Advanced glycation end products in gastric cancer:A promising future

In this editorial,we delve into the article and offer valuable insights into a crucial aspect of gastric cancer aetiology.Gastric cancer is a malignancy emanating from the epithelial lining of the gastric mucosa and one of the most prevalent forms of cancer worldwide.The development of gastric cancer is associated with multiple risk factors,including Helicobacter pylori infection,advanced age,a diet rich in salt,and suboptimal eating patterns.Despite notable reductions in morbidity and mortality rates,gastric cancer remains a formidable public health concern,impacting patients’lives.Advanced glycation end products(AGEs)are complex compounds arising from nonenzymatic reactions within living organisms,the accumulation of which is implicated in cellular and tissue damage;thus,the levels are AGEs are correlated with the risk of diverse diseases.The investigation of AGEs is of paramount importance for the treatment of gastric cancer and can provide pivotal insights into disease pathogenesis and preventive and therapeutic strategies.The reduction of AGEs levels and suppression of their accumulation are promising avenues for mitigating the risk of gastric cancer.This approach underscores the need for further research aimed at identifying innovative interventions that can effectively lower the incidence and mortality rates of this malignancy.

High glucose reduces Nrf2-dependent cRAGE release and enhances inflammasome-dependent IL-1βproduction in monocytes:the modulatory effects of EGCG

Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.

Advanced glycation end products:Key mediator and therapeutic target of cardiovascular complications in diabetes

The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns.Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality.The cardiovascular diseases that accompany diabetes include angina,myocardial infarction,stroke,peripheral artery disease,and congestive heart failure.Among the various risk factors generated secondary to hyperglycemic situations,advanced glycation end products(AGEs)are one of the important targets for future diagnosis and prevention of diabetes.In the last decade,AGEs have drawn a lot of attention due to their involvement in diabetic pathophysiology.AGEs can be derived exogenously and endogenously through various pathways.These are a nonhomogeneous,chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein,lipids,and nucleic acid.AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways.At the cellular level,they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation,inflammation,cellular proliferation,and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics.AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins;altering their structure,stability,and functions.Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities.In the present review,we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications.Furthermore,this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.

融合BlendMask的机械手臂抓取位姿估计模型

针对复杂场景抓取位姿估计速度慢、精度低的问题,基于BlendMask实例分割网络,结合实例分割与抓取位姿估计,设计了一种端到端的机械手臂抓取位姿估计深度模型GPNet。该模型首先依据图像2D信息,在BlendMask网络中增加抓取中心、抓取主方向估计分支,提升抓取位姿估计速度;其次采用霍夫投票获取抓取中心及主方向,提高了2D抓取位姿估计的精度与鲁棒性;然后采用椭圆筛选机制,有效地解决了由圆形物体任意性对抓取主方向估计的干扰;最后依据新的损失函数训练GPNet,并结合图像深度信息获得最终抓取位姿信息。以中国信息通信研究院工业互联网平台、工业和信息化部重点实验室抓取实验场景为对象进行抓取速度与精度验证,以9种物体为抓取目标,结果表明在平均每个场景6种抓取目标实例且有干扰物体遮挡的复杂场景下,所提模型位姿估计平均速度达到0.057 s,平均抓取成功率达到90.2%。

End-group modulation of phenazine based non-fullerene acceptors for efficient organic solar cells with high open-circuit voltage

Phenazine-based non-fullerene acceptors(NFAs)have demonstrated great potential in improving the power conversion efficiency(PCE)of organic solar cells(OSCs).Halogenation is known to be an effective strategy for increasing optical absorption,refining energy levels,and improving molecular packing in organic semiconductors.Herein,a series of NFAs(Pz IC-4H,Pz IC-4F,Pz IC-4Cl,Pz IC-2Br)with phenazine as the central core and with/without halogen-substituted(dicyanomethylidene)-indan-1-one(IC)as the electron-accepting end group were synthesized,and the effect of end group matched phenazine central unit on the photovoltaic performance was systematically studied.Synergetic photophysical and morphological analyses revealed that the PM6:Pz IC-4F blend involves efficient exciton dissociation,higher charge collection and transfer rates,better crystallinity,and optimal phase separation.Therefore,OSCs based on PM6:Pz IC-4F as the active layer exhibited a PCE of 16.48%with an open circuit voltage(Voc)and energy loss of 0.880 V and 0.53 e V,respectively.Accordingly,this work demonstrated a promising approach by designing phenazine-based NFAs for achieving high-performance OSCs.

MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.

Effect of Bogie Cavity End Wall Inclination on Flow Field and Aerodynamic Noise in the Bogie Region of High-Speed Trains

Combining the detached eddy simulation(DES)method and Ffowcs Williams-Hawkings(FW-H)equation,the effect of bogie cavity end wall inclination on the flow field and aerodynamic noise in the bogie region is numerically studied.First,the simulation is conducted based on a simplified cavity-bogie model,including five cases with different inclination angles of the front and rear walls of the cavity.By comparing and analyzing the flow field and acoustic results of the five cases,the influence of the regularity and mechanism of the bogie cavity end wall inclination on the flow field and the aerodynamic noise of the bogie region are revealed.Then,the noise reduction strategy determined by the results of the simplified cavity-bogie model is applied to a three-car marshaling train model to verify its effectiveness when applied to the real train.The results reveal that the forward inclination of the cavity front wall enlarges the influence area of shear vortex structures formed at the leading edge of the cavity and intensifies the interaction between the vortex structures and the front wheelset,frontmotor,and front gearbox,resulting in the increase of the aerodynamic noise generated by the bogie itself.The backward inclination of the cavity rear wall is conducive to guiding the vortex structures flow out of the cavity and weakening the interaction between the shear vortex structures and the cavity rear wall,leading to the reduction of the aerodynamic noise generated by the bogie cavity.Inclining the rear end wall of the foremost bogie cavity of the head car is a feasible aerodynamic noise reduction measure for high-speed trains.

Molecular packing tuning via chlorinated end group enables efficient binary organic solar cells over 18.5%

Designing novel nonfullerene acceptors(NFAs)is of vital importance for the development of organic solar cells(OSC).Modification on the side chain and end group are two powerful tools to construct efficient NFAs.Here,based on the high-performance L8BO,we selected 3-ethylheptyl to substitute the inner chain of 2-ethylhexyl,obtaining the backbone of BON3.Then we introduced different halogen atoms of fluorine and chlorine on 2-(3-oxo-2,3-dihydro-1Hinden-1-ylidene)malononitrile end group(EG)to construct efficient NFAs named BON3-F and BON3-Cl,respectively.Polymer donor D18 was chosen to combine with two novel NFAs to construct OSC devices.Impressively,D18:BON3-Cl-based device shows a remarkable power conversion efficiency(PCE)of 18.57%,with a high open-circuit voltage(V_(OC))of 0.907 V and an excellent fill factor(FF)of 80.44%,which is one of the highest binary PCE of devices based on D18 as the donor.However,BON3-F-based device shows a relatively lower PCE of 17.79%with a decreased FF of 79.05%.The better photovoltaic performance is mainly attributed to the red-shifted absorption,higher electron and hole mobilities,reduced charge recombination,and enhanced molecular packing in the D18:BON3-Cl films.Also,we performed stability tests on two binary systems;the D18:BON3-Cl and D18:BON3-F devices maintain 88.1%and 85.5%of their initial efficiencies after 169 h of storage at 85°C in an N2-filled glove box,respectively.Our work demonstrates the importance of selecting halogen atoms on EG and provides an efficient binary system of D18:BON3-Cl for further improvement of PCE.

Regulatory role of peroxynitrite in advanced glycation end products mediated diabetic cardiovascular complications

The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.

Prognostic value of neutrophil-to-lymphocyte ratio in end-stage liver disease:A meta-analysis

BACKGROUND The neutrophil-to-lymphocyte ratio(NLR)is commonly utilized as a prognostic indicator in end-stage liver disease(ESLD),encompassing conditions like liver failure and decompensated cirrhosis.Nevertheless,some studies have contested the prognostic value of NLR in ESLD.AIM To investigate the ability of NLR to predict ESLD.METHODS Databases,such as Embase,PubMed,Web of Science,Cochrane Library,China National Knowledge Infrastructure,Weipu,and Wanfang,were comprehensively searched to identify studies published before October 2022 assessing the prognostic ability of NLR to predict mortality in patients with ESLD.Effect sizes were calculated using comprehensive meta-analysis software and SATAT 15.1.RESULTS A total of thirty studies involving patients with end-stage liver disease(ESLD)were included in the evaluation.Among the pooled results of eight studies,it was observed that the Neutrophil-to-Lymphocyte Ratio(NLR)was significantly higher in non-survivors compared to survivors(random-effects model:standardized mean difference=1.02,95%confidence interval=0.67-1.37).Additionally,twenty-seven studies examined the associations between NLR and mortality in ESLD patients,reporting either hazard ratios(HR)or odds ratios(OR).The combined findings indicated a link between NLR and ESLD mortality(randomeffects model;univariate HR=1.07,95%CI=1.05-1.09;multivariate HR=1.07,95%CI=1.07-1.09;univariate OR=1.29,95%CI=1.18-1.39;multivariate OR=1.29,95%CI=1.09-1.49).Furthermore,subgroup and meta-regression analyses revealed regional variations in the impact of NLR on ESLD mortality,with Asian studies demonstrating a more pronounced effect.CONCLUSION Increased NLR in patients with ESLD is associated with a higher risk of mortality,particularly in Asian patients.NLR is a useful prognostic biomarker in patients with ESLD.

End-of-Pregnancy Monitoring at CHUMEFJE through the Functional Investigation Centre (FIC) in 2022

Introduction: The end of pregnancy is a high-risk period for both mother and foetus. Rigorous monitoring can prevent complications before delivery. Materials and Method: We conducted a descriptive cross-sectional observational study. It took place in the delivery room of the Teacher hospital Mother and Child of Jeanne Ebori Fondation from the 01 October 2020 to 01 October 2021. All patients followed at the Functional Investigation Centre (FIC) of the CHUMEFJE and who gave birth in that same hospital were included. Data were collected on the basis of pregnancy diaries, the fic register and delivery room registers. They were analysed using SPSS Statistical Software. Results: During the period of our study, 4086 parturients arrived in the delivery room. Of these, 150 were followed up at the FIC, giving a prevalence of 3.7%. The majority of parturients (48%) had only one prenatal contact. 6 (4%) patients underwent pelvic scans, and 4 (2.6%) presented with a narrowed pelvis. A vaginal delivery was performed in 80% of cases, and of the caesarean sections, 9 (30%) could be scheduled. The maternal prognosis was marred by one post-partum complication of hypertension, and newborns with poor adaptation to life outside the womb accounted for 3.3% of cases. Conclusion: The Functional Investigation Centre makes it possible to detect anomalies at the end of pregnancy with a view to better planning of delivery.

融合Dead-ends和离线监督Actor-Critic的动态治疗策略生成模型

强化学习对数学模型依赖性低,利用经验便于架构和优化模型,非常适合用于动态治疗策略学习。但现有研究仍存在以下问题:1)学习策略最优性的同时未考虑风险,导致学到的策略存在一定的风险;2)忽略了分布偏移问题,导致学到的策略与医生策略完全不同;3)忽略患者的历史观测数据和治疗史,从而不能很好地得到患者状态,进而导致不能学到最优策略。基于此,提出了融合Dead-ends和离线监督Actor-Critic的动态治疗策略生成模型DOSAC-DTR。首先,考虑学到的策略所推荐的治疗行动的风险性,在Actor-Critic框架中融入Dead-ends概念;其次,为缓解分布偏移问题,在Actor-Critic框架中融入医生监督,在最大化预期回报的同时,最小化所学策略与医生策略之间的差距;最后,为了得到包含患者关键历史信息的状态表示,使用基于LSTM的编码器解码器模型对患者的历史观测数据和治疗史进行建模。实验结果表明,DOSAC-DTR相比基线方法有更好的性能,可以得到更低的估计死亡率以及更高的Jaccard系数。

Palliative care for end-stage liver disease and acute on chronic liver failure:A systematic review

BACKGROUND End stage liver disease(ESLD)represents a growing health concern characterized by elevated morbidity and mortality,particularly among individual ineligible for liver transplantation.The demand for palliative care(PC)is pronounced in patients grappling with ESLD and acute on chronic liver failure(ACLF).Unfortunately,the historical underutilization of PC in ESLD patients,despite their substantial needs and those of their family caregivers,underscores the imperative of seamlessly integrating PC principles into routine healthcare practices across the entire disease spectrum.AIM To comprehensively investigate the evidence surrounding the benefits of incorporating PC into the comprehensive care plan for individuals confronting ESLD and/or ACLF.METHODS A systematic search in the Medline(PubMed)database was performed using a predetermined search command,encompassing studies published in English without any restrictions on the publication date.Subsequently,the retrieved studies were manually examined.Simple descriptive analyses were employed to summarize the results.RESULTS The search strategies yielded 721 references.Following the final analysis,32 fulllength references met the inclusion criteria and were consequently incorporated into the study.Meticulous data extraction from these 32 studies was undertaken,leading to the execution of a comprehensive narrative systematic review.The review found that PC provides significant benefits,reducing symptom burden,depressive symptoms,readmission rates,and hospital stays.Yet,barriers like the appeal of transplants and misconceptions about PC hinder optimal utilization.Integrating PC early,upon the diagnosis of ESLD and ACLF,regardless of transplant eligibility and availability,improves the quality of life for these patients.CONCLUSION Despite the substantial suffering and poor prognosis associated with ESLD and ACLF,where liver transplantation stands as the only curative treatment,albeit largely inaccessible,PC services have been overtly provided too late in the course of the illness.A comprehensive understanding of PC's pivotal role in treating ESLD and ACLF is crucial for overcoming these barriers,involving healthcare providers,patients,and caregivers.

Investigation of Student Nurses’Attitudes towards End-of-Life Care and Their Influencing Factors

Background: This cross-sectional investigative study aimed to determine student nurses’ attitudes towards end-of-life care. Methods: This study used a descriptive research design with stratified sampling to survey student nurses enrolled in one of four nursing colleges in China from January 2023 to December 2023. Student nurses’ general demographic and prior related information, attitudes towards death and attitudes towards end-of-life care were determined using a general information questionnaire, the Death Attitude Profile—Revised scale and the Professional End-of-Life Attitude Scale (PEAS), respectively. Results: The total PEAS score was 122.91 ± 16.123. Significant differences were noted in the attitude towards end-of-life care scores according to sources of end-of-life care knowledge (P Conclusions: Student nurses lacked an optimistic attitude towards end-of-life care, which was influenced by differences in the sources of end-of-life care knowledge.

Bilateral pericapsular end nerve blocks for steroid-induced avascular necrosis following COVID-19 infection requiring bilateral total hip replacement

BACKGROUND Osteonecrosis or avascular necrosis(AVN)of the hip was one of the dreaded complications of coronavirus disease 2019(COVID-19),which emerged in patients who received steroid therapy.Corticosteroids have been a mainstay in the treatment protocol of COVID-19 patients.Popular corticosteroid drugs used in patients suffering from COVID-19 were intravenous(IV)or oral dexamethasone,methylprednisolone or hydrocortisone.The use of such high doses of corticost-eroids has shown very positive results and has been lifesaving in many cases.Still,long-term consequences were drug-induced diabetes,osteoporosis,Cushing syndrome,muscle wasting,peripheral fat mobilization,AVN,hirsutism,sleep disturbances and poor wound healing.A significant number of young patients were admitted for bilateral total hip replacements(THR)secondary to AVN following steroid use for COVID-19 treatment.AIM To assess the efficacy of bilateral pericapsular end nerve group(PENG)blocks in patients posted for bilateral THR post-steroid therapy after COVID-19 infection and assess the time taken to first ambulate after surgery.METHODS This prospective observational study was conducted between January 2023 and August 2023 at Care Hospitals,Hyderabad,India.Twenty young patients 30-35 years of age who underwent bilateral THR were studied after due consent over 8 months.All the patients received spinal anaesthesia for surgery and bilateral PENG blocks for postoperative analgesia.RESULTS The duration of surgery was 2.5 h on average.Seventeen out of twenty patients(85%)had a Visual Analog Score(VAS)of less than 2 and did not require any supplementation.One patient was removed from the study,as he required re-exploration.The remaining two patients had a VAS of more than 8 and received IV morphine post-operatively as a rescue analgesic drug.Fifteen out of seventeen patients(88.2%)could be mobilized 12 h after the procedure.CONCLUSION Osteonecrosis or AVN of the hip was one of the dreaded complications of COVID-19,which surfaced in patients who received steroid therapy requiring surgical intervention.Bilateral PENG block is an effective technique to provide post-operative analgesia resulting in early mobilization and enhanced recovery after surgery.

Building Custom Spreadsheet Functions with Python: End-User Software Engineering Approach

End-user computing empowers non-developers to manage data and applications, enhancing collaboration and efficiency. Spreadsheets, a prime example of end-user programming environments widely used in business for data analysis. However, Excel functionalities have limits compared to dedicated programming languages. This paper addresses this gap by proposing a prototype for integrating Python’s capabilities into Excel through on-premises desktop to build custom spreadsheet functions with Python. This approach overcomes potential latency issues associated with cloud-based solutions. This prototype utilizes Excel-DNA and IronPython. Excel-DNA allows creating custom Python functions that seamlessly integrate with Excel’s calculation engine. IronPython enables the execution of these Python (CSFs) directly within Excel. C# and VSTO add-ins form the core components, facilitating communication between Python and Excel. This approach empowers users with a potentially open-ended set of Python (CSFs) for tasks like mathematical calculations, statistical analysis, and even predictive modeling, all within the familiar Excel interface. This prototype demonstrates smooth integration, allowing users to call Python (CSFs) just like standard Excel functions. This research contributes to enhancing spreadsheet capabilities for end-user programmers by leveraging Python’s power within Excel. Future research could explore expanding data analysis capabilities by expanding the (CSFs) functions for complex calculations, statistical analysis, data manipulation, and even external library integration. The possibility of integrating machine learning models through the (CSFs) functions within the familiar Excel environment.

Enable Excel-Based Basic Cybersecurity Features for End Users by Using Python-Excel Integration

In the digital age, the global character of the Internet has significantly improved our daily lives by providing access to large amounts of knowledge and allowing for seamless connections. However, this enormously interconnected world is not without its risks. Malicious URLs are a powerful menace, masquerading as legitimate links while holding the intent to hack computer systems or steal sensitive personal information. As the sophistication and frequency of cyberattacks increase, identifying bad URLs has emerged as a critical aspect of cybersecurity. This study presents a new approach that enables the average end-user to check URL safety using Microsoft Excel. Using the powerful VirusTotal API for URL inspections, this study creates an Excel add-in that integrates Python and Excel to deliver a seamless, user-friendly interface. Furthermore, the study improves Excel’s capabilities by allowing users to encrypt and decrypt text communications directly in the spreadsheet. Users may easily encrypt their conversations by simply typing a key and the required text into predefined cells, enhancing their personal cybersecurity with a layer of cryptographic secrecy. This strategy democratizes access to advanced cybersecurity solutions, making attentive digital integrity a feature rather than a daunting burden.

Theory of Flexural Shear, Bending and Torsion for a Thin-Walled Beam of Open Section

Aspects of the general Vlasov theory are examined separately as applied to a thin-walled channel section cantilever beam under free-end end loading. In particular, the flexural bending and shear that arise under transverse shear and axial torsional loading are each considered theoretically. These analyses involve the location of the shear centre at which transverse shear forces when applied do not produce torsion. This centre, when taken to be coincident with the centre of twist implies an equivalent reciprocal behaviour. That is, an axial torsion applied concentric with the shear centre will twist but not bend the beam. The respective bending and shear stress conversions are derived for each action applied to three aluminium alloy extruded channel sections mounted as cantilevers with a horizontal principal axis of symmetry. Bending and shear are considered more generally for other thin-walled sections when the transverse loading axes at the shear centre are not parallel to the section = s centroidal axes of principal second moments of area. The fixing at one end of the cantilever modifies the St Venant free angular twist and the free warping displacement. It is shown from the Wagner-Kappus torsion theory how the end constrained warping generates an axial stress distribution that varies with the length and across the cross-section for an axial torsion applied to the shear centre. It should be mentioned here for wider applications and validation of the Vlasov theory that attendant papers are to consider in detail bending and torsional loadings applied to other axes through each of the centroid and the web centre. Therein, both bending and twisting arise from transverse shear and axial torsion applied to each position being displaced from the shear centre. Here, the influence of the axis position upon the net axial and shear stress distributions is to be established. That is, the net axial stress from axial torsional loading is identified with the sum of axial stress due to bending and axial stress arising from constrained warping displacements at the fixing. The net shear stress distribution overlays the distributions from axial torsion and that from flexural shear under transverse loading. Both arise when transverse forces are displaced from the shear centre.

六味地黄丸介导RAGE抑制MMP-2/MMP-9对Aβ_(1-40)损伤bEnd.3细胞紧密连接蛋白的影响

目的探讨六味地黄丸对β淀粉样蛋白1-40(Aβ_(1-40))损伤的小鼠脑微血管内皮细胞(bEnd.3)的保护作用及其机制。方法采用CCK8法检测Aβ_(1-40)和六味地黄丸含药血清(MSLDP)对细胞活性的影响,筛选合适的作用浓度。将bEnd.3细胞分为对照组、Aβ_(1-40)组、MSLDP+Aβ_(1-40)组和MSLDP组,采用Western blot检测低密度脂蛋白相关蛋白1(LRP1)、晚期糖基化终末产物受体(RAGE)、基质金属蛋白酶2(MMP-2)、MMP-9、闭锁小带蛋白-1(ZO-1)、脑源性神经营养因子(BDNF)蛋白表达,免疫荧光检测LRP1、RAGE、ZO-1表达;再将bEnd.3细胞分为对照组、Aβ_(1-40)组、FPS-ZM1(RAGE抑制剂)+Aβ_(1-40)组和FPS-ZM1+Aβ_(1-40)+MSLDP组,Western blot检测RAGE、MMP-9、MMP-2、ZO-1蛋白表达。结果Aβ_(1-40)呈剂量依赖性降低bEnd.3细胞活性(P<0.01),MSLDP对Aβ_(1-40)损伤的细胞活性具有保护作用(P<0.05,P<0.01),因此选择10μmol/L Aβ_(1-40)和10%MSLDP进行后续实验。与对照组比较,Aβ_(1-40)组RAGE、MMP-2、MMP-9蛋白表达升高(P<0.01),LRP1、ZO-1、BDNF蛋白表达降低(P<0.05,P<0.01),并且LRP1、ZO-1荧光强度降低(P<0.01),RAGE荧光增强(P<0.01);与Aβ_(1-40)组比较,MSLDP组RAGE、MMP-2、MMP-9蛋白表达和RAGE荧光强度降低(P<0.05,P<0.01),而LRP1、ZO-1、BDNF蛋白表达和LRP1、ZO-1荧光强度升高(P<0.05,P<0.01)。与Aβ_(1-40)组比较,Aβ_(1-40)+FPS-ZM1组MMP-2、MMP9、RAGE蛋白表达降低(P<0.05,P<0.01),ZO-1蛋白表达升高(P<0.05);Aβ_(1-40)+FPS-ZM1+MSLDP组MMP-2、MMP9、RAGE蛋白表达降低(P<0.01),ZO-1蛋白表达升高(P<0.01),FPS-ZM1和MSLDP联合使用的效果更佳。结论六味地黄丸能够保护Aβ_(1-40)损伤的脑微血管内皮的细胞紧密连接,减轻血脑屏障障碍,保护神经血管单元防治阿尔茨海默病,可能通过调节RAGE途径抑制MMP-2/MMP-9途径实现。

Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer

Obesity and type 2 diabetes mellitus(T2DM)are chronic pathologies with a high incidence worldwide.They share some pathological mechanisms,including hyperinsulinemia,the production and release of hormones,and hyperglycemia.The above,over time,affects other systems of the human body by causing tissue hypoxia,low-grade inflammation,and oxidative stress,which lay the pathophysiological groundwork for cancer.The leading causes of death globally are T2DM and cancer.Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death(i.e.,damage-associated molecular patterns)such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products(RAGE)-a multiligand receptor involved in inflammatory and metabolic and neoplastic processes.This review analyzes the latest advanced reports on the role of RAGE in the development of obesity,T2DM,and cancer,with an aim to understand the intracellular signaling mechanisms linked with cancer initiation.This review also explores inflammation,oxidative stress,hypoxia,cellular senescence,RAGE ligands,tumor microenvironment changes,and the“cancer hallmarks”of the leading tumors associated with T2DM.The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.