Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments hav...Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking drugs.In this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical investigators.Moreover,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this review.Furthermore,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.展开更多
Urban agglomerations are spatial entities that promote the development of ‘new urbanization' processes within China. In this context, the concept of ‘multiscale urban agglomeration spaces' encompasses three ...Urban agglomerations are spatial entities that promote the development of ‘new urbanization' processes within China. In this context, the concept of ‘multiscale urban agglomeration spaces' encompasses three linked levels: macroscale urban agglomerations, mesoscale cities, and microscale urban centers. Applying a series of multidisciplinary integrated research methods drawn from geography, urban planning, and architecture, this paper reveals two intensive utilization laws that can be generalized to apply to multiscale urban agglomeration spaces, top-to-bottom ‘positive transmission' linkage and inside-to-outside ‘negative transmission' movement. This paper also proposes optimization transmission theory and policy decision technical pathways that can be applied to these three urban agglomeration spatial scales. Specific technical pathways of transmission include intensive expansion and simulated decision-making in macroscale urban agglomerations, ecology, production, and living space intensive layout and dynamic decision-making in mesoscale cities, and four cores(i.e., ‘single, ring, axis, and pole core') progressive linkage and intensive optimization decision-making in microscale urban centers. The theory and technical pathways proposed in this paper solve the technical problem of optimization and provide intensive methods that can be applied not only at the individual level but also at multiple scales in urban agglomeration spaces. This study also advances a series of comprehensive technical solutions that can be applied to both compact and smart growth cities as well as to urban agglomerations. Solid theoretical support is provided for the optimization of Chinese land development, urbanization, agricultural development, and ecological security.展开更多
We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly de...We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly defined. In this study, using various techniques such as high throughput sequencing technology, bioinformatics, quantitative real-time PCR, and immunoblot analysis,we aimed to understand whether matrine serves as a novel regulator of FOXO and PI3K-AKT signaling pathway. DU145 and PC-3 cell lines were cultured for 24 h in vitro. Cells were treated with either matrine or control serum for 48 h, followed by extraction of total RNA. The RNA was sequenced using HiSeq 2500 high-throughput sequencing platform (Illumina). A gene library was established and quality analysis of read data carried out. Integrated database from the website DAVID was used to analyze Gene Ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway of differential genes was used for pathway analysis, screening for fold differences of more than two times. The FOXO and PI3K-AKT signaling pathways were screened, and expression levels of mRNA and core protein detected by real-time PCR and immunoblotting, respectively. High throughput sequencing and GO analysis revealed that differentially expressed genes before and after treatment played an important role in cell metabolic process, growth process, anatomical structure formation, cellular component organization, and biological regulation. KEGG signal pathway analysis revealed that FOXO and PI3K-AKT signal pathways had a significant difference between before and after matrine-treated androgen-independent prostate cancer cells PC-3 and DU145. Real-time PCR showed that matrine treatment led to a significant increase in the expression levels of FOXO1A, FOXO3A, FOXO4, and FOXO6 in DU145 and PC-3 cells (P<0.01 or P<0.05), whereas the PI3K expression levels decreased (P<0.01). Similarly, immunoblotting revealed a significant increase (P<0.05) in the expression levels of FOXO1A FOXO3展开更多
C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, w...C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for CML therapy. Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for CML therapy that takes advantage of natural products.展开更多
1 Introduction Early detection and diagnosis of stable coronary artery disease （SCAD） is essential for proactive secondary prevention of myocardial infarction （MI）, control of disease progress, and reduction of mo...1 Introduction Early detection and diagnosis of stable coronary artery disease （SCAD） is essential for proactive secondary prevention of myocardial infarction （MI）, control of disease progress, and reduction of mortality. Clinical decision-making in modem medicine is increasingly dependent on cardiovascular imaging techniques. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease has been issued by American Heart Association （AHA）. European Society of Cardiology （ESC） has issued 2013 ESC guidelines on the management of stable coronary artery disease.展开更多
The unmodified graphitic carbon nitride(g-C_3N_4) suffers from low photocatalytic activity because of the unfavourable structure.In the present work,we reported a simple self-structural modification strategy to optimi...The unmodified graphitic carbon nitride(g-C_3N_4) suffers from low photocatalytic activity because of the unfavourable structure.In the present work,we reported a simple self-structural modification strategy to optimize the microstructure of g-C_3N_4 and obtained graphene-like g-C_3N_4 nanosheets with porous structure.In contrast to traditional thermal pyrolysis preparation of g-C_3N_4,the present thermal condensation was improved via pyrolysis of thiourea in an alumina crucible without a cover,followed by secondary heat treatment.The popcorn-like formation and layer-by-layer thermal exfoliation of graphene-like porous g-C_3N_4 was proposed to explain the formation mechanism.The photocatalytic removal performance of both NO and NO_2 with the graphene-like porous g-C_3N_4 for was significantly enhanced by selfstructural modification.Trapping experiments and in-situ diffuse reflectance infrared fourier transform spectroscopy(DRIFTS) measurement were conducted to detect the active species during photocatalysis and the conversion pathway of g-C_3N_4 photocatalysis for NO_x purification was revealed.The photocatalytic activity of graphene-like porous g-C_3N_4 was highly enhanced due to the improved charge separation and increased oxidation capacity of the ·O_2^- radicals and holes.This work could not only provide a novel self-structural modification for design of highly efficient photocatalysts,but also offer new insights into the mechanistic understanding of g-C_3N_4 photocatalysis.展开更多
Rats have been the primary model to study the process and underlying mechanisms of recovery after spinal cord injury. Two weeks after a severe spinal cord contusion, rats can regain weight-bearing abilities without th...Rats have been the primary model to study the process and underlying mechanisms of recovery after spinal cord injury. Two weeks after a severe spinal cord contusion, rats can regain weight-bearing abilities without therapeutic interventions, as assessed by the Basso, Beattie and Bresnahan locomotor scale. However, many human patients suffer from permanent loss of motor function following spinal cord injury. While rats are the most understood animal model, major differences in sensorimotor pathways between quadrupeds and bipeds need to be considered. Understanding the major differences between the sensorimotor pathways of rats, non-human primates, and humans is a start to improving targets for treatments of human spinal cord injury. This review will discuss the neuroplasticity of the brain and spinal cord after spinal cord injury in rats, non-human primates, and humans. A brief overview of emerging interventions to induce plasticity in humans with spinal cord injury will also be discussed.展开更多
OBJECTIVE:To observe the effects of Xinfeng capsule on the apoptosis of peripheral blood CD4+ T lymphocytes and changes in the Fas/Fas L-mediated apoptotic pathway in patients with rheumatoid arthritis(RA).METHODS:A t...OBJECTIVE:To observe the effects of Xinfeng capsule on the apoptosis of peripheral blood CD4+ T lymphocytes and changes in the Fas/Fas L-mediated apoptotic pathway in patients with rheumatoid arthritis(RA).METHODS:A total of 28 RA patients were included in the study;they were randomly divided into the Xinfeng capsule(XFC) group(3 capsules,3 per day)and the leflunomide(LEF) group(1 pellet,once per night).The treatment course in each groups was 12 weeks.The normal control(NC) group consisted of10 healthy people.The apoptotic rate was examined using flow cytometry.Fas,Fas L,caspase 8,caspase 3,bcl-2,and bax m RNA were examined using q RT-PCR.Apoptotic proteins Fas,Fas L,caspase8,and caspase 3 were examined using western blotting.RESULTS:After treatment,patients in the two groups all showed some trend of improvement.Disease activity indexes,joint morning stiffness time,joint swelling/tenderness number,health assessment questionnaire(HAQ) score,RA quality of life(RAQOL) questionnaire,and self-rating anxiety scale(SAS),as well as all apoptotic related indicators were reduced in both groups after treatment with no significant difference between groups.But the improvement in terms of the self-rating depression scale(SDS) in the XFC group was better than in the LEF group.RA patients showed lower apoptotic rates in CD4+ T cells,lower bax,Fas,caspase 8,and caspase 3 m RNA,and less protein expression of Fas,caspase 8,and caspase3 than in the NC group.These indicators increased after treatment.However,the level of Bcl-2 m RNA was higher in the XFC group than in the NC group before treatment,and it subsequently decreased.The XFC group expressed lower Bcl-2 m RNA than the LEF group.Negative correlations were found between ESR and the apoptotic rate in CD4 + T cells,Fas,and caspase 3;CRP and Fas;and,swollen joint count and Bax,while positive correlations were found between ESR and Bcl-2.CONCLUSION:XFC can regulate the Fas/Fas L system and promote CD4+ T cell apoptosis and thus reduce the abnormal immune response,which can improv展开更多
OBJECTIVE: To observe the effect of stimulating Qihai(CV 6) and bilateral Tianshu(ST 25) with herb-partitioned moxibustion(HPM) in rats with Crohn's disease(CD), and to investigate the possible anti-inflammatory m...OBJECTIVE: To observe the effect of stimulating Qihai(CV 6) and bilateral Tianshu(ST 25) with herb-partitioned moxibustion(HPM) in rats with Crohn's disease(CD), and to investigate the possible anti-inflammatory mechanism of HPM.METHODS: Forty rats were randomly divided into four groups(n = 10 rats per group): normal control(NC), model control(MC), mesalamine(MES), and HPM. The CD rat model was established in the MC,MES, and HPM groups by administering a mixture of trinitrobenzenesulfonic acid and alcohol via enema. The HPM group received HPM on Qihai(CV 6)and bilateral Tianshu(ST 25), while the MES group received intragastric mesalamine. Colonic histomorphological scores, and serum concentrations of tumor necrosis factor α(TNF-α) and interleukin 1β(IL-1β) were assessed to evaluate the effects of HPM on colonic reparation and anti-inflammation.The expressions of Toll-like receptor 4(TLR-4), nuclear factor κB inhibitor α(IκB-α), IκB kinase α/β(IKKα/β), and NF-κB p65 were further analyzed to investigate the regulatory effects of the interventions on the TLR4/NF-κB pathway.RESULTS: CD rats showed inflammatory colonic damage and increased serum concentrations of TNF-α and IL-1β. The expressions of TLR4, IKKα/β,and NF-κB p65 in the colons of CD rats were significantly increased compared with the NC group,while the expression of IκBα(a key negative regulator of NF-κB p65) was decreased. HPM significantly mitigated colonic damage and reduced the serum concentrations of TNF-α and IL-1β. HPM downregulated the expressions of TLR4, IKKα/β, and NF-κB p65 in the colon, and upregulated the expression of IκBα. The effects of HPM in CD rats were similar to those of mesalamine.CONCLUSION: HPM alleviates colonic inflammation in CD rats. This may be achieved through regulation of TLR4, which induces NF-κB signal transduction.展开更多
The compound(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1 H-inden-1-one(BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase. However, its precise anti-lung cancer ...The compound(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1 H-inden-1-one(BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on the viability of non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460 were evaluated. We confirmed that BCI significantly inhibited the viability of p53(-) NCI-H1299 cells as compared to NCI-H460 and A549 cells, which express wild-type p53. Furthermore, BCI treatment increased the level of cellular reactive oxygen species and pre-treatment of cells with N-acetylcysteine markedly attenuated BCI-mediated apoptosis of NCI-H1299 cells. BCI induced cellular morphological changes, inhibited viability, and produced reactive oxygen species in NCI-H1299 cells in a dose-dependent manner. BCI induced processing of caspase-9, caspase-3, and poly ADP-ribose polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. In addition, BCI downregulated Bcl-2 expression and enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. However, BCI failed to modulate the expression of the death receptor and extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. Thus, BCI induces apoptosis via generation of reactive oxygen species and activation of the intrinsic pathway in NCI-H1299 cells.展开更多
OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHOD...OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the me展开更多
Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growt...Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.展开更多
A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and wa...A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases(PI3 K) signaling pathway were detected via next-generation sequencing(NGS)-based liquid biopsy, including a p. G1007 R missense mutation in exon 21 of PIK3 CA(33.61%), a p.L70 fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten(PTEN)(49.14%), and a p. D1542 Y missense mutation in exon 32 of mammalian target of rapamycin(m TOR)(1.66%). Therefore, only the m TOR inhibitor everolimus was administered to the patient. Partial remission(PR) was observed after 2 months, and sustained stable disease(SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3 CA decreased to 4.17%, and that the PTEN and m TOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3 K/ARK/m TOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.展开更多
Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism ...Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.展开更多
The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aber...The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aberrant accumulated self DNA in the cytoplasm under certain pathological conditions, such as virus induced cell death, DNA damage, mitochondria damage, gene mutations, which results in autoimmune diseases. Therefore, the cGAS-MITA pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases. The regulation of cGAS-MITA pathway at MITA-level have been extensively explored and reviewed elsewhere,here we provide a summary and perspective on recent advances in understanding of the cGAS regulation.展开更多
The epidermal growth factor receptor （EGFR） has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeti...The epidermal growth factor receptor （EGFR） has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeting peptide. Here, we designed and synthesized a novel peptide-Au cluster as AuloPeptides to target to EGFR. We found AumPeptides could target to the natural binding sites of all EGFRs at mem- brane in both active and inactive states by molecular simulations. Its targeted ability was further verified by the co-localization and blocking experiments. We also study the configuration modifications of both active and inactive EGFRs after binding by AumPeptides. For active EGFR, the absorbed AuloPeptide5 might replace the natural ligand in EGFR endocytosis process. Then, the peptide-Au cluster in endochylema could inhibit the cancer relating enzyme activity including thioredoxin reductasel （TrxR1） and induce the oxidative stress mediated apoptosis in tumor cells. For inactive EGFR, it was retained in inactive state by Au10 Peptides binding to inhibit dimerization of EGFR for anticancer. Both pathways might be applied in anticancer drug development based on the theoretical and experimental study here.展开更多
文摘Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking drugs.In this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical investigators.Moreover,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this review.Furthermore,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.
基金Under the auspices of Major Program of the National Natural Science Foundation of China ‘Coupled mechanisms and interactive coercing effects between urbanization and eco-environment in mega-urban agglomerations’(No.41590842)
文摘Urban agglomerations are spatial entities that promote the development of ‘new urbanization' processes within China. In this context, the concept of ‘multiscale urban agglomeration spaces' encompasses three linked levels: macroscale urban agglomerations, mesoscale cities, and microscale urban centers. Applying a series of multidisciplinary integrated research methods drawn from geography, urban planning, and architecture, this paper reveals two intensive utilization laws that can be generalized to apply to multiscale urban agglomeration spaces, top-to-bottom ‘positive transmission' linkage and inside-to-outside ‘negative transmission' movement. This paper also proposes optimization transmission theory and policy decision technical pathways that can be applied to these three urban agglomeration spatial scales. Specific technical pathways of transmission include intensive expansion and simulated decision-making in macroscale urban agglomerations, ecology, production, and living space intensive layout and dynamic decision-making in mesoscale cities, and four cores(i.e., ‘single, ring, axis, and pole core') progressive linkage and intensive optimization decision-making in microscale urban centers. The theory and technical pathways proposed in this paper solve the technical problem of optimization and provide intensive methods that can be applied not only at the individual level but also at multiple scales in urban agglomeration spaces. This study also advances a series of comprehensive technical solutions that can be applied to both compact and smart growth cities as well as to urban agglomerations. Solid theoretical support is provided for the optimization of Chinese land development, urbanization, agricultural development, and ecological security.
基金supported by the National Natural Science Foundation of China (81472382)the National Natural Science Foundation of China for Young Scientists (81101947)+3 种基金the Guangdong Province Natural Science Foundation (2014A030313079)the Fundamental Research Funds for the Central Universities (14ykpy19)Guangdong Province Science and Technology for Social Development Project (2013B021800107)Guangzhou City in 2015 scientific research projects (7415600066401 to Hai Huang)
文摘We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly defined. In this study, using various techniques such as high throughput sequencing technology, bioinformatics, quantitative real-time PCR, and immunoblot analysis,we aimed to understand whether matrine serves as a novel regulator of FOXO and PI3K-AKT signaling pathway. DU145 and PC-3 cell lines were cultured for 24 h in vitro. Cells were treated with either matrine or control serum for 48 h, followed by extraction of total RNA. The RNA was sequenced using HiSeq 2500 high-throughput sequencing platform (Illumina). A gene library was established and quality analysis of read data carried out. Integrated database from the website DAVID was used to analyze Gene Ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway of differential genes was used for pathway analysis, screening for fold differences of more than two times. The FOXO and PI3K-AKT signaling pathways were screened, and expression levels of mRNA and core protein detected by real-time PCR and immunoblotting, respectively. High throughput sequencing and GO analysis revealed that differentially expressed genes before and after treatment played an important role in cell metabolic process, growth process, anatomical structure formation, cellular component organization, and biological regulation. KEGG signal pathway analysis revealed that FOXO and PI3K-AKT signal pathways had a significant difference between before and after matrine-treated androgen-independent prostate cancer cells PC-3 and DU145. Real-time PCR showed that matrine treatment led to a significant increase in the expression levels of FOXO1A, FOXO3A, FOXO4, and FOXO6 in DU145 and PC-3 cells (P<0.01 or P<0.05), whereas the PI3K expression levels decreased (P<0.01). Similarly, immunoblotting revealed a significant increase (P<0.05) in the expression levels of FOXO1A FOXO3
基金supported by the National Natural Science Foundation of China (31471223, 31230042, 31771459, 31770879)the Project of Science and Technology of Guangzhou (201504010022)the National Key R&D Program of China (2017YFA0504400) from the Ministry of Science and Technology of China
文摘C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for CML therapy. Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for CML therapy that takes advantage of natural products.
文摘1 Introduction Early detection and diagnosis of stable coronary artery disease （SCAD） is essential for proactive secondary prevention of myocardial infarction （MI）, control of disease progress, and reduction of mortality. Clinical decision-making in modem medicine is increasingly dependent on cardiovascular imaging techniques. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease has been issued by American Heart Association （AHA）. European Society of Cardiology （ESC） has issued 2013 ESC guidelines on the management of stable coronary artery disease.
基金supported by the National Natural Science Foundation of China(51478070,21501016 and 21777011)the National Key R&D Program of China(2016YFC0204702)+3 种基金the Innovative Research Team of Chongqing(CXTDG201602014)the Natural Science Foundation of Chongqing(cstc2016jcyj A0481,cstc2017jcyj BX0052)the Early Career Scheme(ECS 809813) from Hong Kongthe Internal Research Grant from Hong Kong Institute of Education(R3588)
文摘The unmodified graphitic carbon nitride(g-C_3N_4) suffers from low photocatalytic activity because of the unfavourable structure.In the present work,we reported a simple self-structural modification strategy to optimize the microstructure of g-C_3N_4 and obtained graphene-like g-C_3N_4 nanosheets with porous structure.In contrast to traditional thermal pyrolysis preparation of g-C_3N_4,the present thermal condensation was improved via pyrolysis of thiourea in an alumina crucible without a cover,followed by secondary heat treatment.The popcorn-like formation and layer-by-layer thermal exfoliation of graphene-like porous g-C_3N_4 was proposed to explain the formation mechanism.The photocatalytic removal performance of both NO and NO_2 with the graphene-like porous g-C_3N_4 for was significantly enhanced by selfstructural modification.Trapping experiments and in-situ diffuse reflectance infrared fourier transform spectroscopy(DRIFTS) measurement were conducted to detect the active species during photocatalysis and the conversion pathway of g-C_3N_4 photocatalysis for NO_x purification was revealed.The photocatalytic activity of graphene-like porous g-C_3N_4 was highly enhanced due to the improved charge separation and increased oxidation capacity of the ·O_2^- radicals and holes.This work could not only provide a novel self-structural modification for design of highly efficient photocatalysts,but also offer new insights into the mechanistic understanding of g-C_3N_4 photocatalysis.
文摘Rats have been the primary model to study the process and underlying mechanisms of recovery after spinal cord injury. Two weeks after a severe spinal cord contusion, rats can regain weight-bearing abilities without therapeutic interventions, as assessed by the Basso, Beattie and Bresnahan locomotor scale. However, many human patients suffer from permanent loss of motor function following spinal cord injury. While rats are the most understood animal model, major differences in sensorimotor pathways between quadrupeds and bipeds need to be considered. Understanding the major differences between the sensorimotor pathways of rats, non-human primates, and humans is a start to improving targets for treatments of human spinal cord injury. This review will discuss the neuroplasticity of the brain and spinal cord after spinal cord injury in rats, non-human primates, and humans. A brief overview of emerging interventions to induce plasticity in humans with spinal cord injury will also be discussed.
基金the Key Projects in the National Science & Technology Pillar Program in the Twelfth Five-Year Plan Period:Clinical Research on Xin'an Medicine Prevention and Treatment of Difficult Diseases(No.2012BAI26B02)
文摘OBJECTIVE:To observe the effects of Xinfeng capsule on the apoptosis of peripheral blood CD4+ T lymphocytes and changes in the Fas/Fas L-mediated apoptotic pathway in patients with rheumatoid arthritis(RA).METHODS:A total of 28 RA patients were included in the study;they were randomly divided into the Xinfeng capsule(XFC) group(3 capsules,3 per day)and the leflunomide(LEF) group(1 pellet,once per night).The treatment course in each groups was 12 weeks.The normal control(NC) group consisted of10 healthy people.The apoptotic rate was examined using flow cytometry.Fas,Fas L,caspase 8,caspase 3,bcl-2,and bax m RNA were examined using q RT-PCR.Apoptotic proteins Fas,Fas L,caspase8,and caspase 3 were examined using western blotting.RESULTS:After treatment,patients in the two groups all showed some trend of improvement.Disease activity indexes,joint morning stiffness time,joint swelling/tenderness number,health assessment questionnaire(HAQ) score,RA quality of life(RAQOL) questionnaire,and self-rating anxiety scale(SAS),as well as all apoptotic related indicators were reduced in both groups after treatment with no significant difference between groups.But the improvement in terms of the self-rating depression scale(SDS) in the XFC group was better than in the LEF group.RA patients showed lower apoptotic rates in CD4+ T cells,lower bax,Fas,caspase 8,and caspase 3 m RNA,and less protein expression of Fas,caspase 8,and caspase3 than in the NC group.These indicators increased after treatment.However,the level of Bcl-2 m RNA was higher in the XFC group than in the NC group before treatment,and it subsequently decreased.The XFC group expressed lower Bcl-2 m RNA than the LEF group.Negative correlations were found between ESR and the apoptotic rate in CD4 + T cells,Fas,and caspase 3;CRP and Fas;and,swollen joint count and Bax,while positive correlations were found between ESR and Bcl-2.CONCLUSION:XFC can regulate the Fas/Fas L system and promote CD4+ T cell apoptosis and thus reduce the abnormal immune response,which can improv
基金Supported by Grants from the National Natural Science Foundation of China(No.81072879,No.81202754)National Basic Research Program of China(973 program,No.2015CB554500)+1 种基金Project of Shanghai Municipal Commission of Health and Family Planning(No.20144Y0153)Special Scientific Research Fund for Election and Cultivation of the Elite in College and University(No.szy10071)
文摘OBJECTIVE: To observe the effect of stimulating Qihai(CV 6) and bilateral Tianshu(ST 25) with herb-partitioned moxibustion(HPM) in rats with Crohn's disease(CD), and to investigate the possible anti-inflammatory mechanism of HPM.METHODS: Forty rats were randomly divided into four groups(n = 10 rats per group): normal control(NC), model control(MC), mesalamine(MES), and HPM. The CD rat model was established in the MC,MES, and HPM groups by administering a mixture of trinitrobenzenesulfonic acid and alcohol via enema. The HPM group received HPM on Qihai(CV 6)and bilateral Tianshu(ST 25), while the MES group received intragastric mesalamine. Colonic histomorphological scores, and serum concentrations of tumor necrosis factor α(TNF-α) and interleukin 1β(IL-1β) were assessed to evaluate the effects of HPM on colonic reparation and anti-inflammation.The expressions of Toll-like receptor 4(TLR-4), nuclear factor κB inhibitor α(IκB-α), IκB kinase α/β(IKKα/β), and NF-κB p65 were further analyzed to investigate the regulatory effects of the interventions on the TLR4/NF-κB pathway.RESULTS: CD rats showed inflammatory colonic damage and increased serum concentrations of TNF-α and IL-1β. The expressions of TLR4, IKKα/β,and NF-κB p65 in the colons of CD rats were significantly increased compared with the NC group,while the expression of IκBα(a key negative regulator of NF-κB p65) was decreased. HPM significantly mitigated colonic damage and reduced the serum concentrations of TNF-α and IL-1β. HPM downregulated the expressions of TLR4, IKKα/β, and NF-κB p65 in the colon, and upregulated the expression of IκBα. The effects of HPM in CD rats were similar to those of mesalamine.CONCLUSION: HPM alleviates colonic inflammation in CD rats. This may be achieved through regulation of TLR4, which induces NF-κB signal transduction.
文摘The compound(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1 H-inden-1-one(BCI) is known as an inhibitor of dual specific phosphatase 1/6 and mitogen-activated protein kinase. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on the viability of non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460 were evaluated. We confirmed that BCI significantly inhibited the viability of p53(-) NCI-H1299 cells as compared to NCI-H460 and A549 cells, which express wild-type p53. Furthermore, BCI treatment increased the level of cellular reactive oxygen species and pre-treatment of cells with N-acetylcysteine markedly attenuated BCI-mediated apoptosis of NCI-H1299 cells. BCI induced cellular morphological changes, inhibited viability, and produced reactive oxygen species in NCI-H1299 cells in a dose-dependent manner. BCI induced processing of caspase-9, caspase-3, and poly ADP-ribose polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. In addition, BCI downregulated Bcl-2 expression and enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. However, BCI failed to modulate the expression of the death receptor and extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. Thus, BCI induces apoptosis via generation of reactive oxygen species and activation of the intrinsic pathway in NCI-H1299 cells.
基金Supported by the National Natural Science Foundation of China(Based on JAK/STAT Signaling Pathway to Discuss the Effects of Qingshen Granules for Anti Renal Fibrosis,General Program,No.81473673Based on P-selectin/PSGL-1 mediated MAPK Signaling Pathway to Discuss the Effects of Qingshen granules for Vascular Endothelial Injury Due to Renal Fibrosis,General Program,No.81673931)+1 种基金National Science Fund for Distinguished Young Scholars of China(Based on NF-k B Signaling Pathway and Oxidative Stress to Discuss the Effects of Qingshen granules in Transdifferentiation of Renal Tubular Epithelial Cells,No.81403372)Anhui Natural Science Foundation(Based on Leptin-JAK/STAT-inflammatory pathway to study the effects of Qingshen granules for anti renal fibrosis,No.1508085MH198)
文摘OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the me
文摘Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.
文摘A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases(PI3 K) signaling pathway were detected via next-generation sequencing(NGS)-based liquid biopsy, including a p. G1007 R missense mutation in exon 21 of PIK3 CA(33.61%), a p.L70 fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten(PTEN)(49.14%), and a p. D1542 Y missense mutation in exon 32 of mammalian target of rapamycin(m TOR)(1.66%). Therefore, only the m TOR inhibitor everolimus was administered to the patient. Partial remission(PR) was observed after 2 months, and sustained stable disease(SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3 CA decreased to 4.17%, and that the PTEN and m TOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3 K/ARK/m TOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.
文摘Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with Nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from Nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces Nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to Nutlin-3a.
基金supported by the National Natural Science Foundation of China (31400742)
文摘The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aberrant accumulated self DNA in the cytoplasm under certain pathological conditions, such as virus induced cell death, DNA damage, mitochondria damage, gene mutations, which results in autoimmune diseases. Therefore, the cGAS-MITA pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases. The regulation of cGAS-MITA pathway at MITA-level have been extensively explored and reviewed elsewhere,here we provide a summary and perspective on recent advances in understanding of the cGAS regulation.
基金supported by the National Natural Science Foundation of China(31571026,11404333)the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund(the second phase)under Grant No.U1501501
文摘The epidermal growth factor receptor （EGFR） has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeting peptide. Here, we designed and synthesized a novel peptide-Au cluster as AuloPeptides to target to EGFR. We found AumPeptides could target to the natural binding sites of all EGFRs at mem- brane in both active and inactive states by molecular simulations. Its targeted ability was further verified by the co-localization and blocking experiments. We also study the configuration modifications of both active and inactive EGFRs after binding by AumPeptides. For active EGFR, the absorbed AuloPeptide5 might replace the natural ligand in EGFR endocytosis process. Then, the peptide-Au cluster in endochylema could inhibit the cancer relating enzyme activity including thioredoxin reductasel （TrxR1） and induce the oxidative stress mediated apoptosis in tumor cells. For inactive EGFR, it was retained in inactive state by Au10 Peptides binding to inhibit dimerization of EGFR for anticancer. Both pathways might be applied in anticancer drug development based on the theoretical and experimental study here.
