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Biochanin A,as the Lrg1/TGF-β/Smad2 pathway blockade,attenuates blood-brain barrier damage after cerebral ischemiareperfusion by modulating leukocyte migration patterns

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BIOCELL 2023年第8期47卷 1869-1883页

作者： LONGSHENG FU JINFANG HU FENG SHAO YAOQI WU WEI BAI MINGJIN JIANG HAO CHEN LIHUA CHEN YANNI LV Department of Pharmacy The First Affiliated Hospital of Nanchang UniversityNanchang330006China Key Laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Traditional Chinese MedicineNanchang330006China Translational Medicine Institute of Jiangxi The First Affiliated Hospital of Nanchang UniversityNanchang330006China Neurology Department The First Affiliated Hospital of Nanchang UniversityNanchang330006China

Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns.

关键词： Biochanin A blockade Leukocyte migration Blood-brain barrier damage Ischemia-reperfusion Lrg1

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Pretreatment serum albumin/globulin ratio as a prognostic biomarker in metastatic prostate cancer patients treated with maximal androgen blockade

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Asian Journal of Andrology 2019年第1期21卷 56-61页

作者： Ning Wang Jian-Ye Liu Xiong Li Min-Hua Deng Zhi Long Jin Tang Kun Yao Yi-Chuan Zhang Le-Ye He Department of Urology The Third Xiangya Hospital of Central South UniversityChangsha 410013China institute of Prostate Disease of Central South University Changsha 410013China Center for Molecular Medicine Xiangya HospitalCentral South UniversityChangsha 410008China Hunan Key Laboratory of Molecular Radiation Oncology Xiangya HospitalCentral South UniversityChangsha 410008China.

The pretreatment serum albumin/globulin ratio (AGR)has been used as a prognostic biomarker for various cancer types.However, the prognostic value of the AGR for prostate cancer,especially for metastatic prostate cancer (mPCa)after maximal androgen blockade (MAB),remains unclear.The aim of this study was to evaluate the prognostic value of the pretreatment serum AGR for mPCa treated with MAB.This retrospective study included 214 mPCa patients receiving MAB from October 2007 to March 2017. The correlation of the AGR with survival was estimated using Kaplan-Meier analysis and Cox proportional hazards models.The cutoff value of the AGR was 1.45 according to the receiver operating characteristic curve.Kaplan-Meier analysis demonstrated that patients with a low AGR (<1.45)had poor outcomes in terms of progression-free survival (PFS)and cancer-specific survival (CSS). Multivariate Cox analyses showed that the AGR was an independent predictor of PFS (hazard ratio [HR]=0.642;95%confidence interval [CI]:0.430-0.957;P=0.030)and CSS (HR =0.412;95%CI:0.259-0.654;P<0.001).Furthermore,in a subset of 79 patients with normal serum albumin levels (≥40.0 g l^-1),the serum AGR remained an independent predictor of CSS (P=0.009). The pretreatment AGR was an independent prognostic biomarker for PFS and CSS in patients with mPCa receiving MAB.In addition,the AGR remained effective for the prediction of CSS in patients with normal albumin levels (≥40 g l^-1).However,further prospective studies are needed to confirm our conclusions.

关键词： albumin/globulin ratio maximal androgen blockade metastatic prostate cancer prognosis survival

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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

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Frontiers of Medicine 2019年第4期13卷 438-450页

作者： Yumeng Wang Guiling Li Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases Fudan University Shanghai 200011 China Department of Integration of Western and Traditional Medicine Obstetrics and Gynecology Hospital of Fudan University Shanghai 200011 China

Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-l/PD-Ll-related therapeutic strategies for CC.

关键词： PD-1 PD-L1 immune checkpoint blockade antibody immunotherapy cervical cancer

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Multifunctional polymeric micelle-based chemo-immunotherapy with immune checkpoint blockade for efficient treatment of orthotopic and metastatic breast cancer

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Acta Pharmaceutica Sinica B 2019年第4期9卷 819-831页

作者： Jiaojie Wei Yang Long Rong Guo Xinlei Liu Xian Tang Jingdong Rao Sheng Yin Zhirong Zhang Man Li Qin He Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of Pharmacy Sichuan University

Immunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin(DOX) and Toll-like receptor 7 agonist imiquimod(IMQ) in low molecular weight heparin(LMWH)-D-α-tocopheryl succinate(TOS) micelles(LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles(LT-DOX)generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles(LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1(PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8+ CTLs/Treg and CD4+ Teff/Treg. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.

关键词： Checkpoint blockade Immunotherapy Immunogenic cell death Anti-metastasis Nanoparticle

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Immune-adjuvant loaded Bi2Se3 nanocage for photothermal-improved PD-L1 checkpoint blockade immune-tumor metastasis therapy

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Nano Research 2019年第8期12卷 1770-1780页

作者： Yilin Song Yidan Wang Siyu Wang Yu Cheng Qianglan Lu Lifang Yang Fengping Tan Nan Li Tianjin Key Laboratory of Drug Delivery & High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityTianjin 300072China

Checkpoint blockade based immune therapy has shown to be effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. To overcome this obstacles, a PEG-modified Bi2Se3 nanocage (NC) loaded with imiquimod (R848), which could efficiently destroy the tumors thus producing enough tumor-associated antigens (TAA) and with the existence of R848, a toll-like-receptor-7 agonist, could generate strong anti-cancer immune responses is reported in this study. Moreover, immunogenic Bi2Se3 NC-PEG/R848 mediated photothermal therapy (PTT) sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only ablating cancer cells upon NIR laser but also causing strong anti-cancer immunity to suppress distant tumor growth post PTT. Both in vitro and in vivo experiments demonstrate that the Bi2Se3 NC-PEG/R848 could effectively activate a PTT-induced immune response as well as silence immune resistance based on PD-L1 checkpoint blockade to ablate the primary tumor and further inhibit the tumor metastasis. Bi2Se3 NC reported here exhibits high photothermal conversion efficiency and stability, as well as competent drug loading capacity with large hollow structures and high surface area. Our study not only provides a facial way to synthesize Bi2Se3 NC, but also offers an alternative strategy for tumor metastasis.

关键词： Bi2Se3 nanocage R848 checkpoint blockade photothermal-immune therapy anti-tumor metastasis

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Immune blockade inhibitors and the radiation abscopal effect in gastrointestinal cancers

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World Journal of Gastrointestinal Oncology 2018年第9期10卷 221-227页

作者： Ioannis A Voutsadakis Algoma District Cancer Program Sault Area Hospital Section of Internal Medicine Division of Clinical SciencesNorthern Ontario School of Medicine

The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.

关键词： Abscopal effect Radiation CD28/cytotoxic T-lymphocyte antigen-4 Immune blockade inhibitors Programmed death 1 Programmed death ligand-1

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Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

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World Journal of Clinical Oncology 2016年第5期7卷 340-351页

作者： Zain A Sobani Ashwin Sawant Mikram Jafri Amit Keith Correa Ibrahim Halil Sahin Department of Medicine Maimonides Medical Center Department of Medicine Icahn School of Medicine at Mount Sinai St Luke’s Roosevelt Hospital Center Department of Medicine Albany Stratton Veterans Hospital

Epidermal growth factor receptor(EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer(CRC). Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.

关键词： Epidermal growth factor receptor Oncogenic signature Kirsten RAS BRAF Cetuximab Panitumumab Epidermal growth factor receptor blockade resistance

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Screening responsive or resistant biomarkers of immune checkpoint inhibitors based on online databases

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Frontiers of Medicine 2019年第1期13卷 24-31页

作者： Zhen Xiang Yingyan Yu Department of Surgery Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Gastric NeoplasmsShanghai Jiao Tong University School of MedicineShanghai 200025China

Immune checkpoint inhibitors are a promising strategy in the treatment of cancer, especially advanced types. However, not all patients are responsive to immune checkpoint inhibitors. The response rate depends on the immune microenvironment, tumor mutational burden (TMB), expression level of immune checkpoint proteins, and molecular subtypes of cancers. Along with the Cancer Genome Project, various open access databases, including The Cancer Genome Atlas and Gene Expression Omnibus, provide large volumes of data, which allow researchers to explore responsive or resistant biomarkers of immune checkpoint inhibitors? In this review, we introduced some methodologies on database selection, biomarker screening, current progress of immune checkpoint blockade in solid tumor treatment, possible mechanisms of drug resistance, strategies of overcoming resistance, and indications for immune checkpoint inhibitor therapy.

关键词： immune checkpoint blockade sensitivity resistance data mining

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Properties of collective Rabi oscillations with two Rydberg atoms

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Chinese Physics B 2019年第1期28卷 340-347页

作者：马丹丹张可烨钱静 Quantum Institute for Light and Atoms School of Physics and Material ScienceEast China Normal University

Motivated by experimental advances that the collective excitation of two Rydberg atoms was observed, we provide an elaborate theoretical study for the dynamical behavior of two-atom Rabi oscillations. In the large-intermediate-detuning case, the two-photon Rabi oscillation is found to be significantly affected by the strength of the interatomic van der Waals interaction. With a careful comparison of the exact numbers and values of the oscillation frequency, we propose a new way to determine the strength of excitation blockade, agreeing well with the previous universal criterion for full, partial, and no blockade regions. In the small-intermediate-detuning case, we find a blockade-like effect, but the collective enhancement factor is smaller than ^(1/2) due to the quantum interference of double optical transitions involving the intermediate state.Moreover, a fast two-photon Rabi oscillation in ns timescale is manifested by employing intense lasers with an intensity of ~MW/cm^2, offering a possibility of ultrafast control of quantum dynamics with Rydberg atoms.

关键词： Rydberg atoms collective excitation Rabi oscillation excitation blockade

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Reducing porcine corneal graft rejection, with an emphasis on porcine endogenous retrovirus transmission safety: a review

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International Journal of Ophthalmology(English edition) 2019年第2期12卷 324-332页

作者： Yao-Wen Song Zhi-Qiang Pan Beijing Tongren Eye Center Beijing Tongren Hospital Capital Medical University Beijing Ophthalmology and Visual Science Key Laboratory

Donor cornea shortage is a primary hurdle in the development of corneal transplantation. Of all species, porcine corneas are the ideal transplantation material for humans. However, the xenoimmune rejection induced by porcine corneal xenotransplantation compromises surgical efficacy. Although the binding of IgM/IgG in human serum to a genetically modified porcine cornea is significantly weaker than that of the wild type(WT), genetically modified porcine corneas do not display a prolonged graft survival time in vivo. Conversely, costimulatory blockade drugs, such as anti-CD40 antibodies, can reduce the xenoimmune response and prolong graft survival time in animal experiments. Moreover, porcine endothelial grafts can survive for more than 6mo with only the subconjunctival injection of a steroid-based immunosuppressants regime; therefore, they show great value for treating corneal endothelial disease. In addition, zoonotic transmission is a primary concern of xenotransplantation. Porcine endogenous retrovirus(PERV) is the most significant virus assessed by ophthalmologists. PERV integrates into the porcine genome and infects human cells in vitro. Fortunately, no evidence from in vivo studies has yet shown that PERV can be transmitted to hosts.

关键词： corneal xenotransplantation genetically modified pigs wild type pigs costimulatory blockade drugs porcine endothelial grafts porcine endogenous retrovirus safety

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