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molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/Oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon Comprehensive Cancer center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical *** considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely *** the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint *** aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor *** therapies thus have shown promising results in many clinical trials alone or in *** efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical *** trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair ***,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC *** this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the *** review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in *** underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

Ultrafast molecular Movies:Probing Chemical Dynamics with Femtosecond Electron and X-Ray Diffraction

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CCS Chemistry 2024年第5期6卷 1092-1109页

作者： Qianci Wang Longteng Yun Jie Yang center of Basic molecular Science Department of ChemistryTsinghua UniversityBeijing 100084

Understanding the process of chemical reactions has always been a relentless pursuit for *** development of femtosecond pump-probe techniques since the 1980s has revolutionized the field of chemical dynamics,enabling the capture of timeresolved snapshots of reactions on the femtosecond *** from the 2010s,breakthroughs in femtosecond electron and X-ray sources has enabled ultrafast electron and X-ray diffraction techniques,which is able to directly reveal the temporal evolution of atomic geometries of molecules,allowing for the creation of molecular ***-phase molecular movies reveal intrinsic intramolecular processes,while liquid-phase molecular movies provide insights for complicated solvent-solute *** minireview focuses on the advances in studying gasphase and liquid-phase molecular dynamics(MD)using ultrafast electron and X-ray diffraction techniques on femtosecond and picosecond *** fast-developing experimental capability of the direct observation of molecular structural evolution during chemical reactions,on its natural femtosecond timescale and subangstrom length scale,offers tremendous potential for the field of chemical kinetics and MD.

关键词： molecular movie electron diffraction X-raydiffraction femtosecond gasphase liquidphase

SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer

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Genes & Diseases 2024年第2期11卷 978-992页

作者： Ming-Yan Shi Yarong Wang Ying Shi Ruofei Tian Xiaohong Chen Hai Zhang Ke Wang Zhinan Chen Ruo Chen National Translational Science center for molecular medicine & Department of Cell Biology Fourth Military Medical UniversityXi'anShaanxi 710032China

Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor ***147 is a tumor biomarker with various PTMs,promoting tumor metastasis and metabolism ***,the relationship between the PTMs of CD147 and apoptosis has not been *** our study,we produced a specific anti-CD147-K71 di-methylation(CD147-K71me2)antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer(NSCLC)tissues were lower than that in NSCLC adjacent ***1 was identified as the methyltransferase catalyzing CD147 to generate ***-seq showed that FOSB was the most significant differentially expressed gene(DEG)between wild-type CD147(CD147-WT)and K71-mutant CD147(CD147-K71R)***,we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38,leading to tumor cell *** vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell *** together,our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification,which is distinct from the pro-cancer function of CD147 itself,broadening our perspective on tumor-associated antigen CD147.

关键词： CD147 di-methylation Cell apoptosis FOSB Non-small cell lung cancer SETDB1

Going only half the way:cell cycle exit after the G1 restriction point

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Signal Transduction and Targeted Therapy 2024年第1期9卷 1-2页

作者： Lisa Muller Tony Gutschner Mechthild Hatzfeld Department of Pathobiochemistry Institute of Molecular MedicineMartin Luther University Halle-WittenbergCharles Tanford Protein Research CenterHalleGermany Department of RNA Biology and Pathogenesis Institute of Molecular MedicineMartin Luther University Halle-WittenbergCharles Tanford Protein Research CenterHalleGermany

In a recent article published in Nature,James *** et *** that cyclin A2 levels determine whether cells will make an entrance into mitosis or whether cells will leave the cell cycle after having passed the G1/restriction(R)-point implicating that the decision is fully reversible(Fig.1).This ground-breaking study could impact future approaches for cancer treatment by targeting the mitotic clock.

关键词： point cycle

molecular characterization and structure basis of a malonyltransferase with both substrate promiscuity and catalytic regiospecificity from Cistanche tubulosa

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2333-2348页

作者： Xiao Liu Yuyu Liu Xiping Xu Wenqian Huang Yaru Yan Yingxia Wang Weisheng Tian Ting Mo Xiaoxue Cui Jun Li She-Po Shi Pengfei Tu Modern Research center for Traditional Chinese medicine Beijing Research Institute of Chinese MedicineBeijing University of Chinese MedicineBeijing 100029China Modern Research center for Traditional Chinese medicine School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijing 100029China

Enzymatic malonylation of natural glycosides provides a promising alternative method for drug-like malonylated glycosides ***,the catalytic potential and structural basis of plant malonyltransferase are far from being fully *** work identified a new malonyltransferase CtMaT1 from Cistanche *** displayed unprecedented mono-and/or di-malonylation activity toward diverse glucosides with different aglycons.A“one-pot”system by CtMaT1 and a malonyl-CoA synthetase was established to biosynthesize nine new malonylated *** investigations revealed that CtMaT1 possesses an adequately spacious acyl-acceptor pocket capable of accommodating diverse ***,it recognizes malonyl-CoA through strong electrotactic and hydrogen ***/MM calculation revealed the H167-mediated SN2 reaction mechanism of CtMaT1,while dynamic simulations detected the formation of stable hydrogen bonds between the glucose-6-OH group and H167,resulting in its high malonylation *** energy profiles of two isomeric glycosides highlighted lower reaction energy barriers towards glucoside substrates,emphasizing CtMaT1's preference for ***,a mutant CtMaT1H36A with notably increased di-malonylation activity was *** underlying molecular mechanism was illuminated through MM/GBSA binding free energy *** study significantly advances the understanding of plant acyltransferases from both functional and protein structural perspectives,while also providing a versatile tool for enzymatic malonylation applications in pharmacology.

关键词： Plant acyltransferase Malonyltransferase Malonylated glycosides Enzymatic catalysis Enzyme promiscuity

Wood of trees:Cellular structure,molecular formation,and genetic engineering

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Journal of Integrative Plant Biology 2024年第3期66卷 443-467页

作者： Yingying Zhu Laigeng Li State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems and College of Ecology Lanzhou UniversityLanzhou 730000China National Key Laboratory of Plant molecular Genetics CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 200032China

Wood is an invaluable asset to human society due to its renewable nature,making it suitable for both sustainable energy production and material ***,wood derived from forest trees plays a crucial role in sequestering a significant portion of the carbon dioxide fixed during photosynthesis by terrestrial ***,with the expansion of the global population and ongoing industrialization,forest coverage has been substantially decreased,resulting in significant challenges for wood production and *** production practices have changed away from natural forests toward plantation ***,understanding the underlying genetic mechanisms of wood formation is the foundation for developing high-quality,fast-growing plantation *** ideal forest trees for wood production using genetic technologies has attracted the interest of *** studies have been carried out in recent years on the molecular,genetic,and cell-biological mechanisms of wood formation,and considerable progress and findings have been *** studies and findings indicate enormous possibilities and prospects for tree *** review will outline and assess the cellular and molecular mechanisms of wood formation,as well as studies on genetically improving forest trees,and address future development prospects.

关键词： cambium cell wall Populus wood formation xylem

Simple and robust 3D MINFLUX excitation with a variable phase plate

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Light(Science & Applications) 2024年第7期13卷 1354-1363页

作者： Takahiro Deguchi Jonas Ries European molecular Biology Laboratory Cell Biology and BiophysicsHeidelbergGermany. max Perutz Labs Vienna Biocenter Campus(VBC)ViennaAustria. University of Vienna Center for Molecular BiologyDepartment of Structural and Computational BiologyViennaAustria. University of Vienna Faculty of PhysicsViennaAustria

MINFLUX has achieved extraordinary resolution in superresolution imaging and single fluorophore *** is based on localizing single fluorophores by rapid probing with a patterned beam that features a local intensity *** implementations,however,are complex and expensive and are limited in speed and ***,we show that a combination of an electro-optical modulator with a segmented birefringent element such as a spatial light modulator produces a variable phase plate for which the phase can be scanned on the MHz *** or top-hat phase patterns generate high-contrast compact excitation point-spread functions for MINFLUX localization in the x,y,and z-direction,respectively,which can be scanned across a fluorophore within a microsecond,switched within 60 microseconds and alternated among different excitation *** discuss how to compensate for non-optimal performance of the components and present a robust 3D and multi-color MINFLUX excitation module,which we envision as an integral component of a high-performance and cost-effective open-source MINFLUX.

关键词： excitation phase switched

Peripheral immune cell-derived matrix metalloprotease 8(MMP8):brain trafficking promotes depression-like behavior

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2357-2358页

作者： Dietmar Spengler Theo Rein max Planck Institute of Psychiatry Epigenomics of Early-Life Stress80804 MunichGermany max Planck Institute of Psychiatry Molecular Pathways of Depression80804 MunichGermany

In a study recently published in Nature,Cathomas et al.1 report that social stress in mice increases the levels of matrix metalloprotease(MMP)8 in circulating immune cells,thereby altering extracellular space(ECS)and neuronal activity,and ultimately social behavior in susceptible *** deficits resembled those from major depressive disorder(MDD)raising the prospect of MMP8 as a new druggable target in tailored treatments.

关键词： MMP8 al. behavior

Rheum palmatum L. and Salvia miltiorrhiza Bge. Alleviates Acute Pancreatitis by Regulating Th17 Cell Differentiation: An Integrated Network Pharmacology Analysis, molecular Dynamics Simulation and Experimental Validation

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Chinese Journal of Integrative medicine 2024年第5期30卷 408-420页

作者： FENG Min-chao LUO Fang HUANG Liang-jiang LI Kai CHEN Zu-min LI Hui YAO Chun QIN Bai-jun CHEN Guo-zhong The First Clinical Medical College Guangxi University of Traditional Chinese MedicineNanning 530000China Guangxi Key Laboratory of molecular Biology of Traditional Chinese medicine and Preventive medicine Nanning 530000China Graduate School Guangxi University of Traditional Chinese MedicineNanning 530000China Department of Gastroenterology the First Affiliated Hospital of Guangxi University of Traditional Chinese MedicineNanning 530023China

Objective: To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge.,(Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in acute pancreatitis(AP)using a network pharmacology approach and validate the findings in animal experiments. Methods: Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics ***, the results of network pharmacology enrichment analysis were verified by immunohistochemistry,Western blot analysis and real-time quantitative PCR, respectively. Results: Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3(MAPK3), Janus kinase 2(JAK2), signal transducer and activator of transcription 3(STAT3), protein c-Fos(FOS) were identified as core targets in the protein interaction(PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. molecular dynamics simulation revealed that FOS-isotanshinone Ⅱ and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1β, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation(P<0.01). Conclusion: DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues,which would be functioned by regulating Th17 cell differentiation-related m RNA and protein expressions.

关键词： Rheum palmatum L. Salvia miltiorrhiza Bge. molecular docking simulation network pharmacology acute pancreatitis Th17 cell differentiation