Obtaining the target blood pressure level by monotherapy can be challenging currently,especially for the patients who are suffering from other diseases meanwhile.It is demonstrated that a majority of hypertensive pati...Obtaining the target blood pressure level by monotherapy can be challenging currently,especially for the patients who are suffering from other diseases meanwhile.It is demonstrated that a majority of hypertensive patients need two or more antihypertensive drugs to lower their blood pressure effectively.Consequently,fixed-dose which can be defined as that several active agents were combined in single pharmaceutical formulations appears to be a novel and underlying power in overcoming the cardiovascular disease.Based on the analysis of some literature and relative data from FDA,the advantages of fixed-dose combination are elucidated and formulations of common dual,triple-combinations were summarized.Clinical practices proved that fixed-dose combinations had many benefits comparing with single drug and separate agents in terms of effects,convenience,compliance,and costs to a certain extent.From the patients’perspective,the fixed-dose combination therapy will be increasingly utilized in blood pressure control in the future.展开更多
isTraditional Chinese medicine(TCM)is a highly complex chemical substance system,which not only reflected in the complexity of the chemical components and their interrelationships,but also in the intricacy of the pres...isTraditional Chinese medicine(TCM)is a highly complex chemical substance system,which not only reflected in the complexity of the chemical components and their interrelationships,but also in the intricacy of the prescription’s connection with the human body.Component compatibility strategy has been proposed for developing modern TCM since 2005 and established comprehensive relevant technologies and research approaches.Moreover,to meet the safety and efficacy of current pharmaceuticals,research on fixed-dose combination drugs is directed by modern scientific theories,conforms to TCM compatibility principles and clarifies material basis and pharmacological mechanisms and component-effect correlations.This review summarized gaps and feasibility of fixed-dose combination strategy in the development of modern TCM research and assessed their advantages and disadvantages in light of contemporary drug combination research practices.展开更多
Amlodipine/valsartan(Aml/Val)single-pill combination(SPC)therapy has been widely used and studied in clinical practice in recent years.This article reviews the Chinese and English literature on the clinical use of Aml...Amlodipine/valsartan(Aml/Val)single-pill combination(SPC)therapy has been widely used and studied in clinical practice in recent years.This article reviews the Chinese and English literature on the clinical use of Aml/Val SPC therapy in Chinese hypertensive patients.According to five studies concerning the efficacy and safety of this treatment,Aml/Val SPC therapy was more efficacious than monotherapy with valsartan,amlodipine,or the nifedipine gastrointestinal therapeutic system.This treatment showed greater blood pressure-lowering effects,a higher blood pressure control rate,and a higher response rate.Aml/Val SPC treatment was well tolerated,with adverse event rates similar to those of monotherapy with valsartan or amlodipine and significantly rarer adverse events compared with the nifedipine gastrointestinal therapeutic system.Aml/Val SPC is a highly efficacious and well-tolerated antihypertensive treatment in Chinese hypertensive patients.展开更多
Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fastin...Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.展开更多
Integrase Strand Transfer Inhibitors(INSTIs)have favorable safety and tolerability profiles,potent antiviral activity,and high resistance barriers,solving the limitations of previous antiretrovirals caused by resistan...Integrase Strand Transfer Inhibitors(INSTIs)have favorable safety and tolerability profiles,potent antiviral activity,and high resistance barriers,solving the limitations of previous antiretrovirals caused by resistant mutations.While first-generation INSTIs have exhibited emerging resistance challenges during extended clinical use,second-generation INSTIs provide enhanced resistance barriers and extended plasma half-lives relative to their predecessors.Optimized combination regimens incorporating these agents have substantially improved therapeutic convenience and long-term disease management in human immunodeficiency virus(HIV)care.Current investigations focus on multiple combination strategies employing second-generation INSTIs including dolutegravir(DTG)and bictegravir(BIC),with preliminary findings demonstrating substantial clinical benefits.The DTG/lamivudine(3TC)dual regimen in the GEMINI and TANGO studies achieved 92.1%–99.6%virologic suppression rates at week 48,maintaining efficacy through 144 weeks.The cabotegravir(CAB)/Rilpivirine(RPV)long-acting injectable combination in ATLAS trials demonstrated 92.5%suppression efficacy with validated every-two-month dosing intervals.The BIC/emtricitabine/tenofovir alafenamide triple regimen in studies 1489/1490 maintained>84%suppression at week 144 while retaining activity against resistant variants.Real-world data confirm that these regimens maintained a viral suppression rate of>90%in both treatment-na?ve and-experienced patients,with treatment interruption rates of<5%.Recent advances include the US Food and Drug Administration's approval of DTG/3TC for use in adolescents≥12 years old and adaptive studies of CAB/RPV in special populations.This article summarizes the research progress of current combination formulations based on second-generation INSTIs to provide new therapeutic options and clinical insights for the treatment of patients with HIV.展开更多
Background：Decreases in the bioavailability of rifampicin （RFP） can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug ...Background：Decreases in the bioavailability of rifampicin （RFP） can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination （FDC; formulation A） and three two-drug FDCs （formulations B,C,and D） used in China,compared with RFP in free combinations of these drugs （reference）,in healthy volunteers.Methods：Eighteen and twenty healthy Chinese male volunteers participated in two open-label,randomized two-period crossover （formulations A and C） or one three-period crossover （formulations B and D） study,respectively.The washout period between treatments was 7 days.Bioequivalence was assessed based on 90％ confidence intervals,according to two one-sided t-tests.All analyses were done with DAS 3.1.5 （Mathematical Pharmacology Professional Committee of China,Shanghai,China）.Results：Mean pharmacokinetic parameter values of RFP obtained for formulations A,B,C,and D products were 11.42 ± 3.41 μg/ml,7.86 ± 5.78 μg/ml,13.05 ± 6.80 μg/ml,and 16.18 ± 3.87 μg/ml,respectively,for peak plasma concentration （Cmax）,91.43± 30.82 μg·h-1 ·ml-1,55.49 ± 37.58 μg·h-1·ml-1,96.50 ± 47.24 μg·h-1·ml-1,101.47 ± 33.07 μg·h-1·ml-1,respectively,for area under the concentration-time curve （AUC0-2,4 h）.Conclusions：Although the concentrations of RFP for formulations A,C,and D were within the reported acceptable therapeutic range,only formulation A was bioequivalent to the reference product.The three two-drug FDCs （formulations B,C and D） displayed inferior RFP bioavailability compared with the reference （Chinese Clinical Trials registration number：ChiCTR-TTRCC-12002451）.展开更多
Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2]....Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2].Non-adherence is a serious problem linked to worsening symptoms and increased motor fluc-tuations[3-5].Levodopa(LD)remains the most effective treatment for PD[6].However,a single dosing treatment is only effective in the early phase of the disease.In the severe phase,4-5 years after diagnosis,the therapeutic window of dopamine becomes narrow,and due to its short half-life of between 0.7 and 1.4 h dosing of LD will be required every 2 h[7-9].One way to ameliorate this issue is to co-admin-ister LD with carbidopa(CD),which can increase LD’s oral bioavailability to 40-70%[10].展开更多
Background:Human skin is affected by ultraviolet rays on a daily basis,and excessive ultraviolet radiation(UVR)can lead to sunburn erythema,tanning,photoaging,and skin tumors.The combination of Astragali Radix(AR)and ...Background:Human skin is affected by ultraviolet rays on a daily basis,and excessive ultraviolet radiation(UVR)can lead to sunburn erythema,tanning,photoaging,and skin tumors.The combination of Astragali Radix(AR)and Anemarrhenae Rhizoma(AAR)is a common pairing in traditional Chinese medicine(TCM).According to earlier studies,they possess properties capable of alleviating the adverse impacts of UVR on the skin.However,the specific actions and underlying mechanisms require further investigation.The study aims to analyze the efficacy of AR-AAR in preventing UVR-induced skin damage and to clarify the associated molecular mechanisms.Methods:Potential signaling pathways by which AR and AAR may protect against UVR-induced skin damage were identified with network pharmacology,molecular docking techniques and molecular dynamics(MD)simulation.Except the normal group,the back skin of SD rats was exposed to 1.1 mW/cm^(2) UVA combined with 0.1 mW/cm^(2) UVB daily,and the UVR skin damage model was established.Morphological features of skin tissues of different groups were discovered through Hematoxylin and Eosin(HE)staining,Masson staining,Weigert staining.ELISA was utilized to measure the levels of reactive oxygen species(ROS),Interleukin 6(IL-6),Interleukin 1β(IL-1β)and Tumor necrosis factos-α(TNF-α)in skin tissues.RT-PCR and Western blot were employed to quantify the mRNA and protein contents of PI3K,AKT,and MMP-9.Results:Network pharmacology analysis predicts that AR-AAR may improve skin damage induced by UVR through the PI3K/AKT signaling pathway.Histological staining shows that AR-AAR can significantly reduce inflammatory infiltration and fibrosis in damaged skin.Treatment with AR-AAR(2:1)significantly reduced the expression levels of IL-1β,IL-6,TNF-αand ROS in UVR-damaged rat skin.After treatment with AR-AAR(2:1),not only did the relative mRNA expression levels of PI3K and AKT and the protein expression levels of PI3K,AKT,P-PI3K,and P-AKT increase,but the mRNA and protein expression levels of MMP-9 decreased.Conclusion:The study indicate that the AR-AAR combination and its active components may mitigate UVR skin damage by modulating the PI3K/AKT signaling pathway.展开更多
Urban forests are highly multifunctional and provide numerous ecological functions.Plant functional traits individually or jointly influence the ecological multifunctionality of tree species(TS-EMF)and can also modify...Urban forests are highly multifunctional and provide numerous ecological functions.Plant functional traits individually or jointly influence the ecological multifunctionality of tree species(TS-EMF)and can also modify TSEMF in response to environmental changes.However,there has been limited exploration of multitrait combinations for predicting TS-EMF across seasons and of trait thresholds that enhance TS-EMF.Here,for 10 dominant tree species in urban forests of Northeast China,14 traits were measured and four aboveground and three belowground ecological functions assessed in three seasons.Ecological functions and TS-EMF differed significantly throughout the seasons(P<0.05).Synergistic relationships were found between carbon sequestration and oxygen release,between cooling and humidification,and between organic carbon accumulation and nutrient cycling.Notably,aboveground multifunctionality played a leading role in TS-EMF.With seasonal changes,resource allocation shifted toward traits related to resource acquisition rather than conservation to maintain TS-EMF.The combination of traits that predicted TS-EMF varied by type,accounting for up to 66.45%of the variation.TS-EMF was primarily driven by leaf structure in spring and by nutrient accumulation in autumn.Leaf carbon content(LCC)consistently served as a stabilizing factor for predicting TS-EMF across seasons.At 36.5-36.8 mg g^(-1),LCC had its optimal effect on TS-EMF.Other traits in combination that positively influence total TS-EMF include leaf nitrogen content(3.43-3.45 mg g^(-1)),leaf phosphorus content(0.80-0.83 mg g^(-1)),and leaf area(65.86-68.43 cm^(2)).Within these specified trait thresholds,Morus alba and Quercus mongolica were identified as key species.These findings suggest that the trade-off between various ecological functions can be managed by altering plant traits across seasons.This approach could provide a theoretical foundation for enhancing the TS-EMF of urban forests through trait-based management,offering practical guidance for selecting tree species.展开更多
The vibration response and noise caused by subway trains can affect the safety and comfort of superstructures.To study the dynamic response characteristics of subway stations and superstructures under train loads with...The vibration response and noise caused by subway trains can affect the safety and comfort of superstructures.To study the dynamic response characteristics of subway stations and superstructures under train loads with a hard combination,a numerical model is developed in this study.The indoor model test verified the accuracy of the numerical model.The influence laws of different hard combinations,train operating speeds and modes were studied and evaluated accordingly.The results show that the frequency corresponding to the peak vibration acceleration level of each floor of the superstructure property is concentrated at 10–20 Hz.The vibration response decreases in the high-frequency parts and increases in the lowfrequency parts with increasing distance from the source.Furthermore,the factors,such as train operating speed,operating mode,and hard combination type,will affect the vibration of the superstructure.The vibration response under the reversible operation of the train is greater than that of the unidirectional operation.The operating speed of the train is proportional to its vibration response.The vibration amplification area appears between the middle and the top of the superstructure at a higher train speed.Its vibration acceleration level will exceed the limit value of relevant regulations,and vibration-damping measures are required.Within the scope of application,this study provides some suggestions for constructing subway stations and superstructures.展开更多
Natural product-based drug combinations(NPDCs)present distinctive advantages in treating complex diseases.While high-throughput screening(HTS)and conventional computational methods have partially accelerated synergist...Natural product-based drug combinations(NPDCs)present distinctive advantages in treating complex diseases.While high-throughput screening(HTS)and conventional computational methods have partially accelerated synergistic drug combination discovery,their applications remain constrained by experimental data fragmentation,high costs,and extensive combinatorial space.Recent developments in artificial intelligence(AI),encompassing traditional machine learning and deep learning algorithms,have been extensively applied in NPDC identification.Through the integration of multi-source heterogeneous data and autonomous feature extraction,prediction accuracy has markedly improved,offering a robust technical approach for novel NPDC discovery.This review comprehensively examines recent advances in AI-driven NPDC prediction,presents relevant data resources and algorithmic frameworks,and evaluates current limitations and future prospects.AI methodologies are anticipated to substantially expedite NPDC discovery and inform experimental validation.展开更多
The lamina(combination)types,reservoir characteristics and shale oil occurrence states of organic-rich shale in the Triassic Yanchang Formation Chang 73 sub-member in the Ordos Basin were systematically investigated t...The lamina(combination)types,reservoir characteristics and shale oil occurrence states of organic-rich shale in the Triassic Yanchang Formation Chang 73 sub-member in the Ordos Basin were systematically investigated to reveal the main controlling factors of shale oil occurrence under different lamina combinations.The differential enrichment mechanisms and patterns of shale oil were discussed using the shale oil micro-migration characterization and evaluation methods from the perspectives of relay hydrocarbon supply,stepwise migration,and multi-stage differentiation.The results are obtained in five aspects.First,Chang 73 shale mainly develops five types of lamina combination,i.e.non-laminated shale,sandy laminated shale,tuffaceous laminated shale,mixed laminated shale,and organic-rich laminated shale.Second,shales with different lamina combinations are obviously different in the reservoir space.Specifically,shales with sandy laminae and tuffaceous laminae have a large number of intergranular pores,dissolution pores and hydrocarbon generation-induced fractures.The multi-scale pore and fracture system constitutes the main place for liquid hydrocarbon occurrence.Third,the occurrence and distribution of shale oil in shale with different lamina combinations are jointly controlled by organic matter abundance,reservoir property,thermal evolution degree,mineral composition and laminae scale.The micro-nano-scale pore-fracture networks within shales containing rigid laminae,particularly sandy and tuffaceous laminations,primarily contain free-state light hydrocarbon components.In contrast,adsorption-phase heavy hydrocarbon components predominantly occupy surfaces of organic matter assemblages,clay mineral matrices,and framework mineral particulates.Fourth,there is obvious shale oil micro-migration between shales with different lamina combinations in Chang 73.Generally,such micro-migration is stepwise in a sequence of organic-rich laminated shale→tuffaceous laminated shale→mixed laminated shale→sandy lamiated shale→non-laminated shale.Fifth,the relay hydrocarbon supply of organic matter under the control of the spatial superposition of shales with various laminae,the stepwise migration via multi-scale pore and fracture network,and the multi-differentiation in shales with different lamina combinations under the control of organic-inorganic interactions fundamentally decide the differences of shale oil components between shales with different lamina combinations.展开更多
Astragali Radix(AR), a traditional Chinese medicine(TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use.While doxorubicin serves as an effec...Astragali Radix(AR), a traditional Chinese medicine(TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use.While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy(DIC);however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action.Through network medicine analysis, astragaloside Ⅳ(AsⅣ) and formononetin(FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsⅣ-FMT combination(AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsⅣ and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α(PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.展开更多
Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease in...Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.展开更多
To tackle the difficulties of the point prediction in quantifying the reliability of landslide displacement prediction,a data-driven combination-interval prediction method(CIPM)based on copula and variational-mode-dec...To tackle the difficulties of the point prediction in quantifying the reliability of landslide displacement prediction,a data-driven combination-interval prediction method(CIPM)based on copula and variational-mode-decomposition associated with kernel-based-extreme-learningmachine optimized by the whale optimization algorithm(VMD-WOA-KELM)is proposed in this paper.Firstly,the displacement is decomposed by VMD to three IMF components and a residual component of different fluctuation characteristics.The key impact factors of each IMF component are selected according to Copula model,and the corresponding WOA-KELM is established to conduct point prediction.Subsequently,the parametric method(PM)and non-parametric method(NPM)are used to estimate the prediction error probability density distribution(PDF)of each component,whose prediction interval(PI)under the 95%confidence level is also obtained.By means of the differential evolution algorithm(DE),a weighted combination model based on the PIs is built to construct the combination-interval(CI).Finally,the CIs of each component are added to generate the total PI.A comparative case study shows that the CIPM performs better in constructing landslide displacement PI with high performance.展开更多
A later heading date generally leads to higher grain yield in favorable ecological regions;however,grain yield reaches a limit as the heading date exceeds a certain threshold.Ghd7 is the first cloned major gene that r...A later heading date generally leads to higher grain yield in favorable ecological regions;however,grain yield reaches a limit as the heading date exceeds a certain threshold.Ghd7 is the first cloned major gene that regulates heading date,plant height and grain number.Here,we investigated the relationship between Ghd7 and florigen genes Hd3a and RFT1,to determine their roles in regulating heading date and grain number under different photoperiods.Our results revealed that under long-day(LD)conditions,Hd3a acts prior to RFT1 to promote heading while negatively regulating plant height and grain number.In contrast,Ghd7 positively regulates heading date,plant height,and grain number by inhibiting both Hd3a and RFT1.Under short-day(SD)conditions,the functions of Hd3a and RFT1 remain consistent with those under LD conditions,but Ghd7 does not inhibit their expression,resulting in a weaker phenotypic effect compared to Hd3a.Additionally,under both LD and SD conditions,increased Ghd7 expression enhances its inhibitory effect on Hd3a and RFT1,leading to later heading and increased grain number;however,once the heading date exceeds 94 d,grain number no longer increases.Moreover,the gn1a allele increased grain number by 16.5%to 42.5%,while combinations of the elite alleles from Ghd7,Hd3a,RFT1,and Gn1a significantly increased grain number by up to 240.9%.Therefore,we propose a new breeding strategy to optimize the heading date and grain number using the Ghd7Hd3aRFT1gn1a combination of Ghd7,Hd3a,RFT1,and Gn1a under LD conditions,and the Ghd7hd3aRFT1gn1a combination under SD conditions.This strategy improved the yield of the high-quality Northeast variety Kongyu 131(KY131)by 69.1%in Beijing and 93.7%in Hainan.This strategy will greatly improve the efficiency of north-to-south adaptation in rice,providing theoretical guidance for expanding the geographical adaptability of rice varieties.展开更多
BACKGROUND Chemotherapy combined with anti-angiogenic therapy has become an important strategy for the treatment of advanced gastric cancer(AGC);however,the regimen needs optimization.AIM To evaluate the efficacy of a...BACKGROUND Chemotherapy combined with anti-angiogenic therapy has become an important strategy for the treatment of advanced gastric cancer(AGC);however,the regimen needs optimization.AIM To evaluate the efficacy of albumin-bound paclitaxel(nab-ptx)combined with the small molecule vascular endothelial growth factor inhibitor anlotinib in secondline and beyond treatment of AGC.METHODS We collected data from AGC patients at our hospital who experienced disease progression after first-line chemotherapy and received anlotinib combined with nab-ptx.The primary endpoints included overall survival(OS)and progressionfree survival(PFS),while the secondary endpoints were objective response rate(ORR),disease control rate(DCR),and adverse events(AEs).RESULTS Preliminary results indicated that anlotinib combined with nab-ptx can provide significant efficacy in second-line or above treatment for AGC(median PFS=6.0 months,median OS=12.0 months),with an ORR of 42%and a DCR of 78%.Further analysis revealed that patients who experienced hypertension,proteinuria,and hand-foot syndrome during treatment had better efficacy compared to those who did not experience these AEs.Mechanistic studies suggest that this regimen likely exerts synergistic anti-tumor effects by activating the immune response through the reduction of regulatory T-cell proportions.Common adverse reactions included bone marrow suppression,peripheral neuropathy,hypertension,proteinuria,and hand-foot syndrome,which were manageable and resolved with appropriate interventions,indicating the promising application of this regimen in second-line or above treatment for AGC.CONCLUSION The combination of anlotinib and nab-ptx shows promising efficacy with fewer toxicities in AGC treatment.The regimen holds promise as a second-line treatment of AGC;however,its specific clinical value requires further research.展开更多
Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances m...Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances made in recent years with regard to immunotherapy in both basic research and clinical practice,there remains scope for further improvement,particularly with respect to its efficacy against solid tumors.With advancements in nanotechnology,tumor nanovaccines hold immense potential for preventing tumor recurrence and treating metastatic tumors.Nevertheless,the considerable heterogeneity of tumor immunogenicity presents a number of significant challenges in the development of nanometrescale vaccines targeting solid tumors.Recent findings indicate that immune checkpoint inhibitor(ICI)therapy can improve the immunosuppressive microenvironment within tumors,while nanovaccines can also augment tumor sensitivity toward ICIs.Consequently,combining tumor nanovaccine with ICI therapy holds promise for effectively eradicating tumors or controlling their recurrence and metastasis during cancer treatment.This review delves into the mechanism behind combining tumor nanovaccine with ICI while focusing on factors influencing this combined therapy approach.Moreover,it offers an overview of the current research status regarding the combination of tumor nanovaccines with chemotherapy,radiotherapy,photothermal therapy,and sonodynamic therapy,as well as prospects for future developments in this field.展开更多
Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.Howe...Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.展开更多
Recently,Choe-Koo-Wang(J Funct Anal,2020,278)demonstrated the rigid phenomenon:The compact linear combination of composition operators under the Coefficient Non-cancellation Condition(CNC),implies that each difference...Recently,Choe-Koo-Wang(J Funct Anal,2020,278)demonstrated the rigid phenomenon:The compact linear combination of composition operators under the Coefficient Non-cancellation Condition(CNC),implies that each difference is compact on the weighted Bergman space in the unit disk.Motivated by the subtle connection of composition operator theory on the weighted Bergman spaces,Korenblum spaces and bounded holomorphic function spaces,we first explore the rigid phenomenon which also holds on the Korenblum space over the unit ball.Furthermore,we discuss which difference of composition operators is compact when the compact combination of composition operators does not satisfy the condition(CNC)on Korenblum spaces and bounded holomorphic function spaces over the unit ball setting.展开更多
文摘Obtaining the target blood pressure level by monotherapy can be challenging currently,especially for the patients who are suffering from other diseases meanwhile.It is demonstrated that a majority of hypertensive patients need two or more antihypertensive drugs to lower their blood pressure effectively.Consequently,fixed-dose which can be defined as that several active agents were combined in single pharmaceutical formulations appears to be a novel and underlying power in overcoming the cardiovascular disease.Based on the analysis of some literature and relative data from FDA,the advantages of fixed-dose combination are elucidated and formulations of common dual,triple-combinations were summarized.Clinical practices proved that fixed-dose combinations had many benefits comparing with single drug and separate agents in terms of effects,convenience,compliance,and costs to a certain extent.From the patients’perspective,the fixed-dose combination therapy will be increasingly utilized in blood pressure control in the future.
文摘isTraditional Chinese medicine(TCM)is a highly complex chemical substance system,which not only reflected in the complexity of the chemical components and their interrelationships,but also in the intricacy of the prescription’s connection with the human body.Component compatibility strategy has been proposed for developing modern TCM since 2005 and established comprehensive relevant technologies and research approaches.Moreover,to meet the safety and efficacy of current pharmaceuticals,research on fixed-dose combination drugs is directed by modern scientific theories,conforms to TCM compatibility principles and clarifies material basis and pharmacological mechanisms and component-effect correlations.This review summarized gaps and feasibility of fixed-dose combination strategy in the development of modern TCM research and assessed their advantages and disadvantages in light of contemporary drug combination research practices.
文摘Amlodipine/valsartan(Aml/Val)single-pill combination(SPC)therapy has been widely used and studied in clinical practice in recent years.This article reviews the Chinese and English literature on the clinical use of Aml/Val SPC therapy in Chinese hypertensive patients.According to five studies concerning the efficacy and safety of this treatment,Aml/Val SPC therapy was more efficacious than monotherapy with valsartan,amlodipine,or the nifedipine gastrointestinal therapeutic system.This treatment showed greater blood pressure-lowering effects,a higher blood pressure control rate,and a higher response rate.Aml/Val SPC treatment was well tolerated,with adverse event rates similar to those of monotherapy with valsartan or amlodipine and significantly rarer adverse events compared with the nifedipine gastrointestinal therapeutic system.Aml/Val SPC is a highly efficacious and well-tolerated antihypertensive treatment in Chinese hypertensive patients.
文摘Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.
基金National Key R&D Program of China(2023YFC-2308300,2022YFC2305200)High-Level Public Health Specialized Talents Project of Beijing Municipal Health Commission(2022-2-018)+2 种基金Beijing Key Laboratory for HIV/AIDS Research(BZ0089)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX24_0484)SEU Innovation Capability Enhancement Plan for Doctoral Students(CXJH_SEU 24042)
文摘Integrase Strand Transfer Inhibitors(INSTIs)have favorable safety and tolerability profiles,potent antiviral activity,and high resistance barriers,solving the limitations of previous antiretrovirals caused by resistant mutations.While first-generation INSTIs have exhibited emerging resistance challenges during extended clinical use,second-generation INSTIs provide enhanced resistance barriers and extended plasma half-lives relative to their predecessors.Optimized combination regimens incorporating these agents have substantially improved therapeutic convenience and long-term disease management in human immunodeficiency virus(HIV)care.Current investigations focus on multiple combination strategies employing second-generation INSTIs including dolutegravir(DTG)and bictegravir(BIC),with preliminary findings demonstrating substantial clinical benefits.The DTG/lamivudine(3TC)dual regimen in the GEMINI and TANGO studies achieved 92.1%–99.6%virologic suppression rates at week 48,maintaining efficacy through 144 weeks.The cabotegravir(CAB)/Rilpivirine(RPV)long-acting injectable combination in ATLAS trials demonstrated 92.5%suppression efficacy with validated every-two-month dosing intervals.The BIC/emtricitabine/tenofovir alafenamide triple regimen in studies 1489/1490 maintained>84%suppression at week 144 while retaining activity against resistant variants.Real-world data confirm that these regimens maintained a viral suppression rate of>90%in both treatment-na?ve and-experienced patients,with treatment interruption rates of<5%.Recent advances include the US Food and Drug Administration's approval of DTG/3TC for use in adolescents≥12 years old and adaptive studies of CAB/RPV in special populations.This article summarizes the research progress of current combination formulations based on second-generation INSTIs to provide new therapeutic options and clinical insights for the treatment of patients with HIV.
文摘Background：Decreases in the bioavailability of rifampicin （RFP） can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination （FDC; formulation A） and three two-drug FDCs （formulations B,C,and D） used in China,compared with RFP in free combinations of these drugs （reference）,in healthy volunteers.Methods：Eighteen and twenty healthy Chinese male volunteers participated in two open-label,randomized two-period crossover （formulations A and C） or one three-period crossover （formulations B and D） study,respectively.The washout period between treatments was 7 days.Bioequivalence was assessed based on 90％ confidence intervals,according to two one-sided t-tests.All analyses were done with DAS 3.1.5 （Mathematical Pharmacology Professional Committee of China,Shanghai,China）.Results：Mean pharmacokinetic parameter values of RFP obtained for formulations A,B,C,and D products were 11.42 ± 3.41 μg/ml,7.86 ± 5.78 μg/ml,13.05 ± 6.80 μg/ml,and 16.18 ± 3.87 μg/ml,respectively,for peak plasma concentration （Cmax）,91.43± 30.82 μg·h-1 ·ml-1,55.49 ± 37.58 μg·h-1·ml-1,96.50 ± 47.24 μg·h-1·ml-1,101.47 ± 33.07 μg·h-1·ml-1,respectively,for area under the concentration-time curve （AUC0-2,4 h）.Conclusions：Although the concentrations of RFP for formulations A,C,and D were within the reported acceptable therapeutic range,only formulation A was bioequivalent to the reference product.The three two-drug FDCs （formulations B,C and D） displayed inferior RFP bioavailability compared with the reference （Chinese Clinical Trials registration number：ChiCTR-TTRCC-12002451）.
文摘Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2].Non-adherence is a serious problem linked to worsening symptoms and increased motor fluc-tuations[3-5].Levodopa(LD)remains the most effective treatment for PD[6].However,a single dosing treatment is only effective in the early phase of the disease.In the severe phase,4-5 years after diagnosis,the therapeutic window of dopamine becomes narrow,and due to its short half-life of between 0.7 and 1.4 h dosing of LD will be required every 2 h[7-9].One way to ameliorate this issue is to co-admin-ister LD with carbidopa(CD),which can increase LD’s oral bioavailability to 40-70%[10].
基金supported by the Shaanxi Qinchuang Yuan“scientist+engineer”team construction(No.2023KXJ-080)Shaanxi Chiral Drug Engineering Technology Research Center(Department of Science and Technology of Shaanxi Province.No.[2011]-251).
文摘Background:Human skin is affected by ultraviolet rays on a daily basis,and excessive ultraviolet radiation(UVR)can lead to sunburn erythema,tanning,photoaging,and skin tumors.The combination of Astragali Radix(AR)and Anemarrhenae Rhizoma(AAR)is a common pairing in traditional Chinese medicine(TCM).According to earlier studies,they possess properties capable of alleviating the adverse impacts of UVR on the skin.However,the specific actions and underlying mechanisms require further investigation.The study aims to analyze the efficacy of AR-AAR in preventing UVR-induced skin damage and to clarify the associated molecular mechanisms.Methods:Potential signaling pathways by which AR and AAR may protect against UVR-induced skin damage were identified with network pharmacology,molecular docking techniques and molecular dynamics(MD)simulation.Except the normal group,the back skin of SD rats was exposed to 1.1 mW/cm^(2) UVA combined with 0.1 mW/cm^(2) UVB daily,and the UVR skin damage model was established.Morphological features of skin tissues of different groups were discovered through Hematoxylin and Eosin(HE)staining,Masson staining,Weigert staining.ELISA was utilized to measure the levels of reactive oxygen species(ROS),Interleukin 6(IL-6),Interleukin 1β(IL-1β)and Tumor necrosis factos-α(TNF-α)in skin tissues.RT-PCR and Western blot were employed to quantify the mRNA and protein contents of PI3K,AKT,and MMP-9.Results:Network pharmacology analysis predicts that AR-AAR may improve skin damage induced by UVR through the PI3K/AKT signaling pathway.Histological staining shows that AR-AAR can significantly reduce inflammatory infiltration and fibrosis in damaged skin.Treatment with AR-AAR(2:1)significantly reduced the expression levels of IL-1β,IL-6,TNF-αand ROS in UVR-damaged rat skin.After treatment with AR-AAR(2:1),not only did the relative mRNA expression levels of PI3K and AKT and the protein expression levels of PI3K,AKT,P-PI3K,and P-AKT increase,but the mRNA and protein expression levels of MMP-9 decreased.Conclusion:The study indicate that the AR-AAR combination and its active components may mitigate UVR skin damage by modulating the PI3K/AKT signaling pathway.
基金supported by the National Natural Science Foundation(32130068,32271634,and 32071597)CAS Key Laboratory of Forest Ecology and Silviculture,Institute of Applied Ecology,Chinese Academy of Sciences(KLFES-2025)。
文摘Urban forests are highly multifunctional and provide numerous ecological functions.Plant functional traits individually or jointly influence the ecological multifunctionality of tree species(TS-EMF)and can also modify TSEMF in response to environmental changes.However,there has been limited exploration of multitrait combinations for predicting TS-EMF across seasons and of trait thresholds that enhance TS-EMF.Here,for 10 dominant tree species in urban forests of Northeast China,14 traits were measured and four aboveground and three belowground ecological functions assessed in three seasons.Ecological functions and TS-EMF differed significantly throughout the seasons(P<0.05).Synergistic relationships were found between carbon sequestration and oxygen release,between cooling and humidification,and between organic carbon accumulation and nutrient cycling.Notably,aboveground multifunctionality played a leading role in TS-EMF.With seasonal changes,resource allocation shifted toward traits related to resource acquisition rather than conservation to maintain TS-EMF.The combination of traits that predicted TS-EMF varied by type,accounting for up to 66.45%of the variation.TS-EMF was primarily driven by leaf structure in spring and by nutrient accumulation in autumn.Leaf carbon content(LCC)consistently served as a stabilizing factor for predicting TS-EMF across seasons.At 36.5-36.8 mg g^(-1),LCC had its optimal effect on TS-EMF.Other traits in combination that positively influence total TS-EMF include leaf nitrogen content(3.43-3.45 mg g^(-1)),leaf phosphorus content(0.80-0.83 mg g^(-1)),and leaf area(65.86-68.43 cm^(2)).Within these specified trait thresholds,Morus alba and Quercus mongolica were identified as key species.These findings suggest that the trade-off between various ecological functions can be managed by altering plant traits across seasons.This approach could provide a theoretical foundation for enhancing the TS-EMF of urban forests through trait-based management,offering practical guidance for selecting tree species.
基金National Natural Science Foundation of China under Grant No.51578463。
文摘The vibration response and noise caused by subway trains can affect the safety and comfort of superstructures.To study the dynamic response characteristics of subway stations and superstructures under train loads with a hard combination,a numerical model is developed in this study.The indoor model test verified the accuracy of the numerical model.The influence laws of different hard combinations,train operating speeds and modes were studied and evaluated accordingly.The results show that the frequency corresponding to the peak vibration acceleration level of each floor of the superstructure property is concentrated at 10–20 Hz.The vibration response decreases in the high-frequency parts and increases in the lowfrequency parts with increasing distance from the source.Furthermore,the factors,such as train operating speed,operating mode,and hard combination type,will affect the vibration of the superstructure.The vibration response under the reversible operation of the train is greater than that of the unidirectional operation.The operating speed of the train is proportional to its vibration response.The vibration amplification area appears between the middle and the top of the superstructure at a higher train speed.Its vibration acceleration level will exceed the limit value of relevant regulations,and vibration-damping measures are required.Within the scope of application,this study provides some suggestions for constructing subway stations and superstructures.
基金supported by National Natural Science Foundation of China(Nos.82404511,82373790)Central Guidance on Local Science and Technology Development Fund of Hebei Province(No.226Z2605G)Program for Young Scientists in the Field of Natural Science of Hebei Medical University(No.CYCZ2023011).
文摘Natural product-based drug combinations(NPDCs)present distinctive advantages in treating complex diseases.While high-throughput screening(HTS)and conventional computational methods have partially accelerated synergistic drug combination discovery,their applications remain constrained by experimental data fragmentation,high costs,and extensive combinatorial space.Recent developments in artificial intelligence(AI),encompassing traditional machine learning and deep learning algorithms,have been extensively applied in NPDC identification.Through the integration of multi-source heterogeneous data and autonomous feature extraction,prediction accuracy has markedly improved,offering a robust technical approach for novel NPDC discovery.This review comprehensively examines recent advances in AI-driven NPDC prediction,presents relevant data resources and algorithmic frameworks,and evaluates current limitations and future prospects.AI methodologies are anticipated to substantially expedite NPDC discovery and inform experimental validation.
基金Supported by the National Natural Science Foundation of China(42302184)Innovation Group Project of Basic Research in Gansu Province,China(22JR5RA045)。
文摘The lamina(combination)types,reservoir characteristics and shale oil occurrence states of organic-rich shale in the Triassic Yanchang Formation Chang 73 sub-member in the Ordos Basin were systematically investigated to reveal the main controlling factors of shale oil occurrence under different lamina combinations.The differential enrichment mechanisms and patterns of shale oil were discussed using the shale oil micro-migration characterization and evaluation methods from the perspectives of relay hydrocarbon supply,stepwise migration,and multi-stage differentiation.The results are obtained in five aspects.First,Chang 73 shale mainly develops five types of lamina combination,i.e.non-laminated shale,sandy laminated shale,tuffaceous laminated shale,mixed laminated shale,and organic-rich laminated shale.Second,shales with different lamina combinations are obviously different in the reservoir space.Specifically,shales with sandy laminae and tuffaceous laminae have a large number of intergranular pores,dissolution pores and hydrocarbon generation-induced fractures.The multi-scale pore and fracture system constitutes the main place for liquid hydrocarbon occurrence.Third,the occurrence and distribution of shale oil in shale with different lamina combinations are jointly controlled by organic matter abundance,reservoir property,thermal evolution degree,mineral composition and laminae scale.The micro-nano-scale pore-fracture networks within shales containing rigid laminae,particularly sandy and tuffaceous laminations,primarily contain free-state light hydrocarbon components.In contrast,adsorption-phase heavy hydrocarbon components predominantly occupy surfaces of organic matter assemblages,clay mineral matrices,and framework mineral particulates.Fourth,there is obvious shale oil micro-migration between shales with different lamina combinations in Chang 73.Generally,such micro-migration is stepwise in a sequence of organic-rich laminated shale→tuffaceous laminated shale→mixed laminated shale→sandy lamiated shale→non-laminated shale.Fifth,the relay hydrocarbon supply of organic matter under the control of the spatial superposition of shales with various laminae,the stepwise migration via multi-scale pore and fracture network,and the multi-differentiation in shales with different lamina combinations under the control of organic-inorganic interactions fundamentally decide the differences of shale oil components between shales with different lamina combinations.
基金supported by the National Natural Science Foundation of China(No.82173947).
文摘Astragali Radix(AR), a traditional Chinese medicine(TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use.While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy(DIC);however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action.Through network medicine analysis, astragaloside Ⅳ(AsⅣ) and formononetin(FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsⅣ-FMT combination(AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsⅣ and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α(PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.
基金supported by grants from the National Natural Science Foundation of China(U21A20400,81973789,82004327).
文摘Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.
基金financially supported by the National Natural Science Foundation of China(Nos.42277149,41502299,41372306)the Research Planning of Sichuan Education Department,China(No.16ZB0105)+3 种基金the State Key Laboratory of Geohazard Prevention and Geoenvironment Protection Independent Research Project(Nos.SKLGP2016Z007,SKLGP2018Z017,SKLGP2020Z009)Chengdu University of Technology Young and Middle Aged Backbone Program(No.KYGG201720)Sichuan Provincial Science and Technology Department Program(No.19YYJC2087)China Scholarship Council。
文摘To tackle the difficulties of the point prediction in quantifying the reliability of landslide displacement prediction,a data-driven combination-interval prediction method(CIPM)based on copula and variational-mode-decomposition associated with kernel-based-extreme-learningmachine optimized by the whale optimization algorithm(VMD-WOA-KELM)is proposed in this paper.Firstly,the displacement is decomposed by VMD to three IMF components and a residual component of different fluctuation characteristics.The key impact factors of each IMF component are selected according to Copula model,and the corresponding WOA-KELM is established to conduct point prediction.Subsequently,the parametric method(PM)and non-parametric method(NPM)are used to estimate the prediction error probability density distribution(PDF)of each component,whose prediction interval(PI)under the 95%confidence level is also obtained.By means of the differential evolution algorithm(DE),a weighted combination model based on the PIs is built to construct the combination-interval(CI).Finally,the CIs of each component are added to generate the total PI.A comparative case study shows that the CIPM performs better in constructing landslide displacement PI with high performance.
基金supported by grants from the Chinese Academy of Sciences(XDA24010101)the Biological Breeding-National Science and Technology Major Project(2024ZD04077)+2 种基金the National Key Research and Development Program of China(2023YFF1001200)Natural Science Foundation of Zhejiang Province(LD24C130001)the Agricultural Science and Technology Innovation Program(ASTIP)of CAAS。
文摘A later heading date generally leads to higher grain yield in favorable ecological regions;however,grain yield reaches a limit as the heading date exceeds a certain threshold.Ghd7 is the first cloned major gene that regulates heading date,plant height and grain number.Here,we investigated the relationship between Ghd7 and florigen genes Hd3a and RFT1,to determine their roles in regulating heading date and grain number under different photoperiods.Our results revealed that under long-day(LD)conditions,Hd3a acts prior to RFT1 to promote heading while negatively regulating plant height and grain number.In contrast,Ghd7 positively regulates heading date,plant height,and grain number by inhibiting both Hd3a and RFT1.Under short-day(SD)conditions,the functions of Hd3a and RFT1 remain consistent with those under LD conditions,but Ghd7 does not inhibit their expression,resulting in a weaker phenotypic effect compared to Hd3a.Additionally,under both LD and SD conditions,increased Ghd7 expression enhances its inhibitory effect on Hd3a and RFT1,leading to later heading and increased grain number;however,once the heading date exceeds 94 d,grain number no longer increases.Moreover,the gn1a allele increased grain number by 16.5%to 42.5%,while combinations of the elite alleles from Ghd7,Hd3a,RFT1,and Gn1a significantly increased grain number by up to 240.9%.Therefore,we propose a new breeding strategy to optimize the heading date and grain number using the Ghd7Hd3aRFT1gn1a combination of Ghd7,Hd3a,RFT1,and Gn1a under LD conditions,and the Ghd7hd3aRFT1gn1a combination under SD conditions.This strategy improved the yield of the high-quality Northeast variety Kongyu 131(KY131)by 69.1%in Beijing and 93.7%in Hainan.This strategy will greatly improve the efficiency of north-to-south adaptation in rice,providing theoretical guidance for expanding the geographical adaptability of rice varieties.
基金Supported by Natural Science Foundation of Hubei Province,No.2019CFC929.
文摘BACKGROUND Chemotherapy combined with anti-angiogenic therapy has become an important strategy for the treatment of advanced gastric cancer(AGC);however,the regimen needs optimization.AIM To evaluate the efficacy of albumin-bound paclitaxel(nab-ptx)combined with the small molecule vascular endothelial growth factor inhibitor anlotinib in secondline and beyond treatment of AGC.METHODS We collected data from AGC patients at our hospital who experienced disease progression after first-line chemotherapy and received anlotinib combined with nab-ptx.The primary endpoints included overall survival(OS)and progressionfree survival(PFS),while the secondary endpoints were objective response rate(ORR),disease control rate(DCR),and adverse events(AEs).RESULTS Preliminary results indicated that anlotinib combined with nab-ptx can provide significant efficacy in second-line or above treatment for AGC(median PFS=6.0 months,median OS=12.0 months),with an ORR of 42%and a DCR of 78%.Further analysis revealed that patients who experienced hypertension,proteinuria,and hand-foot syndrome during treatment had better efficacy compared to those who did not experience these AEs.Mechanistic studies suggest that this regimen likely exerts synergistic anti-tumor effects by activating the immune response through the reduction of regulatory T-cell proportions.Common adverse reactions included bone marrow suppression,peripheral neuropathy,hypertension,proteinuria,and hand-foot syndrome,which were manageable and resolved with appropriate interventions,indicating the promising application of this regimen in second-line or above treatment for AGC.CONCLUSION The combination of anlotinib and nab-ptx shows promising efficacy with fewer toxicities in AGC treatment.The regimen holds promise as a second-line treatment of AGC;however,its specific clinical value requires further research.
基金financially supported by the Key Scientific Research Project of Henan Provincial Universities in 2024(No.24A350013)the Project of Basic Research Fund of Henan Institute of Medical and Pharmaceutical Sciences(No.2024BP0202)+1 种基金the Key Scientific and Technological Project of Henan Province(No.242102311213)the Henan Province Postdoctoral Program(No.343915)。
文摘Cancer remains one of the major threats to public health.Traditional chemotherapy,radiotherapy,and other anti-tumor therapies have numerous limitations in clinical treatment.Notwithstanding the considerable advances made in recent years with regard to immunotherapy in both basic research and clinical practice,there remains scope for further improvement,particularly with respect to its efficacy against solid tumors.With advancements in nanotechnology,tumor nanovaccines hold immense potential for preventing tumor recurrence and treating metastatic tumors.Nevertheless,the considerable heterogeneity of tumor immunogenicity presents a number of significant challenges in the development of nanometrescale vaccines targeting solid tumors.Recent findings indicate that immune checkpoint inhibitor(ICI)therapy can improve the immunosuppressive microenvironment within tumors,while nanovaccines can also augment tumor sensitivity toward ICIs.Consequently,combining tumor nanovaccine with ICI therapy holds promise for effectively eradicating tumors or controlling their recurrence and metastasis during cancer treatment.This review delves into the mechanism behind combining tumor nanovaccine with ICI while focusing on factors influencing this combined therapy approach.Moreover,it offers an overview of the current research status regarding the combination of tumor nanovaccines with chemotherapy,radiotherapy,photothermal therapy,and sonodynamic therapy,as well as prospects for future developments in this field.
基金Supported by National Natural Science Foundation of China,No.32270768,No.82273970,No.32070726 and No.82370715Hubei Natural Science Foundation of China,No.2024AFB218+1 种基金National Key R&D Program of China,No.2023YFC2507904Doctoral Startup Foundation of Hubei University of Technology,No.XJ2022003901.
文摘Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.
基金supported by National Science Foundations of China(Grant No.11771340,12171373).
文摘Recently,Choe-Koo-Wang(J Funct Anal,2020,278)demonstrated the rigid phenomenon:The compact linear combination of composition operators under the Coefficient Non-cancellation Condition(CNC),implies that each difference is compact on the weighted Bergman space in the unit disk.Motivated by the subtle connection of composition operator theory on the weighted Bergman spaces,Korenblum spaces and bounded holomorphic function spaces,we first explore the rigid phenomenon which also holds on the Korenblum space over the unit ball.Furthermore,we discuss which difference of composition operators is compact when the compact combination of composition operators does not satisfy the condition(CNC)on Korenblum spaces and bounded holomorphic function spaces over the unit ball setting.
