N-group attached alkynes generated the intramolecular hydroarylation products in high yields.
A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2...A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2)-unprotected five-membered cyclic guanidines in good to excellent yields under mildconditions without metals and strong bases.Moreover,the highly biologically interesting urea analoguescould also be conveniently obtained via hydrolysis of the produced guanidines.展开更多
Radiotherapy is a mainstay treatment for malignant tumors in clinical practice.However,enhancing radiation damage to tumor cells meanwhile sparing normal tissues is still a great challenge in radiotherapy.Nanomaterial...Radiotherapy is a mainstay treatment for malignant tumors in clinical practice.However,enhancing radiation damage to tumor cells meanwhile sparing normal tissues is still a great challenge in radiotherapy.Nanomaterials with high atomic number(Z)values are promising radiosensitizers by promoting the radiation energy deposition in irradiated tumor cells,thus enhancing the therapeutic ratio of radiotherapy.In this review,we described the mechanisms of high-Z element based-radiosensitizers and systematically summarized the recent progress on high-Z metal-based nanomaterials,including high-Z metal-based nanoparticles,high-Z metal-based nanoscale metal-organic frameworks and high-Z metal-doping nanomaterials.Finally,further potential and challenges in this field were discussed.展开更多
Hypoxia-inducible factor 1(HIF-1),as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment,participates in many physiological and pathological processes in the body,and is close...Hypoxia-inducible factor 1(HIF-1),as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment,participates in many physiological and pathological processes in the body,and is closely related to the pathogenesis of many diseases.This review outlines the mechanisms of HIF-1 activation,its signaling pathways,natural inhibitors,and its roles in diseases.This article can provide new insights in the diagnosis and treatment of human diseases,and recent progress on the development of HIF-1 inhibitors.展开更多
基金supported by the Project of Henan Provincial Medical Science and Technology Research Plan(No.SBGJ202301004 and No.LHGJ20210186)the Key Science Fund project of Henan Provincial Natural Science Foundation(No.232300421119).
文摘Gastric cancer is one of the most prevalent cancers worldwide,and human epidermal growth factor receptor 2(HER2)-positive cases account for approximately 20%of the total cases.Currently,trastuzumab+chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer,and the combination has exhibited definite efficacy in HER2-targeted therapy.However,the emergence of drug resistance during treatment considerably reduces its effectiveness;thus,it is imperative to investigate the potential mechanisms underlying resistance.In the present review article,we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases,aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.
基金Discipline Key Special ProjectGrant/Award Number:XKZDQY202001+7 种基金Henan Provincial Key R&D and Promotion Special ProjectGrant/Award Number:212102310033Henan Provincial Medical Science and Technology Tackling ProgramGrant/Award Number:LHGJ20220557Key R&D Program of ChinaGrant/Award Number:2020YFC2006100,2020YFC2009000 and 2020YFC2009006National Natural Science Foundation of ChinaGrant/Award Number:31471330 and 81870408。
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.
基金financially supported by the National Natural Science Foundation of China(No.82001189)The Project Tackling of Key Scientific and Technical Problems of Henan Provine(No.232102311163).
文摘Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.
基金The National Natural Science Foundation of China under contract Nos 31800079 and 41530960the Scientific Research Foundation of SKLEC under contract No. 2017RCDW04+1 种基金the Zhengzhou University Startup Foundation under contract No.32210876the China Postdoctoral Science Foundation under contract No. 2021M691018。
文摘Coastal zones are active reactors of continental material including that transported by rivers via a series of microbiota-mediated reactions. Nevertheless, current knowledge of the ecology and functioning of the microbiota in coastal areas affected by large riverine inputs remains insufficient on a global scale. Here, an investigation on sediment microbial composition, including taxonomy and metabolic network, as well as their relationship with major benthic reaction substrates, namely carbon, nitrogen, sulphur and phosphorus, was conducted in the continental shelf affected by the spread of the Changjiang River plume. Surface sediment samples(48 samples)were collected during March 2018, obtaining a mean Operational Taxonomic Units(OTUs) number of 3 341.Proteobacteria, Acidobacteria and Actinobacteria were abundant phyla in the studied sediments. Bray-Curtis distance analysis classified the 48 samples into 4 clusters(MG1 to MG4) at the phylum-level. MG1 and MG2 are found near the river mouth, receiving substantial land-derived particles from the Changjiang River runoff.Particle-attached microbes may be settled in these regions and influenced the observed sediment microbial diversity and biomass, e.g., increased Crenarchaeota relative abundance. The relative enrichment of these two groups in heterotrophic microbes further suggests a reliance of benthic microbiota on substrates with terrestrial origin, particularly specialized on processing sulphur-rich substrates. Regions MG3 and MG4 are located in the outer margin of the area affected by the Changjiang River plume, mainly fed by settling pelagic particles from phytoplankton. Compared to MG1 and MG2, a significant increase in the abundance of Thaumarcheota(phylumlevel) and Nitrosopumilus(genus-level) was found in MG3, suggesting nitrogen-related transformations as the key reactions to sustain microbial metabolism in this region. Coupled with the identified variations in the taxonomic composition, significant differences in the keystone taxa between MG1/MG2 and MG3/MG4 were identified via OTU co-occurrence analyses. A higher abundance of Actinobacteria, Thaumarchaeota and Acidobacteria in MG3 and MG4 reinforced the identified spatial variability in benthic metabolism and highlighted the significance of substrate inputs on the sediment microbial structure and biogeography.
基金supported by the National Natural Science Foundation of China(81903526,81991523,82072240,and 32270192)the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK008 to W.L.)+3 种基金the Open Project of State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences(No.SIMM2205KF to W.L.)the Open Project of State Key Laboratory of Microbial Resources,Institute of Microbiology,Chinese Academy of Sciences(No.SKLMR-20220704 to W.L.)Jiangsu Graduate Research Innovation Program Project(KYCX22_2024 to CJ.L.)the Open Funding Project of the State Key Laboratory of Bioreactor Engineering,East China University of Science and Technology to W.L.,the Fok Ying Tung Education Foundation,and Jiangsu Specially-Appointed Professor Talent Program to W.L.
文摘Medicarpin is an important bioactive compound with multiple medicinal activities,including anti-tumor,anti-osteoporosis,and anti-bacterial effects.Medicarpin is associated with pterocarpans derived from medicinal plants,such as Sophora japonica,Glycyrrhiza uralensis Fisch.,and Glycyrrhiza glabra L.However,these medicinal plants contain only low amounts of medicarpin.Moreover,the planting area for medicarpin-producing plants is limited;consequently,the current medicarpin supply cannot meet the high demands of medicinal markets.In this study,eight key genes involved in medicarpin biosynthesis were identified using comparative transcriptome and bioinformatic analyses.In vitro and in vivo enzymatic reaction confirmed the catalytic functions of candidate enzymes responsible for the biosynthesis of medicarpin and medicarpin intermediates.Further engineering of these genes in Saccharomyces cerevisiae achieved the heterologous biosynthesis of medicarpin using liquiritigenin as a substrate,with a final medicarpin yield of 0.82±0.18 mg/L.By increasing the gene copy numbers of vestitone reductase(VR)and pterocarpan synthase(PTS),the final medicarpin yield was increased to 2.05±0.72 mg/L.This study provides a solid foundation for the economic and sustainable production of medicarpin through a synthetic biology strategy.
基金supported by the National Natural Science Foundation of China(No.U2004101 for Peng-xing He,No.U21A20416 for Hong-min Liu).
文摘Lysine-specific demethylase 1(LSD1),as a histone lysine demethylase,demethylates monomethyl and dimethyl of histone H3 on lysine 4(H3K4)and lysine 9(H3K9).Studies have reported that high LSD1 expression promotes cell proliferation,migration,and invasion by regulating chromatin morphology and gene expression,and is closely related to the development of non-small cell lung cancer(NSCLC).1 However,the underlying mechanism of LSD1 on cell proliferation and migration remains unclear.
基金supported by the National Key Research Program of Proteins(China)(No.2018YFE0195100 for H.-M.L.)the National Natural Science Foundation of China(No.82020108030 and U21A20416 for H.-M.L.and No.82103996 for X.-J.S.).
文摘S-phase kinase-associated protein 2(Skp2)is a well-characterized oncoprotein localized mainly in the nucleus and cytoplasm.It is an integral component of SCFskp2 E3 ubiquitin ligase complex which confers substrate selectivity to the ligase by specifically targeting a distinct set of proteins destined for proteasomal degradation such as p21,p27,cyclin E,and c-Myc.1 Skp2 is crucial in a multitude of cellular processes including cell cycle,cell proliferation,apoptosis,differentiation,and survival.However,despite its immense and well-established role in ubiquitin-proteasome system-mediated protein turnover,much is unknown about the function of Skp2 independent of the ubiquitination pathway.Previously,Skp2 has been reported to regulate RhoA gene transcription and the p300 signaling pathway in an E3 ligase-independent manner.2Moreover,Skp2 also acts as a cofactor for c-Myc-regulated gene expression.
基金funded the National Natural Science Foundation of China(No.32111530179).
文摘Artificial sweeteners(AS)have been widely applied in the food industry as sugar substitutes with reduced calorie content but high sweetening power[1].The consumption of sugar-sweetened beverages is associated with the incidence of obesity and type 2 diabetes[2,3].Non-caloric AS(NCAS)have been recommended for weight management and as a treatment strategy for type 2 diabetes[4].While AS are generally considered safe with acceptable daily intake by regulatory agencies(e.g.,European Food Safety Authority,US Food and Drug Administration),mounting epidemiological evidence shows that the consumption of AS is associated with the risk of cardiometabolic disease[2,3,5].
基金This study was funded by the National Natural Science Foundation of China(No.32111530179).
文摘Fungi are widely distributed in the environment,and some are beneficial to medicine,industry,agriculture,and food.For example,Penicillium chrysogenum,Acremonium chrysogenum,and Aspergillus terreus can synthesizeβ-lactams,which can be used as drugs[1];Aspergillus niger and Trichoderma reesei are well-known industrial enzyme producers[2].
基金supported by grants from the National Natural Science Foundation of China (Nos. 81773562, 82020108030, and U1904163)National Key Research and Development Project (No. 2018YFE0195100, China)the Science and Technology Program of Henan Province (No. 202102310152, China)。
文摘Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently required.Jiyuan oridonin A(JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical application.Here,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer cells.Subsequently,we discovered for the first time that a2 induced ferroptosis.Importantly,compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2.Furthermore,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition.Moreover,a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric canc er cell line-derived xenograft mice models.Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2,and GPX4 downregulation indicated the sensitivity of tumors to a2.Finally,a2 exhibited well pharmacokinetic characteristic s.Overall,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.
基金supported by the National Key Research Program of Proteins(Nos.2016YFA0501800 and 2017YFD0501401,China)the National Natural Science Foundation of China(Nos.81703326,81773562,81430085 and 21403200,China)+5 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nan-jing University,China(No.KF-GN-201902,China)Outstanding Young Talent Research Fund of Zhengzhou University(No.1521331002,China)Scientific Program of Henan Province(Nos.182102310123 and 161100310100,China)China Postdoctoral Science Foundation(No.2018M630840,China)Key Research Program of Higher Education of Henan Province(Nos.15A350018 and 18B350009,China)the Starting Grant of Zhengzhou University(No.32210533,China)
文摘Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.
基金supported by National Natural Science Foundation of China(Project No.81602961 for Yichao ZhengNos.81430085,81773562,and 82020108030 for Hongmin Liu)+2 种基金National Key Research Program of Proteins(Nos.2016YFA0501800 and 2018YFE0195100 for Hongmin Liu,China)Key Research Program of Henan Province(No.161100310100,for Hongmin Liu,China)Science and Technology Innovation Talents of Henan Provincial Education Department(19IRTSTHN001,China)。
文摘Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.
基金supported by the National Key Research Program(No.2018YFE0195100)the National Natural Science Foundation of China (No.82020108030,No.U21A20416 and No.82103997)+2 种基金Science and Technology Innovation Talents of Henan Provincial Education Department (No.19IRTSTHN001,China)Basic and Frontier Technology Research Project of Henan Province (No.212102310313,China)Basic Research of the Key Project of the High Education from the Education Department of Henan Province (No.22ZX008,China)。
文摘N6-Methyladenosine(m^(6)A) is the most abundant internal modification in eukaryotic mRNA,playing critical role in various bioprocesses. Like other epigenetic modifications, m^(6)A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m^(6)A demethylases have been reported, fat mass and obesity-associated protein(FTO)and alkylation protein AlkB homolog 5(ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.
基金supported by the National Natural Science Foundation of China (Nos. 81773276, 81972907, 81874304, and U1804183)Key Scientific Research Project (Education Department of Henan Province)(No. 20HASTIT049)Modern Analysis and Computer Center of Zhengzhou University。
文摘Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cluster bomb” oral drug delivery system (DOX@PFeL@L100) with core-shell structure to overcome the complex absorption barriers. The inner core termed as “bomb” that contains a lot of ultra-small diameter Fe_(3)O_(4) nanoparticles (DOX@PFeL NPs) loaded with doxorubicin (DOX) and modified with l-valine, which can efficiently penetrate the epithelial cells via PePT1 receptor mediated endocytosis. The outer shell of this “cluster bomb” is a layer of pH-sensitive polymer (Eudragit®L100) that can be served as a pH-responsive switch and effectively control the “bomb” release in the intestinal microenvironment to improve the antitumor efficiency by the Fenton like reaction of DOX and Fe^(2+)/Fe^(3+). This study demonstrates that the “cluster comb” oral drug delivery system can sequentially overcome the multiple biological barriers, providing a safe and effective approach for tumor therapy.
基金National Key R&D Program of China(2021YFA1101000 to Y.S.,and 2018YFE0195100 to H.L.)Zhejiang Provincial Natural Science Foundation of China(LD22H300003 to Y.S.)+1 种基金A grant from Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University(ZY202205SMKY007 to Y.S.)National Natural Science Foundation of China(82020108030 for H.L.).
文摘Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.
基金financially supported by the National Natural Science Foundation of China(Nos.U1804183,81901878 and 81874304)China Postdoctoral Science Foundation(No.2019M662553)Key Scientific Research Project(Education Department of Henan Province,No.20HASTIT049)。
文摘Photothermal therapy(PTT)-induced immune response has attracted much attention,however,which cannot work at full capacity.In this study,the simvastatin(SV)adjuvant is loaded into gold nanocages(AuNCs)to develop a simple drug delivery system,which can efficiently utilize the tumor-associated antigens(TAAs)for improving immune responses.AuNCs/SV-mediated PTT treatment enhances tumor cells damage and promotes the release of TAAs which are immediately captured by Au NCs/SV to form AuNCs/SV/TAAs recombinant nanoparticle.Impressively,AuNCs/SV/TAAs can accumulate in lymph nodes effectively due to the suitable size of~55 nm and hyperthermia-induced vasodilative effect.And the codelivery of antigen and adjuvant is beneficial to stimulating the maturation of dendritic cells for further activating T cells.In a word,the recombinant strategy could make full use of TAAs to produce an individual powerful immunotherapy.
基金We thank the National Natural Science Foundation of China(no.81803406 and U1804283)the Foundation of Henan Educational Committee(19A150009)for financial support.
文摘An efficient metal-free intramolecular hydroarylation reaction of alkynes is described here.A series of aryl and N-group attached alkynes generated the intramolecular hydroarylation products in high yields.
基金support from the Natural Science Foundation of Henan Province(grant no.212300410152)the Key Scientific and Technological Project of Henan Province(grant no.212102110439)+1 种基金Henan University of Animal Husbandry and Economy(grant no.2019HNUAHEDF011 and XKYCXJJ2020006)the Key Scientific Research Project for Colleges and Universities of Henan Province(grant no.22B150005)。
文摘A novel and efficient[3+2]annulation of 2-substituted aziridines and N-tosyl cyanamides via a dominoregioselective ring-opening/5-exo-dig cyclization procedure has been developed,allowing the directpreparation of N_(2)-unprotected five-membered cyclic guanidines in good to excellent yields under mildconditions without metals and strong bases.Moreover,the highly biologically interesting urea analoguescould also be conveniently obtained via hydrolysis of the produced guanidines.
基金supported by the National Natural Science Foundation of China(Nos.82172762,21904119,31900991,82073395)the Innovation Talent Support Program of Henan Province(No.21HASTIT043)+1 种基金the Postdoctoral Science Foundation of China(Nos.2020TQ0288,2021M690140)the Postdoctoral Innovative Talent Support Program of Henan Province(No.ZYYCYU202012179).
文摘Radiotherapy is a mainstay treatment for malignant tumors in clinical practice.However,enhancing radiation damage to tumor cells meanwhile sparing normal tissues is still a great challenge in radiotherapy.Nanomaterials with high atomic number(Z)values are promising radiosensitizers by promoting the radiation energy deposition in irradiated tumor cells,thus enhancing the therapeutic ratio of radiotherapy.In this review,we described the mechanisms of high-Z element based-radiosensitizers and systematically summarized the recent progress on high-Z metal-based nanomaterials,including high-Z metal-based nanoparticles,high-Z metal-based nanoscale metal-organic frameworks and high-Z metal-doping nanomaterials.Finally,further potential and challenges in this field were discussed.
基金supported by the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMKF 202005)the Macao Science and Technology Development Fund(No.071/2017/A2).
文摘Hypoxia-inducible factor 1(HIF-1),as a main transcriptional regulator of metabolic adaptation to changes in the oxygen environment,participates in many physiological and pathological processes in the body,and is closely related to the pathogenesis of many diseases.This review outlines the mechanisms of HIF-1 activation,its signaling pathways,natural inhibitors,and its roles in diseases.This article can provide new insights in the diagnosis and treatment of human diseases,and recent progress on the development of HIF-1 inhibitors.