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Immune checkpoint inhibitors:breakthroughs in cancer treatment

Cancer Biology & Medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University Department of Biology School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade(ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies(mAbs) are currently available as immune checkpoint inhibitors(ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4) and programmed cell death protein 1(PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response.Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1(anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains(TIGIT), mucin domain containing-3(TIM-3), lymphocyte activation gene-3(LAG-3), V-domain immunoglobulin suppressor of T cell activation(VISTA), B and T lymphocyte attenuator(BTLA), and signal-regulatory protein α(SIRPα). Functional m Abs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： CTLA-4 ICIs Immunotherapy PD-1 cancer

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DNA methylation profiles in cancer:functions,therapy,and beyond

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Cancer Biology & Medicine 2024年第2期21卷 111-116页

作者： Jinrong Zhu Yongjie Yang Li Li Jiuren Tang Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China

DNA methylation in cancer DNA methylation,a reversible post-replication modification,defines gene expression and function in different physiologic processes.Hypomethylation is quite common among global DNA modifications,while promoter hypermethylation often occurs in local regions during cancer,as in CpG island formation,thereby perpetuating the inactivation of tumor suppressor genes.

关键词： cancer suppressor thereby

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A novel alternative for pyrogen detection based on a transgenic cell line

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1221-1229页

作者： Qing He Chuan-Fei Yu Gang Wu Kai-Qin Wang Yong-Bo Ni Xiao Guo Zhi-Hao Fu Lan Wang De-Jiang Tan Hua Gao Can Wang Gang Chen Xu-Hong Chen Bo Chen Jun-Zhi Wang National Institutes for Food and Drug Control BeijingChina school of Life Science and biopharmaceutics Shenyang Pharmaceutical UniversityShenyangChina Shanghai Institute for Food and Drug Control ShanghaiChina KeyMed biosciences Inc. ChengduChina

Pyrogen,often as a contaminant,is a key indicator affecting the safety of almost all parenteral drugs(including biologicals,chemicals,traditional Chinese medicines and medical devices).It has become a goal to completely replace the in vivo rabbit pyrogen test by using the in vitro pyrogen test based on the promoted‘reduction,replacement and refinement’principle,which has been highly considered by regulatory agencies from different countries.We used NF-κB,a central signalling molecule mediating inflammatory responses,as a pyrogenic marker and the monocyte line THP-1 transfected with a luciferase reporter gene regulated by NF-κB as an in vitro model to detect pyrogens by measuring the intensity of a fluorescence signal.Here,we show that this test can quantitatively and sensitively detect endotoxin(lipopolysaccharide from different strains)and nonendotoxin(lipoteichoic acid,zymosan,peptidoglycan,lectin and glucan),has good stability in terms of NF-κB activity and cell phenotypes at 39 cell passages and can be applied to detect pyrogens in biologicals(group A&C meningococcal polysaccharide vaccine;basiliximab;rabies vaccine(Vero cells)for human use,freeze-dried;Japanese encephalitis vaccine(Vero cells),inactivated;insulin aspart injection;human albumin;recombinant human erythropoietin injection(CHO Cell)).The within-laboratory reproducibility of the test in three independent laboratories was 85%,80%and 80%and the interlaboratory reproducibility among laboratories was 83.3%,95.6%and 86.7%.The sensitivity(true positive rate)and specificity(true negative rate)of the test were 89.9%and 90.9%,respectively.In summary,the test provides a novel alternative for pyrogen detection.

关键词： pyrogen rabbit replace

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Higher levels of the lipophilic antioxidants coenzyme Q_(10) and vitamin E in long-lived termite queens than in short-lived workers

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Insect Science 2024年第1期31卷 201-210页

作者： Eisuke Tasaki Yorihiro Yamamoto Yoshihito Iuchi Department of Biological Chemistry Graduate School of Sciences and Technology for InnovationYamaguchi UniversityYamaguchiJapan school of bioscience and Biotechnology Tokyo University of TechnologyHachiojiTokyoJapan

Termite queens and kings live longer than nonreproductive workers.Several molecular mechanisms contributing to their long lifespan have been investigated;however,the underlying biochemical explanation remains unclear.Coenzyme Q(CoQ),a component of the mitochondrial electron transport chain,plays an essential role in the lipophilic antioxidant defense system.Its beneficial effects on health and longevity have been well studied in several organisms.Herein,we demonstrated that long-lived termite queens have significantly higher levels of the lipophilic antioxidant CoQ_(10) than workers.Liquid chromatography analysis revealed that the levels of the reduced form of CoQ_(10) were 4 fold higher in the queen's body than in the worker's body.In addition,queens showed 7 fold higher levels of vitamin E,which plays a role in antilipid peroxidation along with CoQ,than workers.Furthermore,the oral administration of CoQ_(10) to termites increased the CoQ_(10) redox state in the body and their survival rate under oxidative stress.These findings suggest that CoQ_(10) acts as an efficient lipophilic antioxidant along with vitamin E in long-lived termite queens.This study provides essential biochemical and evolutionary insights into the relationship between CoQ_(10) concentrations and termite lifespan extension.

关键词： antioxidant defense system coenzyme Q termite queens vitamin E

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Magnetic Fields Reduce Apoptosis by Suppressing Phase Separation of Tau-441

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Research 2024年第1期2023卷 181-197页

作者： Wen-Juan Lin Wen-Pu Shi Wan-Yi Ge Liang-Liang Chen Wei-Hong Guo Peng Shang Da-Chuan Yin Key Laboratory for Space bioscience and Biotechnology School of Life SciencesNorthwestern Polytechnical University127 Youyixi RoadXi'an 710072ShaanxiPR China

The biological effects of magnetic fields(MFs)have been a controversial issue.Fortunately,in recent years,there has been increasing evidence that MFs do affect biological systems.However,the physical mechanism remains unclear.Here,we show that MFs(16 T)reduce apoptosis in cell lines by inhibiting liquid–liquid phase separation(LLPS)of Tau-441,suggesting that the MF effect on LLPS may be one of the mechanisms for understanding the“mysterious”magnetobiological effects.The LLPS of Tau-441 occurred in the cytoplasm after induction with arsenite.The phase-separated droplets of Tau-441 recruited hexokinase(HK),resulting in a decrease in the amount of free HK in the cytoplasm.In cells,HK and Bax compete to bind to the voltage-dependent anion channel(VDAC I)on the mitochondrial membrane.A decrease in the number of free HK molecules increased the chance of Bax binding to VDAC I,leading to increased Bax-mediated apoptosis.In the presence of a static MF,LLPS was marked inhibited and HK recruitment was reduced,resulting in an increased probability of HK binding to VDAC I and a decreased probability of Bax binding to VDAC I,thus reducing Bax-mediated apoptosis.Our findings revealed a new physical mechanism for understanding magnetobiological effects from the perspective of LLPS.In addition,these results show the potential applications of physical environments,such as MFs in this study,in the treatment of LLPS-related diseases.

关键词： inhibited Apoptosis finding

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Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 170-187页

作者： Bao Li Haoran Niu Xiaoyun Zhao Xiaoyu Huang Yu Ding Ke Dang Tianzhi Yang Yongfeng Chen Jizhuang Ma Xiaohong Liu Keda Zhang Huichao Xie Pingtian Ding school of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China school of Life Science and biopharmaceutics Shenyang Pharmaceutical University Shenyang 110016 China Department of Basic Pharmaceutical Sciences school of Pharmacy Husson University Bangor ME 04401USA College of Pharmacy Shenzhen Technology UniversityShenzhen 518118China

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

关键词： Anti-angiogenesis Tumor apoptosis Nanoparticles VEGF siRNA Hypoxia inducible factor(HIF)-1 protein Phenethyl isothi ocyanate(PEITC)

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Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging

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Neural Regeneration Research 2025年第3期20卷 794-796页

作者： Neville Ng Michelle Newbery Nicole Miles Lezanne Ooi Molecular Horizons and school of Chemistry and Molecular bioscience University of WollongongWollongongNSWAustralia

Mitochondrial dysfunction and neurodegeneration:Progressive neurodegenerative diseases affect a significant proportion of the population;in a single year,there are as many as 276 million disabilities and 9 million dea... 详细信息

关键词： degenerative diseases Mitochondrial

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The infection kinetics and transmission potential of two Guaico Culex viruses in Culex quinquefasciatus mosquitoes

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Virologica Sinica 2024年第2期39卷 228-234页

作者： Ru-Yi Chen Teng Zhao Jing-Jing Guo Feng Zhu Na-Na Zhang Xiao-Feng Li Hai-Tao Liu Fei Wang Yong-Qiang Deng Cheng-Feng Qin College of bioscience and Bioengineering Jiangxi Agricultural UniversityNanchang330045China State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and EpidemiologyAMMSBeijing100071China school of Life Sciences Southwest Forestry UniversityKunming650224China

Guaico Culex virus(GCXV)is a newly identified segmented Jingmenvirus from Culex spp.mosquitoes in Central and South America.The genome of GCXV is composed of four or five single-stranded positive RNA segments.However,the infection kinetics and transmission capability of GCXV in mosquitoes remain unknown.In this study,we used reverse genetics to rescue two GCXVs(4S and 5S)that contained four and five RNA segments,respectively,in C6/36 cells.Further in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics,protein expression and viral titers.Importantly,GCXV RNAs were detected in the bodies,salivary glands,midguts and ovaries of Culex quinquefasciatus at 4–10 days after oral infection.In addition,two GCXVs can colonize Cx.quinquefasciatus eggs,resulting in positive rates of 15%–35%for the second gonotrophic cycle.In conclusion,our results demonstrated that GCXVs with four or five RNA segments can be detected in Cx.quinquefasciatus eggs during the first and second gonotrophic cycles after oral infection.

关键词： Guaico Culex virus(GCXV) Jingmenvirus Culex quinquefasciatus Vertical transmission

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Long-term efficacy and safety of Huangqi(Radix Astragali Mongolici)-based Traditional Chinese Medicine in diabetic peripheral neuropathy:a Meta-analysis of randomized controlled trials

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Journal of Traditional Chinese Medicine 2024年第2期44卷 229-242页

作者： PING Jing HAO Hongzheng WU Zhenqi ZOU Meijuan LI Zuojing CHENG Gang school of Life Sciences and biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110000China Department of Endocrinology Affiliated Hospital of Liaoning University of Traditional Chinese MedicineShenyang 110000China Department of Research Administration Affiliated Hospital of Liaoning University of Traditional Chinese MedicineShenyang 110000China school of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110000China

OBJECTIVE:To assess the long-term effectiveness of Huangqi(Radix Astragali Mongolici,HQ)-based Traditional Chinese Medicine(TCM)in the treatment of diabetic peripheral neuropathy(DPN).METHODS:Nine databases were searched to retrieve available randomized controlled trials that compared HQbased TCM and Western Medicines in the treatment of DPN.The methodological quality of the included studies was assessed using the Cochrane bias risk tool,and RevMan 5.4 was used for data analysis.The effect estimates of interest were risk ratio(RR),mean difference(MD)or standardized mean difference(SMD)with 95%confidence interval(CI).RESULTS:The results from 48 available studies assessing 3759 patients demonstrated that cases administered HQ-based TCM[RR=1.30,95%CI(1.21,1.40),P<0.00001]or HQ-based TCM combined with Western Medicines[RR=1.25,95%CI(1.19,1.31),P<0.00001]exhibited higher total efficacy rates than individuals who received Western Medicine alone.The results showed that the HQ-based TCM group had decreased Toronto Clinical Scoring System scores[MD=-1.50,95%CI(-1.83,-1.17),P<0.00001],and reduced serum interleukin 6[SMD=-0.57,95%CI(-0.87,-0.27),P=0.0002]and tumor necrosis factors-αlevels[SMD=-0.60,95%CI(-0.95,-0.25),P=0.0009].In addition,both HQ-based TCM and HQbased TCM combined with Western Medicine increased nerve conduction velocity and decreased glycaemia compared with Western Medicine alone.In terms of blood lipids,oxidative stress and adverse drug reactions,there were no significant differences between the HQ-based TCM groups and the Western Medicine control group.CONCLUSION:The current Meta-analysis revealed that HQ-based TCM yields higher efficacy and safety than Western Medicine alone for the treatment of DPN,although further well-designed RCTs are required to validate these findings.

关键词： Huangqi(Radix Astragali Mongolici) medicine Chinese traditional diabetic peripheral neuropathy Meta-analysis

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A novel insight of enhancing the hydrogen peroxide tolerance of unspecific peroxygenase from Daldinia caldariorum based on structure

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Chinese Chemical Letters 2024年第4期35卷 426-430页

作者： Tiantian Li Ruochen Jin Bin Wu Dongming Lan Yunjian Ma Yonghua Wang school of Food Science and Engineering South China University of TechnologyGuangzhou 510640China school of bioscience and Bioengineering South China University of TechnologyGuangzhou 510006China Guangdong Youmei Institute of Intelligent Bio-manufacturing Co. Ltd.Foshan 528200China

Unspecific peroxygenases(UPOs, EC 1.***.2.1) is a kind of thioheme enzyme capable of catalyzing various oxidations of inert C–H bonds using H_(2)O_(2) as an oxygen donor without cofactors. However, the enhancement of the H_(2)O_(2) tolerance of UPOs is always challenging. In this study, the A161C mutant of r Dca UPO,which originates from Daldinia caldariorum, was found to be highly H_(2)O_(2)-resistant. Compared with the wild type, the mutant r Dca UPO-A161C showed a 10-h prolonged half-life and a 64% improved enzyme activity when incubated in 10 mmol/L H_(2)O_(2). The crystal structure analysis at 1.47 A showed that r Dca UPOA161C exhibited 10 α-helixes(cyan) and a series of ordered rings, forming a single asymmetric spherical structure. The two conserved domains near heme formed an active site with the catalytic PCP and EHD regions(Glu86, His87, Asp88 residues). The H_(2)O_(2) tolerance of r Dca UPO-A161C was preliminarily explored by comparing its structure with the wild type. Notably, r Dca UPO-A161C showed significantly higher catalytic efficiency than the wild type for the production of hydroxyl fatty acids. This study is anticipated to provide an insight into the structure-function relationship and expand potential applications of UPOs.

关键词： Unspecific peroxygenase Molecular modification Hydrogen peroxide stability Crystal structure Hydroxyl fatty acids

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