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Pharmacological intervention for chronic phase of spinal cord injury

Neural Regeneration Research 2025年第5期20卷 1377-1389页

作者： Chihiro Tohda Section of Neuromedical Science Institute of Natural MedicineUniversity of ToyamaToyamaJapan

Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challenging issues in spinal cord injury. As spinal cord injury progresses to the chronic phase, lost motor and sensory functions are not recovered. Several reasons may be attributed to the failure of recovery from chronic spinal cord injury. These include factors that inhibit axonal growth such as activated astrocytes, chondroitin sulfate proteoglycan, myelin-associated proteins, inflammatory microglia, and fibroblasts that accumulate at lesion sites. Skeletal muscle atrophy due to denervation is another chronic and detrimental spinal cord injury–specific condition. Although several intervention strategies based on multiple outlooks have been attempted for treating spinal cord injury, few approaches have been successful. To treat chronic spinal cord injury, neural cells or tissue substitutes may need to be supplied in the cavity area to enable possible axonal growth. Additionally, stimulating axonal growth activity by extrinsic factors is extremely important and essential for maintaining the remaining host neurons and transplanted neurons. This review focuses on pharmacotherapeutic approaches using small compounds and proteins to enable axonal growth in chronic spinal cord injury. This review presents some of these candidates that have shown promising outcomes in basic research(in vivo animal studies) and clinical trials: AA-NgR(310)ecto-Fc(AXER-204), fasudil, phosphatase and tensin homolog protein antagonist peptide 4, chondroitinase ABC, intracellular sigma peptide,(-)-epigallocatechin gallate, matrine, acteoside, pyrvate kinase M2, diosgenin, granulocyte-colony stimulating factor, and fampridine-sustained release. Although the current situation suggests that drug-based therapies to recover function in chronic spinal cord injury are limited, potential candidat

关键词： axonal growth chronic phase clinical study pharmacotherapy spinal cord injury

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Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation

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Chinese Journal of natural medicines 2024年第5期22卷 387-401页

作者： FENG Qianwen SUN Lu Muhammad Jibran Sualeh ZHAO Qingli ZHAO Songji CUI Zhengguo INADERA Hidekuni Department of Public Health Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyama 930-8501Japan Department of Pediatric Cardiology Heart CenterGuangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangzhou 510000China Department of Basic Medical Sciences College of MedicineUniversity of SharjahSharjah 57545United Arab Emirates Department of Radiology Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyama 930-8501Japan Advanced Clinical Research Center Fukushima Global Medical Science CenterFukushima Medical UniversityFukushima CityFukushima 960-8074Japan Department of Environmental Health School of Medical SciencesUniversity of FukuiFukui 910-8580Japan

Hernandezine(Her),a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum,is recognized for its range of biological activities inherent to this herbal *** its notable properties,the anti-cancer effects of Her have remained largely *** this study,we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis ***,Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems,leading to LC3 *** findings revealed that Her caused damage to the mitochondrial membrane,with the damaged mitochondria undergoing mitophagy,as evidenced by the elevated expression of mitophagy ***,Her disrupted autophagic flux,demonstrated by the upregulation of p62 and accumulation of autolysosomes,as observed in the RFP-GFP-LC3 reporter ***,we determined that Her did not prevent the fusion of autophagosomes and ***,it inhibited the maturation of cathepsin D and increased lysosomal pH,indicating an impairment of lysosomal *** use of the early-stage autophagy inhibitor,3-methyladenine(3-MA),did not suppress LC3II,suggesting that Her also induces noncanonical autophagy in autophagosome *** application of Bafilomycin A1,an inhibitor of noncanonical autophagy,diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her,thereby augmenting Her-induced cell *** observations imply that while autophagy initially plays a protective role,the disruption of the autophagic process by Her promotes programmed cell *** study provides the first evidence of Her’s dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell *** insights contribute to a deeper understanding of the mechanisms underlying programmed cell death,offering potential avenues for enhancing cancer prevention and therapeutic st

关键词： Hernandezine Apoptosis Mitophagy Autophagic flux Lysosome Noncanonical autophagy

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Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation

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Chinese Journal of natural medicines 2024年第4期22卷 307-317页

作者： TAO Lei DOU Renjie CHEN Xueming CAO Yu DAI Zhen HU Ziyan MA Zhi GE Xiaoming ZHANG Ling WANG Xiaoping Nanjing institute for Food and Drug Control Nanjing 211198China State Key Laboratory of natural medicines School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 211198China

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellaria baicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg^(−1), i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.

关键词： Oroxyloside ER stress PPARγ Colitis

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Mapping Network-Coordinated Stacked Gated Recurrent Units for Turbulence Prediction

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IEEE/CAA Journal of Automatica Sinica 2024年第6期11卷 1331-1341页

作者： Zhiming Zhang Shangce Gao MengChu Zhou Mengtao Yan Shuyang Cao Faculty of Engineering University of ToyamaToyama 930-8555Japan Helen and John C.Hartmann Department of Electrical and Computer Engineering New Jersey Institute of TechnologyNewark NJ 07102 USA Gaoling School of Artificial Intelligence Renmin University of ChinaBeijing 100872China College of Civil Engineering Tongji UniversityShanghai 200092China IEEE

Accurately predicting fluid forces acting on the sur-face of a structure is crucial in engineering ***,this task becomes particularly challenging in turbulent flow,due to the complex and irregular changes in the flow *** this study,we propose a novel deep learning method,named mapping net-work-coordinated stacked gated recurrent units(MSU),for pre-dicting pressure on a circular cylinder from velocity ***-cally,our coordinated learning strategy is designed to extract the most critical velocity point for prediction,a process that has not been explored *** our experiments,MSU extracts one point from a velocity field containing 121 points and utilizes this point to accurately predict 100 pressure points on the *** method significantly reduces the workload of data measure-ment in practical engineering *** experimental results demonstrate that MSU predictions are highly similar to the real turbulent data in both spatio-temporal and individual ***,the comparison results show that MSU predicts more precise results,even outperforming models that use all velocity field *** with state-of-the-art methods,MSU has an average improvement of more than 45%in various indicators such as root mean square error(RMSE).Through comprehensive and authoritative physical verification,we estab-lished that MSU’s prediction results closely align with pressure field data obtained in real turbulence *** confirmation underscores the considerable potential of MSU for practical applications in real engineering *** code is available at https://***/zhangzm0128/MSU.

关键词： Convolutional neural network deep learning recurrent neural network turbulence prediction wind load predic-tion.

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Tryptophan-specific peptide modification through metal-free photoinduced N-H alkylation employing N-aryl glycines

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Chinese Chemical Letters 2024年第6期35卷 316-319页

作者： Jianhui Yin Wenjing Huang Changyong Guo Chao Liu Fei Gao Honggang Hu School of medicine or institute of Translation medicine Shanghai UniversityShanghai 200444China

Tryptophan(Trp)carries a unique heteroaromatic indole side chain and plays a critical role in peptide or protein ***,we have reported a metal-free photoinduced N-H alkylation strategy using N-aryl glycines for specific modification of tryptophan-containing *** robustness of our approach is demonstrated by its wide substrate scope,excellent isolated yields,as well as almost unobservable side *** this highly efficiently metal-free condition,alkylated Trp-containing peptides can be smoothly *** study provides a reliable and practical tool for the chemo-selective modification of various tryptophan containing oligopeptides.

关键词： Tryptophan Peptide Modification Glycine Photoinduced

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Tuina alleviates neuropathic pain through regulate the activation of microglia and the secretion of inflammatory cytokine in spinal cord

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Journal of Traditional Chinese medicine 2024年第4期44卷 762-769页

作者： WU Zhiwei ZHU Qingguang KONG Lingjun SONG Pengfei ZHOU Xin GUO Guangxin ZHANG Shuaipan HE Tianxiang CHENG Yanbin FANG Min Yueyang Hospital of Integrated Traditional Chinese and Western medicine Shanghai University of Traditional Chinese Medicine institute of Tuina Shanghai Institute of Traditional Chinese Medicine Shuguang Hospital Shanghai University of Traditional Chinese Medicine Department of Acupuncture and Tuina Shanghai University of Traditional Chinese Medicine

OBJECTIVE: To observe the analgesic effects of Tuina on neuropathic pain(NPP) and the underlying mechanisms. METHODS: Forty-eight Sprague-Dawley(SD) rats were assigned by random into three treatment groups: sham, chronic constriction injury(CCI), and Tuina. Each group contained sixteen rats. CCI model was generated by ligating the right sciatic nerve. Behavioral changes of CCI were assessed by the paw withdrawal threshold(PWT) and paw withdrawal latency(PWL). In addition, biochemical techniques such as immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA) and Western blotting were used to profile levels of microglia activation and inflammatory factors in the spinal dorsal horn(SDH) of rats. Tuina(clockwise pressing and rubbing) was performed at Chengshan(BL57) to observe the analgesic effects on CCI rats and the underlying mechanisms. RESULTS: Rats with CCI experienced significant reduction in the PWT and PWL of the right hind paw relative to CCI group at day 3. Tuina treatment rescued this situation significantly on days 10 and 14. Besides, Iba-1, microglia M1 receptor CD68, tumor necrosis factor-α(TNF-α), and interleukin-1β(IL-1β) were higher in the right SDH for CCI group compared to the sham group on day 14. As expected, Tuina partially downregulated the CCI-induced overexpressed Iba-1, CD68, TNF-α, and IL-1β in the SDH of CCI model. CONCLUSION: Tuina induces a time-dependent cumulative analgesic effect in CCI rats by inhibiting the activation of microglia and the secretion of IL-1β and TNF-α in SDH.

关键词： Tuina inflammatory cytokine microglia neuralgia spinal cord

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Amyloid-beta and tau protein beyond Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1262-1276页

作者： Morteza Abyadeh Vivek Gupta Joao A.Paulo Arezoo Gohari Mahmoudabad Sina Shadfar Shahab Mirshahvaladi Veer Gupta Christine T.O.Nguyen David I.Finkelstein Yuyi You Paul A.Haynes Ghasem H.Salekdeh Stuart L.Graham Mehdi Mirzaei ProGene Technologies Pty Ltd. 2. Department of Clinical medicine Faculty of Medicine Health and Human Sciences Macquarie Medical School Macquarie University Department of Cell Biology Harvard Medical School School of medicine Deakin University Department of Optometry and Vision Sciences School of Health Sciences Faculty of Medicine Dentistry and Health Sciences University of Melbourne The Florey institute of Neuroscience and Mental Health The University of Melbourne School of natural Sciences Macquarie University

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer’s disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, posttranslational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

关键词： amyloid-beta cancer cardiovascular diseases diabetes neurodegeneration Tau traumatic brain injury

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Parkland trees on smallholder farms ameliorate soil physical-chemical properties in the semi-arid area of Tigray,Ethiopia

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Journal of Arid Land 2024年第1期16卷 1-13页

作者： Selam LJALEM Emiru BIRHANE Kassa TEKA Daniel H BERHE Department of Land Resources Management and Environmental Protection College of Dryland Agriculture and Natural ResourcesMekelle UniversityMekelle 231Ethiopia institute of Climate and Society Mekelle UniversityMekelle 231Ethiopia Faculty of Environmental Sciences and natural Resource Management Norwegian University of Life Sciences(NMBU)Ås 1432Norway Department of natural Resources Management Adigrat UniversityAdigrat 50Ethiopia

Proposed agroforestry options should begin with the species that farmers are most familiar with,which would be the native multipurpose trees that have evolved under smallholder farms and socioeconomic *** African birch(Anogeissus leiocarpa(DC.)Guill.&Perr.)and pink jacaranda(Stereospermum kunthianum Cham.)trees are the dominant species in the agroforestry parkland system in the drylands of Tigray,*** farmers highly value these trees for their multifunctional uses including timber,firewood,charcoal,medicine,*** trees also could improve soil ***,the amount of soil physical and chemical properties enhanced by the two species must be determined to maintain the sustainable conservation of the species in the parklands and to scale up to similar agroecological ***,we selected twelve isolated trees,six from each species that had similar dendrometric characteristics and were growing in similar environmental *** divided the canopy cover of each tree into three radial distances:mid-canopy,canopy edge,and canopy gap(control).At each distance,we took soil samples from three different *** collected 216 soil samples(half disturbed and the other half undisturbed)from each canopy position and soil *** density(BD),soil moisture content(SMC),soil organic carbon(SOC),total nitrogen(TN),available phosphorus(AP),available potassium(AK),p H,electrical conductivity(EC),and cation exchange capacity(CEC)were *** revealed that soil physical and chemical properties significantly improved except for soil texture and EC under both species,CEC under ***,and soil p H under ***,all the studied soils were improved under both species canopy as compared with canopy ***,TN,AP,and AK under canopy of these trees were respectively 24.1%,11.1%,55.0%,and 9.3% higher than those soils under *** two parkland agroforestry species significantly enhanced soil fertility near the canopy of top

关键词： agroforestry bulk density carbon stock dispersed tree soil texture tree canopy

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A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

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Chinese Journal of natural medicines 2024年第2期22卷 112-126页

作者： REN Boxue LI Yang DI Lei CHENG Ranran LIU Lijuan LI Hongmei LI Yi TANG Zhangrui YAN Yongming LU Tao FU Rong CHENG Yongxian WU Zhaoqiu State Key Laboratory of natural medicines Department of PharmacologySchool of PharmacyChina Pharmaceutical UniversityNanjing 211198China institute for Inheritance-Based Innovation of Chinese medicine School of Pharmaceutical SciencesShenzhen University Health Science CenterShenzhen 518060China

The tumor suppressor protein p53 is central to cancer biology,with its pathway reactivation emerging as a promising therapeutic strategy in *** study introduced LZ22,a novel compound that selectively inhibits the growth,migration,and metastasis of tumor cells expressing wild-type p53,demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant ***22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 *** interaction disrupted the MDM2-p53 binding,consequently stabilizing p53 by shielding it from proteasomal ***22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling ***,LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT,effectively reducing tumor cell migration and distal ***,LZ22 administration in tumor-bearing mice did not manifest notable side *** findings position LZ22 as a structurally unique reactivator of p53,offering therapeutic promise for the management of human cancers with wild-type TP53.

关键词： LZ22 Wild-type p53 p53 Reactivator Snail-driven EMT Tumor growth and metastasis

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TCP-1,a novel peptide to diagnose early colon cancer

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Chinese Chemical Letters 2024年第3期35卷 226-233页

作者： Hang Yu Baoying Wen Min Huang Ru Feng Libin Pan Manyi Xu Hao Lin Lin Cong Sen Zhang Yan Li Chi-Hin Cho Chongjing Zhang Xiaoguang Chen Yan Wang State Key Laboratory of Bioactive Substances and Functions of natural medicines Institute of Materia MedicaChinese Academy of Medical SciencesBeijing 100050China School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongHong KongChina

A nine cyclic peptide(TCP-1)showed excellent specificity for colon ***-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon *** mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and *** screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor *** studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/*** tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other *** TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in *** tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal *** proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-*** high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the *** applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.

关键词： Colon cancer TCP-1 Peptide Cytokeratin 5 Pharmacokinetics/pharmacodynamics(PK/PD)

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