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Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats

Chinese Journal of Integrative Medicine 2022年第9期28卷 833-839页

作者： WANG Feng-jiao SHI She WANG Yong-qiang WANG Ke FAN Shen-dong ZHANG Ya-nan FENG Chen-chen JU Zi-yong College of Acumox and Tuina Shanghai University of Traditional Chinese MedicineShanghai201203China Department of Anesthesiology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai200120China Acupuncture Anesthesia Clinical Research Institute Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghai200437China

Objective:To study the effect of electroacupuncture(EA)on Oxaliplatin-induced peripheral neuropathy(OIPN)in rats.Methods:Male Sprague-Dawley rats were equally divided into 3 groups using a random number table:the control group,the OIRN group,and the EA(OIPN+EA)group,with 10 rats in each.The time courses of mechanical,cold sensitivity,and microcirculation blood flow intensity were determined.The morphology of the dorsal root ganglion(DRG)was observed by electron microscopic examination.The protein levels of nuclear factor E2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and the transient receptor potential(TRP)protein family in DRGs were assayed by Western blot.Results:EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats(POxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs(POxaliplatin(P<0.01).In addition,the expression levels of Nrf2 and HO-1 were down-regulated,and the TRP protein family was over-expressed in the DRGs of OIPN rats(P<0.01).EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG(P<0.05 or P<0.01).Conclusion:EA may be a potential alternative therapy for OIPN,and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

关键词： electroacupuncture Oxaliplatin peripheral neuropathy dorsal root ganglion nuclear factor-erythroid-2-related factor 2

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Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory Oxaliplatin(Ⅳ) prodrug delivery and enhanced colorectal cancer therapy

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Chinese Chemical Letters 2024年第4期35卷 280-286页

作者： Wenjia Wang Xingyue He Xiaojie Wang Tiantian Zhao Osamu Muraoka Genzoh Tanabe Weijia Xie Tianjiao Zhou Lei Xing Qingri Jin Hulin Jiang State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Faculty of Pharmacy Kinki University HigashiosakaOsaka 577-8502Japan State Key Laboratory of Natural Medicines(SKLNM)and Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 210009China School of Pharmacy Hangzhou Medical CollegeHangzhou 311399China College of Pharmacy Yanbian UniversityYanji 133002China

Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.

关键词： Oxaliplatin Glutathione depletion Tetravalent platinum prodrug Synergistic therapy Colorectal cancer

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Treatment outcome analysis of bevacizumab combined with cyclophosphamide and Oxaliplatin in advanced pseudomyxoma peritonei

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World Journal of Gastrointestinal Surgery 2023年第6期15卷 1149-1158页

作者： Ying Zhang Xin Zhao Chao Gao Lin-Yu Lin Yan Li Department of Peritoneal Cancer Surgery Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China

BACKGROUND Pseudomyxoma peritonei(PMP)is a rare peritoneal malignant tumor syndrome.Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is its standard treatment.However,there are few studies and insufficient evidence regarding systemic chemotherapy of advanced PMP.Regimens for colorectal cancer are often used clinically,but there is no uniform standard for late-stage treatment.AIM To determine if bevacizumab combined with cyclophosphamide and Oxaliplatin(Bev+CTX+OXA)is effective for treatment of advanced PMP.The primary study endpoint was progression-free survival(PFS).METHODS Retrospective analysis was conducted on the clinical data of patients with advanced PMP who received Bev+CTX+OXA regimen(bevacizumab 7.5 mg/kg ivgtt d1,Oxaliplatin 130 mg/m2 ivgtt d1 and cyclophosphamide 500 mg/m2 ivgtt d1,q3w)in our center from December 2015 to December 2020.Objective response rate(ORR),disease control rate(DCR)and incidence of adverse events were evaluated.PFS was followed up.Kaplan-Meier method was used to draw survival curve,and log-rank test was used for comparison between groups.Multivariate Cox proportional hazards regression model was used to analyze the independent influencing factors of PFS.RESULTS A total of 32 patients were enrolled.After 2 cycles,the ORR and DCR were 3.1%and 93.7%,respectively.The median follow-up time was 7.5 mo.During the follow-up period,14 patients(43.8%)had disease progression,and the median PFS was 8.9 mo.Stratified analysis showed that the PFS of patients with a preoperative increase in CA125(8.9 vs 2.1,P=0.022)and a completeness of cytoreduction score of 2-3(8.9 vs 5.0,P=0.043)was significantly longer than that of the control group.Multivariate analysis showed that a preoperative increase in CA125 was an independent prognostic factor for PFS(HR=0.245,95%CI:0.066-0.904,P=0.035).CONCLUSION Our retrospective assessment confirmed that the Bev+CTX+OXA regimen is effective in second-or posterior-line treatment of advanced PMP and that adverse reactions can be tolera

关键词： Pseudomyxoma peritonei Bevacizumab Oxaliplatin Cyclophosphamide

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Attention and Intervention of Oncologists on Oxaliplatin-induced Adverse Reactions in China' Mainland:A Cross-sectional Internet-based Survey

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Current Medical Science 2022年第6期42卷 1319-1324页

作者： Wei LI Lu XIAO Zao-qin YU Min LI Xi-min WANG Dong LIU Cheng-liang ZHANG Department of Pharmacy Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Rehabilitation Division Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective This cross-sectional study aimed to investigate the current attention and intervention of oncologists on Oxaliplatin(OXA)-induced adverse reactions(ADRs).Methods In 31 provinces or administrative regions across China,401 oncologists were surveyed through a self-designed questionnaire.The survey queried the basic information of respondents,clinical use of OXA,OXA-induced ADRs,and relative interventions.Chi-square tests and multiple logistic regression were used to explore the sociodemographic factors influencing the safety perception of OXA and the relevant interventions.Results The survey showed that the age of respondents was mainly distributed between 30 and 40 years and the working period for most oncologists was no more than 5 years.Oncologists with long working years were more willing to conduct patient education and inquire about ADRs than those with short working years.The rate of ADRs reported by oncologists with intermediate professional titles was significantly higher than that reported by oncologists with junior and senior professional titles.Conclusion Our findings indicate that oncologists in China's Mainland are concerned about OXA-induced ADRs,but the reporting of ADRs still needs to be strengthened.Therefore,training and educational programs are urgently needed to improve the risk management of OXA-induced ADRs among oncologists.

关键词： Oxaliplatin adverse reaction intervention cross-sectional survey

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HOXB8 contributed to Oxaliplatin chemo-resistance in colon cancercells by activating STAT3

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BIOCELL 2023年第10期47卷 2245-2254页

作者： LIANLI NI YUN YU HAN LIN WEISHAN ZHUGE LU TAO YIWEI SHEN RI CUI SHAOTANG LI Department of Colorectal Surgery The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China Cancer and Anticancer Drug Research Center School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou325035China

Background:Homeobox B8(HOXB8),a member of HOX family,plays a key role in the development of colorectal cancer(CRC).However,the function of HOXB8 in Oxaliplatin(OXA)resistance in CRC is still unclear.This study investigated the role and precise molecular mechanism of HOXB8 in OXA-resistant CRC cells.Methods:The cell viability was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay,and the colony forming ability was determined by colony formation assay.The silencing RNA(siRNA)approach was used to knockdown HOXB8 in CRC cells while the lentiviral transfection system was used to establish stable HOXB8 overexpressing CRC cells.The protein and mRNA levels were evaluated by western blot and real-time reverse transcription-polymerase chain reaction.Results:HOXB8 expression was upregulated in OXA-resistant HCT116 cells(HCT116/OXA)compared to its level in the parent HCT116 cells.Knockdown of HOXB8 significantly inhibited CRC cell growth by suppressing the signal transducer and activator of transcription 3(STAT3)pathway.HOXB8 knockdown also potentiated cytotoxicity of OXA in CRC cells.Inversely,HOXB8 overexpression attenuated OXAinduced growth inhibition of HCT116 cells and RKO cells by activating STAT3 signaling.HOXB8 knockdown effectively inhibited HCT116/OXA cell viability regardless of OXA treatment by suppressing STAT3 signaling.Conclusions:These results shed light on the important functions of HOXB8 in OXA-resistant CRC and suggested that targeting HOXB8 might be an effective therapeutic strategy for select OXA-resistant CRC patients.

关键词： HOXB8 Drug-resistance Colorectal cancer STAT3 Oxaliplatin

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Hepatic arterial infusion of Oxaliplatin plus raltitrexed in unresectable hepatocellular carcinoma with or without portal vein tumour thrombosis

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Gastroenterology Report 2022年第1期10卷 341-348页

作者： Shiguang Chen Wenchang Yu Kongzhi Zhang Weifu Liu Xiaolong Wang Chuanben Chen Department of Interventional Oncology Fujian Medical University Cancer HospitalFuzhouChina Department of Radiotherapy Oncology Fujian Medical University Cancer HospitalFuzhouChina

Background Unresectable hepatocellular carcinoma(HCC)has a poor prognosis.According to the HCC management guidelines in China,the standard treatment of Barcelona Clinic Liver Cancer(BCLC)stage B or C HCC with portal vein tumour thrombosis(PVTT)is chemoembolization.However,some patients with BCLC stage B or C HCC with PVTT respond poorly to chemoembolization.We aimed to compare tumour responses and survival benefits between patients with unresectable HCC with or without PVTT.Methods We reviewed 119 consecutive patients with unresectable HCC with PVTT(n=67)and without PVTT(n=52)who underwent hepatic arterial infusion of Oxaliplatin plus raltitrexed between January 2018 and April 2021.Overall survival,progression-free survival,tumour responses,and adverse events were compared between the groups.Results There were no significant between-group differences in the objective response rates and median progression-free survival.The median overall survival was significantly longer in the group without PVTT than in that with PVTT(17.0 vs 10.4 months,respectively;P=0.024).Conclusion Hepatic arterial infusion of Oxaliplatin plus raltitrexed may be efficacious in patients with unresectable HCC with or without PVTT.

关键词： hepatic arterial infusion hepatocellular carcinoma Oxaliplatin portal vein tumour thrombosis raltitrexed

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Prostaglandin F_(2α)synthase promotes Oxaliplatin resistance in colorectal cancer through prostaglandin F_(2α)-dependent and F_(2α)-independent mechanism

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World Journal of Gastroenterology 2023年第39期29卷 5452-5470页

作者： Yi-Jun Wang Xiao-Li Xie Hong-Qun Liu Hui Tian Xiao-Yu Jiang Jiu-Na Zhang Sheng-Xiong Chen Ting Liu Shu-Ling Wang Xue Zhou Xiao-Xu Jin Shi-Mao Liu Hui-Qing Jiang Department of Gastroenterology The Second Hospital of Hebei Medical UniversityShijiazhuang 050000Hebei ProvinceChina Liver Unit University of CalgaryCalgary T1W0K6Canada Department of Gastroenterology The Affiliated Hospital of Hebei Engineering UniversityHandan 056000Hebei ProvinceChina Department of Hepatobiliary Surgery The Second Hospital of Hebei Medical UniversityShijiazhuang 050000Hebei ProvinceChina Department of Gastroenterology The First Hospital of Hebei Medical UniversityShijiazhuang 050000Hebei ProvinceChina Department of Gastroenterology Hebei Youfu HospitalShijiazhuang 050000Hebei ProvinceChina

BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanism

关键词： Prostaglandin F_(2α)synthase Colorectal cancer Oxaliplatin Drug resistance DNA damage

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Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-a/NF-j B Signaling in Rats

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Neuroscience Bulletin 2021年第1期37卷 55-69页

作者： Xin Zhou Zhuo Huang Jun Zhang Jia-Liang Chen Pei-Wen Yao Chun-Lin Mai Jie-Zhen Mai Hui Zhang Xian-Guo Liu Department of Physiology and Pain Research Center Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China Department of Anesthesiology Guangdong Second Provincial General HospitalGuangzhou 510317China Department of Urology Third Affiliated Hospital of Sun Yatsen UniversityGuangzhou 510630China Guangdong Province Key Laboratory of Brain Function and Disease Guangzhou 510080China

Antineoplastic drugs such as Oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2 B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from ~0.8 mmol/L to ~ 0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L) upregulated tumor necrosis factor(TNF-α) and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2 B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.

关键词： Magnesium-L-threonate Oxaliplatin Tumor necrosis factor-alpha Nuclear factor-kappaB Cognitive deficit Hippocampus Medial prefrontal cortex

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Effects of long non-coding RNA Opa-interacting protein 5 antisense RNA 1 on colon cancer cell resistance to Oxaliplatin and its regulation of micro RNA-137

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World Journal of Gastroenterology 2020年第13期26卷 1474-1489页

作者： Jing Liang Xiao-Feng Tian Wei Yang Department of Gastrointestinal Surgery China-Japan Union Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina Department of Hepatopancreatobiliary Surgery China-Japan Union Hospital of Jilin UniversityChangchun 130000Jilin ProvinceChina

BACKGROUND The incidence of colon cancer(CC)is currently high,and is mainly treated with chemotherapy.Oxaliplatin(L-OHP)is a commonly used drug in chemotherapy;however,long-term use can induce drug resistance and seriously affect the prognosis of patients.Therefore,this study investigated the mechanism of Opainteracting protein 5 antisense RNA 1(OIP5-AS1)on L-OHP resistance by determining the expression of OIP5-AS1 and micro RNA-137(miR-137)in CC cells and the effects on L-OHP resistance,with the goal of identifying new targets for the treatment of CC.AIM To study the effects of long non-coding RNA OIP5-AS1 on L-OHP resistance in CC cell lines and its regulation of miR-137.METHODS A total of 114 CC patients admitted to China-Japan Union Hospital of Jilin University were enrolled,and the expression of miR-137 and OIP5-AS1 in tumor tissues and corresponding normal tumor-adjacent tissues was determined.The influence of OIP5-AS1 and miR-137 on the biological behavior of CC cells was evaluated.Resistance to L-OHP was induced in CC cells,and their activity was determined and evaluated using cell counting kit-8.Flow cytometry was used to analyze the apoptosis rate,Western blot to determine the levels of apoptosisrelated proteins,and dual luciferase reporter assay combined with RNA-binding protein immunoprecipitation to analyze the relationship between OIP5-AS1 and miR-137.RESULTS OIP5-AS1 was up-regulated in CC tissues and cells,while miR-137 was downregulated in CC tissues and cells.OIP5-AS1 was inversely correlated with miR-137(P<0.001).Silencing OIP5-AS1 expression significantly hindered the proliferation,invasion and migration abilities of CC cells and markedly increased the apoptosis rate.Up-regulation of miR-137 expression also suppressed these abilities in CC cells and increased the apoptosis rate.Moreover,silencing OIP5-AS1 and up-regulating miR-137 expression significantly intensified growth inhibition of drug-resistant CC cells and improved the sensitivity of CC cells to LOHP.OIP5-AS1 targetedly inhibited miR-

关键词： Long non-coding RNA Opa-interacting protein 5 antisense RNA 1 Micro RNA-137 Colon cancer Drug resistance Oxaliplatin Biological behavior

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Analgesic effect of AG490, a Janus kinase inhibitor, on Oxaliplatin-induced acute neuropathic pain

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Neural Regeneration Research 2018年第8期13卷 1471-1476页

作者： Shuang-Feng Li Bi-Shan Ouyang Xin Zhao Ya-Ping Wang Department of Anesthesiology The Second Xiangya Hospital Xiangya School of Medicine Central South University Department of Anesthesiology Hainan General Hospital Department of Neurology Xiangya Hospital Xiangya School of Medicine Central South University

Neuropathic pain often occurs during chemotherapy with Oxaliplatin. AG490 has been shown to exert an antagonistic effect on inflammatory pain, but its effect on Oxaliplatin-induced neuropathic pain remains poorly understood. This study sought to observe the analgesic effect of AG490 on acute neuropathic pain induced by a single Oxaliplatin treatment and to address the possible mechanism. In this study, we estab- lished a model of Oxaliplatin-induced acute neuropathic pain by intraperitoneal injection of 6 mg/kg Oxaliplatin. On day 2 after injection, models were intraperitoneally injected with i, 5, or 10 mg/kg AG490. Paw withdrawal threshold to mechanical stimuli and tail withdrawal latency to cold stimuli were determined. Western blot assay was performed to detect the expression of spinal phosphorylated signal transducer and activator of transcription 3 （p-STAT3）. Immunohistochemistry was used to determine the immunoreactivity of p-STAT3 and inter- leukin-6. Results demonstrated that paw withdrawal threshold and tail withdrawal latency were significantly increased by the treatment of AG490 in rats. There was no significant difference in the effect among the different doses of AG490. AG490 10 mg/kg decreased the expression of p-STAT3, the immunoreactivity of p-STAT3 and interleukin-6 in spinal cord of acute neuropathic pain rats. These findings confirm that AG490 can attenuate Oxaliplatin-induced acute neuropathic pain and is associated with the inhibition in the JAK/STAT3 signaling pathway.

关键词： nerve regeneration A G490 analgesia Oxaliplatin cancer chemotherapy neuropathic pain phosphorylated STA T3 JAK/STA Tsignaling pathway interleukin-6 neural regeneration

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