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Simple and versatile in situ thermo-sensitive hydrogel for rectal administration of SZ-A to alleviate inflammation and repair mucosal barrier in ulcerative colitis

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Chinese Chemical Letters 2024年第6期35卷 462-468页

作者： Yu Yan Jiawei Song Dongdong Liu Zihan Liu Jialing Cheng Zhiyang Chen Yanfang Yang Weizhe Jiang Hongliang Wang Jun Ye Yuling Liu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China college of Pharmacy Guangxi Medical UniversityNanning 530021China Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function.Ramulus mori(Sangzhi)alkaloids(SZ-A),derived from twigs of mulberry,were approved by the National medical Products Administration in 2020 for treating type 2 diabetes mellitus.Accumulated evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation,indicating its potential to address inflammation in UC.However,the treatment of UC faces challenges due to low drug delivery efficiency and short retention time.To overcome these challenges,an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery,utilizing the thermo-sensitive polymers Poloxamer 407and 188.The thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32±0.5℃,a short gelation time of 64 s,a p H range of 7-10,high moisturizing capability exceeding 90%,and moderate mechanical strength of 4-5 s.In a rat model with UC,the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal administration.Symptoms of UC were markedly reduced following rectal administration of SZ-A thermosensitive hydrogel.Furthermore,the release of inflammatory factors,such as interleukin-1β(IL-1β),IL-6,IL-18,tumor necrosis factor-α(TNF-α),and transforming growth factor-β1(TGF-β1),significantly decreased in the SZ-A thermo-sensitive hydrogel group.The integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive hydrogel.In conclusion,rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms,inhibited the secretion of inflammatory factors,and promoted the repair of the colonic mucosal barrier.This approach holds promise as a potential treatment for UC.

关键词： Ulcerative colitis SZ-A Thermo-sensitive hydrogel Rectal administration Alleviation of inflammation Mucosal barrier repair

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Complete blood and urine paraprotein tests as response assessments in multiple myeloma patients treated with bortezomib,cyclophosphamide,and dexamethasone

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Chronic Diseases and Translational Medicine 2024年第1期10卷 62-68页

作者： Xialu Lan Fujing Zhang Chen Yang Wei Su Jianhua Du Shuangjiao Liu Miao Chen Bing Han Daobin Zhou Junling Zhuang Department of Hematology Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina Department of Pathology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouChina Department of Laboratory Medicine Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina

Background: This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma(MM)during the induction phase of treatment with bortezomib,cyclophosphamide,and dexamethasone(BCD).Methods :We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front-line regimen at peking union medical college Hospital from January 1,2013 to December 31,2018.Results: There were 107 patients with International Staging System(ISS)III and 51 with paraprotein of light chain.Of these,77 completed nine cycles of the BCD regimen.As the number of treatment cycles increased,the proportions of serum and urine immunofixation electrophoresis(IFE)tests elevated from 40.39%to 62.22%and 16.75%to 37.78%,respectively.More than 90%of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle,but that of urinary M protein was less than 60%.The detection rate of urinary M protein in light chain MM was more than 70%per cycle.Patients with a very good partial response(VGPR)had longer progression-free survival(PFS)than those with uncertain VGPR(32 vs.26 months,p=0.0336).Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation,those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly(27 vs.22 months,p=0.059).Conclusion: Urinary M protein detection rate is significantly lower than that in serum,leading to an overestimation of efficacy,premature reduction of treatment intensity,and shortened PFS.Precise response assessments are critical to treatment decisions and clinical diagnoses.

关键词： bortezomib light chain subtype multiple myeloma response assessment

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Age-specific differences in the association between prediabetes and cardiovascular diseases in China:A national cross-sectional study

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World Journal of Diabetes 2024年第2期15卷 240-250页

作者： Shuo Xie Li-Ping Yu Fei Chen Yao Wang Rui-Fen Deng Xue-Lian Zhang Bo Zhang Department of Endocrinology Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100730China Department of Endocrinology China-Japan Friendship HospitalBeijing 100029China

BACKGROUND Cardiovascular disease(CVD)is a leading cause of morbidity and mortality worldwide,the global burden of which is rising.It is still unclear the extent to which prediabetes contributes to the risk of CVD in various age brackets among adults.To develop a focused screening plan and treatment for Chinese adults with prediabetes,it is crucial to identify variations in the connection between prediabetes and the risk of CVD based on age.AIM To examine the clinical features of prediabetes and identify risk factors for CVD in different age groups in China.METHODS The cross-sectional study involved a total of 46239 participants from June 2007 through May 2008.A thorough evaluation was conducted.Individuals with prediabetes were categorized into two groups based on age.Chinese atherosclerotic CVD risk prediction model was employed to evaluate the risk of developing CVD over 10 years.Random forest was established in both age groups.SHapley Additive exPlanation method prioritized the importance of features from the perspective of assessment contribution.RESULTS In total,6948 people were diagnosed with prediabetes in this study.In prediabetes,prevalences of CVD were 5(0.29%)in the younger group and 148(2.85%)in the older group.Overall,11.11%of the younger group and 29.59% of the older group were intermediate/high-risk of CVD for prediabetes without CVD based on the Prediction for ASCVD Risk in China equation in ten years.In the younger age group,the 10-year risk of CVD was found to be more closely linked to family history of CVD rather than lifestyle,whereas in the older age group,resident status was more closely linked.CONCLUSION The susceptibility to CVD is age-specific in newly diagnosed prediabetes.It is necessary to develop targeted approaches for the prevention and management of CVD in adults across various age brackets.

关键词： Age Cardiovascular diseases Prediabetes Risk factors Differences

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Heart failure in China:epidemiology and current management

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Journal of Geriatric Cardiology 2024年第6期21卷 631-641页

作者： Sheng-Shou HU the Writing Committee of the Report on Cardiovascular Health and Diseases in China Fuwai Hospital National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

The Annual Report on Cardiovascular Health and Diseases in China(2022)intricate landscape of cardiovascularhealth in China.In connection with the previous section,this sixth section of the report offers a comprehensive analysis of heart failure(HF)in China.HF is one of the most important cardiovascular disease in the 21st century.Its mortality is equivalent to that of cancer.It is an important public health problem that seriously affects the health of Chinese residents.In recent years,with the deepeningof understanding,the change of treatment principles,the innovation of treatment methods and the update of treatment guidelines,the in-hospital mortality of HF patients has declined,and the long-term prognosis is also improving.However,there are stilldifferences in the management level of HF among different hospitals in China.How to improve the standardized diagnosis andtreatment level of HF in China remains an important challenge.

关键词： epidemiology diagnosis treatment

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Comprehensive characterization of cell disulfidptosis in human cancers:An integrated pan-cancer analysis

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Genes & Diseases 2024年第4期11卷 5-8页

作者： Guo Zhao Yale Jiang Yuning Wang Shuhang Wang Ning Li Clinical Trial Center National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Excessive accumulation of disulfide molecules,like cystine,can induce disulfide stress and high toxicity in cells,but the reduced form of nicotinamide adenine dinucleotide phosphate can reverse this process and mitiga... 详细信息

关键词： disulfide cancer characterization

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Integrin β5 subunit regulates hyperglycemia-induced vascular endothelial cell apoptosis through FoxO1-mediated macroautophagy

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Chinese medical Journal 2024年第5期137卷 565-576页

作者： Xuze Lin Sizhuang Huang Side Gao Jinxing Liu Jiong Tang Mengyue Yu Department of Cardiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100037China Department of Cardiology Fuwai Yunnan Cardiovascular HospitalKunmingYunnan 650000China

Background:Hyperglycemia frequently induces apoptosis in endothelial cells and ultimately contributes to microvascular dysfunction in patients with diabetes mellitus(DM).Previous research reported that the expression of integrins as well as their ligands was elevated in the diseased vessels of DM patients.However,the association between integrins and hyperglycemia-induced cell death is still unclear.This research was designed to investigate the role played by integrin subunit β5(ITGB5)in hyperglycemia-induced endothelial cell apoptosis.Methods:We used leptin receptor knockout(Lepr-KO)(db/db)mice as spontaneous diabetes animal model.Selective deletion of ITGB5 in endothelial cell was achieved by injecting vascular targeted adeno-associated virus via tail vein.Besides,we also applied small interfering RNA in vitro to study the mechanism of ITGB5 in regulating high glucose-induced cell apoptosis.Results:ITGB5 and its ligand,fibronectin,were both upregulated after exposure to high glucose in vivo and in vitro.ITGB5 knockdown alleviated hyperglycemia-induced vascular endothelial cell apoptosis and microvascular rarefaction in vivo.In vitro analysis revealed that knockdown of either ITGB5 or fibronectin ameliorated high glucose-induced apoptosis in human umbilical vascular endothelial cells(HUVECs).In addition,knockdown of ITGB5 inhibited fibronectin-induced HUVEC apoptosis,which indicated that the fibronectin-ITGB5 interaction participated in high glucose-induced endothelial cell apoptosis.By using RNA-sequencing technology and bioinformatic analysis,we identified Forkhead Box Protein O1(FoxO1)as an important downstream target regulated by ITGB5.Moreover,we demonstrated that the excessive macroautophagy induced by high glucose can contribute to HUVEC apoptosis,which was regulated by the ITGB5-FoxO1 axis.Conclusion:The study revealed that high glucose-induced endothelial cell apoptosis was positively regulated by ITGB5,which suggested that ITGB5 could potentially be used to predict and treat DM-related vascular complic

关键词： Endothelial cell apoptosis Integrin Autophagy Diabetes

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Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1675-1689页

作者： Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo Department of Immunology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Collaborative Innovation Center for Biotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Department of Lung Cancer Surgery Tianjin Medical University General HospitalTianjin 300052China Immunology Research Center National Health Research InstitutesZhunanMiaoliTaiwanROC Department of Immunology Nankai UniversityTianjin 300071China

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung cancer.Cancer stem cells(CSCs)have been identified as a crucial player in immunotherapy-related resistance.Ferroptosis,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy.Metabolic adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive.Here,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung cancer.Mechanistically,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A expression.The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in CSCs.Significantly,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关键词： immunotherapy metabolism peroxidation

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The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2057-2076页

作者： Chenglu Zhang Ruxue Bo Tiantian Zhou Naihong Chen Yuhe Yuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Materia MedicaBeijing 100050China

Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.

关键词： Raphe nuclei α-Synuclein Gastrointestinal tract Electrophysiology Locus coeruleus Substantia nigra pars compacta Parkinson's disease Spinal cord

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Effective assignment of positional isomers in dimeric shikonin and its analogs by ^(1)H NMR spectroscopy

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Chinese Chemical Letters 2024年第5期35卷 223-226页

作者： Ling-Hao Zhao Hai-Wei Yan Jian-Shuang Jiang Xu Zhang Xiang Yuan Ya-Nan Yang Pei-Cheng Zhang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

An approach for distinguishing two types of positional isomers of dimeric shikonin and its analogs was explored with ^(4)JC,H long-range correlation by prolonging the acquisition time at ^(2,3)JC,H values of 2.0 and 8.0Hz.Furthermore,the ^(1)H(proton)nuclear magnetic resonance(NMR)pattern of phenolic hydroxyl protons was developed as a“diagnosis signal”to ascertain the relative location of each side chain in DMSO-d_(6) at sample concentrations of 0.022-0.034 mol/L.The chemical shift differences of 0.6ppm between OH-5' and OH-1 and between OH-8'and OH-4 are assigned to Type A and Type B,respectively.All reported ambiguous structures were corrected by this pattern.Additionally,the steric structures of isolated compounds were elucidated by quantum chemical calculations of electronic circular dichroism(ECD)spectra.

关键词： Arnebia euchroma Dimeric hydroxyl naphthoquinones Positional isomers ^(1)H NMR spectroscopy Chemical shift difference

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Epidemiology and current management of cardiovascular disease in China

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Journal of Geriatric Cardiology 2024年第4期21卷 387-406页

作者： Sheng-Shou HU the Writing Committee of the Report on Cardiovascular Health and Dis-eases in China Fuwai Hospital National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

The Annual Report on Cardiovascular Health and Diseases in China(2022) intricate landscape of cardiovascular health in China. This is the fourth section of the report with a specific focus on epidemiology and current management of cardiovascular disease(CVD) in China. This section of the report highlights the epidemiological trends of CVD in China. It reveal a concerning rise in prevalence, with approximately 330 million affected individuals, including significant numbers with stroke, coronary artery disease(CAD), heart failure, and other conditions. CVD stands as the primary cause of mortality among both urban and rural populations, accounting for nearly half of all deaths in 2020. Mortality rates are notably higher in rural areas compared to urban centers since 2009. While age-standardized mortality rates have decreased, the absolute number of CVD deaths has increased, primarily due to population aging. Ischemic heart disease, hemorrhagic and ischemic strokes are the leading causes of CVD-related deaths. Notably, the burden of atherosclerotic cardiovascular disease has risen substantially, with atherosclerotic cardiovascular disease-related deaths increasing from 1990 to 2016. The incidence of ischemic stroke and ischemic heart disease has shown similar increasing trends over the past three decades. CAD mortality, particularly acute myocardial infarction, has been on the rise, with higher mortality rates observed in rural areas since 2016. The prevalence of CAD has increased significantly, with over 11 million patients identified in 2013. Studies assessing hospital performance in managing acute coronary syndrome reveal gaps in adherence to guideline-recommended strategies, with disparities in care quality across hospitals. However, initiatives like the China Patient-centered Evaluative Assessment of Cardiac Events(PEACE)-Retrospective AMI Study and the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome(CCC-ACS) project aim to improve patient outcomes through enhanced care protocols. More

关键词： epidemiology landscape deaths

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