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Background: We aimed to investigate effect of radiotherapy (RT) applications with different dose rates on cytogenetic damages, which focused on micronucleus (MN) formation, and evaluate how this damage varies by cisplatin in rats receiving head–neck RT. Material and Methods: Thirty?six Sprague Dawley rats were divided into five groups. The first and second groups were irradiated at a dose rate of 300 monitor unit/minute (MU/min) and 600 MU/min, respectively. The third group was irradiated at a dose rate of 300 MU/min and given cisplatin. The fourth group was irradiated at a dose rate of 600 MU/min and given cisplatin. The fifth group received neither irradiation nor cisplatin (control group). One thousand polychromatic erythrocytes were scored, and MN frequency in polychromatic erythrocytes was determined for each rat. Results: There was a significant difference among five groups in terms of the number of MN (p: 0.001). The number of MN was significantly higher in the 600 MU/min + cisplatin group (fourth group) compared to the control group [9.5 (1.0–23.0) vs. 1.5 (1.0–2.0), respectively]. It was also significantly higher in 600 MU/min + cisplatin group (fourth group) compared to 300 MU/min group (first group) [9.5 (1.0–23.0) vs. 2.0 (1.0–3.0), respectively]. On the other hand, there was no significant difference among other groups. Conclusions: Our findings suggest that RT given at a higher dose rate causes more cytogenetic damage, and this damage is increased by concurrent administration of cisplatin.
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Drug-induced cardiotoxicity is a major concern during drug development, prompting the need for reliable experimental models to thoroughly assess potential cardioprotective drugs. The review delves into the intricacies of various models for drug-induced cardiotoxicity in experimental animals, with a specific focus on streptozotocin, isoprenaline, and antineoplastic drugs like cisplatin, doxorubicin, and 5-fluorouracil in rats and mice. Streptozotocin-induced cardiotoxicity is characterized by oxidative stress, inflammation, and mitochondrial dysfunction, resulting in myocardial damage and impaired cardiac function. Preclinical studies employing streptozotocin-induced cardiotoxicity models have revealed crucial pathways related to diabetic cardiomyopathy, aiding the evaluation of potential cardioprotective interventions. Isoprenaline, a beta-adrenergic agonist, is known for inducing acute myocardial injury resembling cardiac ischemia and heart failure in animals. Its mechanism involves overstimulation of beta-adrenergic receptors, calcium overload, oxidative stress, and apoptosis. Isoprenaline-induced models have offered insights into acute myocardial injury pathophysiology and facilitated the screening of cardioprotective agents against Myocardial Infarction (MI) and injury. Antineoplastic drugs, such as cisplatin, doxorubicin, and 5-fluorouracil, are linked to significant cardiotoxic effects, including cardiomyopathy and heart failure. Animal models have revealed dose-dependent cardiomyopathy, shedding light on underlying mechanisms like oxidative stress, Deoxyribonucleic Acid (DNA) damage, and mitochondrial dysfunction. The article aims to consolidate the current understanding of the pathophysiology and mechanisms behind drug-induced cardiac damage. Additionally, it underscores the importance of using animal models in preclinical evaluations to assess drug safety and efficacy and to develop potential cardioprotective therapies.
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Background: Cancer is a set of diseases that include the unchecked proliferation and spread of abnormal body cell types. The primary treatment modalities are surgery, radiation, chemotherapy, immunotherapy, and hormones. As it describes the scope, nature, and causes of drug exposures, drug use research is a key and vital component of pharmacoepidemiology. Aim and Objectives: To conduct a study in a tertiary care teaching hospital to examine drug usage patterns among indoor radiotherapy patients. Materials and Methods: A prospective, cross-sectional, observational study was conducted in indoor patients of the radiotherapy department of a tertiary care teaching hospital. Six hundred patients of different types of cancers were involved in the study. At the end of data collection, the data were entered and analyzed with Microsoft Excel 2019. Descriptive statistics were used to analyze the results. Results: Buccal mucosa, tongue, and breast cancers had the highest admission rate with 24.17%, 13.33%, and 12.83%, respectively. The average number of drugs per encounter was 13.58 with a range of 5–17. The most frequently used anticancer drugs were cisplatin, carboplatin, paclitaxel, 5-fluorouracil, cyclophosphamide, and Adriamycin. Out of 32 drugs, 30 drugs were prescribed from the World Health Organization Model List of Essential Medicines, 2021, and National List of Essential Medicines, 2022, and 8 drugs were prescribed by brand name. Conclusion: Compared to other systems such as the pulmonary, breast, genitourinary, and gastrointestinal tract, oral malignancies were more common. The most frequently used anticancer drugs were cisplatin, carboplatin, paclitaxel, 5-fluorouracil, cyclophosphamide, and Adriamycin. Prescribing drugs were mainly from Essential Drug List with generic names.
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Background: In our country, head and neck cancers account for about a third of all cancers. Moreover, the patients typically present in advanced stages, which entails intensive multimodality therapy; but there is not much scope for improved survival outcomes. In view of this, a study was conducted to know the effects of treatment intensification, wherein moderately accelerated fractionation radiotherapy was given to patients presenting with advanced cancer of head and neck. This treatment was further intensified by accompanying radiation with concurrent cisplatin chemotherapy in daily doses. The control arm received the current standard therapy of conventional fractionation radiotherapy with weekly cisplatin chemotherapy. Methods: The primary objective of the study was to determine the prospect of tumor control (TC), disease-free survival (DFS), and overall survival (OS). The secondary objective was to study acute toxicity and late toxicity of the highest grade in both treatment groups. The study was conducted on a total of 60 patients who presented with locally advanced squamous cell carcinoma of the head and neck. The 30 patients in the control group received conventional fractionated radiotherapy (five fractions per week) with weekly cisplatin chemotherapy (40 mg/m2 ), whereas the remaining 30 in the study group received moderately accelerated radiotherapy (six fractions per week with same treatment field) along with daily cisplatin chemotherapy (6 mg/m2 ) with a reduction in treatment time by 1 week. Results: The overall response to therapy assessed as TC, DFS, and OS was compared, and no statistically significant difference between the two treatment arms was observed. However, the mean overall treatment time was reduced in the study group to 45 days as compared with 49 days in the control group (P = 0.001). The acute toxicities of xerostomia (P = 0.057) and skin (P = 0.052) and late toxicity of aspiration/laryngeal toxicity (P = 0.002) were higher in grade and number in the study group with accelerated fractionation. Conclusions: Hence, the study results suggest that it is a feasible option to combine the therapeutic benefits of accelerated fractionation radiotherapy with concurrent chemotherapy in patients with locally advanced head and neck carcinomas. There is a significant decrease in the overall treatment time and a considerable reduction in the load on the resource-constrained healthcare system. It would be equitable to point out that higher grade of few toxicities in the acceleration arm are likely due to doses to organs at risk being intensified with accelerated fractionation, which can now be delivered in a controlled manner with the latest high precision techniques, resulting in improved toxicity profile and quality of life which is the way forward for future studies.
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Introduction: Adjuvant chemoradiotherapy (CRT) is the optimal management strategy in resectable gastric cancer. There is a debate about the efficacy of more aggressive CRT plus chemotherapy regimens in adjuvant setting. This study aimed to compare the efficacy of adjuvant CRT plus docetaxel–cisplatin–fluorouracil (DCF) versus CRT plus fluorouracil–folinic acid (FUFA) in stage III gastric cancer. Methods: Patients with a diagnosis of stage III gastric cancer treated with adjuvant therapy after curative resection were analyzed. Patients’ disease characteristics and impacts of the regimens on median disease?free survival (DFS) and median overall survival (OS) were analyzed retrospectively. Results: One hundred sixty?one patients (102 in FUFA arm and 59 in DCF arm) with a median age of 56.0 (29–79) were evaluated. In the DCF arm, there were more renal toxicities (31.6% vs 6.4% P < 0.001), emergency department admissions (64.9% vs 23.7%, P < 0.001), and dose reductions/treatment modifications in the DCF arm (51.6% vs 37.2, P < 0.001). The median follow?up was 23 months (1–124) in the FUFA arm and 26.0 months (1–77) in the DCF arm. The median DFS was 25.0 months (%95 CI, 12.7–37.2) in the DCF arm and 17.0 months (%95 CI, 2.6–31.3) in the FUFA arm, P = 0.66. The median OS was 28.0 months (%95 CI, 17.0–38.9) in the DCF arm and 25.0 months (%95 CI, 11.9–36.0) in the FUFA arm, P = 0.70. Conclusion: In conclusion, when compared with FUFA regimen, more aggressive therapy with DCF was more toxic and did not improve OS in adjuvant setting of stage III gastric cancer.
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Background: Advanced biliary tract carcinoma is a malignancy associated with poor prognosis and limited treatment options. This study aimed to compare the treatment effects in terms of toxicities of Capecitabine-Cisplatin and Gemcitabine-Cisplatin regimens as palliative chemotherapy for ABTC in Bangladesh. Methods: This quasi-experimental study was conducted at the Department of Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, involving 78 patients with histopathologically confirmed ABTC (AJCC Stage IV). Participants were divided into two groups: Arm-A received Capecitabine-Cisplatin, and Arm-B received Gemcitabine-Cisplatin. Treatment response, hematological and non-hematological toxicities were assessed and compared between the two groups. Results: No significant differences in baseline demographic and clinical characteristics were observed between the two groups. Arm-A demonstrated a higher rate of partial response in the final assessment (51.28% vs. 41.03%, p=0.029). Acute hematological toxicities were more frequent in Arm-B, with a higher incidence of Grade 2 and 3 anemia, neutropenia, and leukopenia (p<0.05). Non-hematological toxicities were comparable, except for Hand-Foot Syndrome, which was significantly higher in Arm-A (p=0.03). Conclusions: The Capecitabine-Cisplatin regimen exhibited a different toxicity profile compared to the Gemcitabine-Cisplatin regimen for palliative chemotherapy in advanced biliary tract carcinoma. While both regimens were generally well-tolerated, the Capecitabine-Cisplatin regimen demonstrated lower incidences of hematological toxicities. These findings emphasize the importance of considering toxicity profiles when selecting treatment options for patients with advanced biliary tract carcinoma.
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Cisplatin (CP) is an important platinum-based chemotherapy agent widely used to treat solid tumors. However, nephrotoxicity is the main limiting adverse effect in 25%–35% of patients treated with even a single dose of CP. This study aimed to evaluate the role of liraglutide (LIRA) and alfacalcidol (ALFA), each of them alone and in combination, in prevention of CP-induced nephrotoxicity. Forty male albino mice were divided into five groups including normal control group and groups CP, CP with LIRA, CP with ALFA, or CP with LIRA and ALFA. Nephrotoxicity was induced by single intraperitoneal injection of CP in a dose 12mg/kg. LIRA and/or ALFA treatment was started 5 days before induction of nephrotoxicity and continued till the end of experiment. Kidney function tests, oxidative stress and ferroptosis parameters were assessed. Histopathological and immunohistochemical examination were performed on kidney tissues. Both LIRA and ALFA monotherapy resulted in a significant improvement in kidney function tests, increased antioxidant levels, inhibition of ferroptosis and improved histopathological findings. LIRA showed more improvement compared to ALFA and their combination showed better results than each one alone. In conclusion, LIRA and ALFA either alone or in combination, represent a promising preventive modality for amelioration of CP-induced nephrotoxicity.
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Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (P<0.05) compared to the control group. Both exercise and ATP prevented (P<0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (P<0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (P<0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.
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Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.
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Objective: Cisplatin?associated acute kidney injury is a common clinical event that causes increased morbidity and mortality in cancer patients even if they are categorized as having normal functioning kidneys. We aimed to determine predictive factors that can predict acute kidney injury associated with cisplatin therapy in patients with normal renal function by comparison of pre?chemotherapy estimated glomerular filtration rates calculated separately by Cockcroft and Gault (CG), the Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD?EP?) equations and accompanying patient?associated factors. Materials and Methods: A total of 200 patients diagnosed with lung cancer and determined to have normal functioning kidneys and considered cisplatin eligible by the attending physician before chemotherapy were included in this retrospective study. Acute kidney injury after cisplatin chemotherapy (c?AKI) was determined according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v4.03. Pre?chemotherapy serum laboratory parameters and clinico?histopathological characteristics of patients were recorded from the hospital electronic system. The optimal cut?off for eGFR methods was determined by the area under the receiver operating characteristic curve (ROC?AUC) analysis. Predictive factor analysis for c?AKI was performed by regression analyses. Results: C?AKI developed in 39 (19.5%) patients. In the univariate analysis, a significant correlation was observed between c?AKI and high body mass index (BMI) before treatment, older age (>62.5), female gender, eGFR by MDRD (?94.5 mL/min) and eGFR by CKD?EPI (?91.5 mL/min). There was no relation between eGFR by CG and c?AKI. Two different multivariate models were established. Model 1 showed that female gender (odds ratio [OR] =4.90, 95% confidence interval [CI]: 1.52–15.79, P = 0.008) and eGFR by MDRD less than or equal to 94.5 mL/min (OR = 3.52, 95% CI: 1.68–7.38, P = 0.001) were predictive markers for c?AKI. In Multivariate Model 2, female gender (OR = 5.51, 95% CI: 1.70–17.83, P = 0.004) and eGFR by CKD?EPI less than or equal to 91.5 mL/min (OR = 3.52, 95% CI: 1.67–7.42, P = 0.001) were found to be predictive markers for c?AKI. Conclusions: This study revealed that eGFR calculated based on MDRD (?94.5 mL/min/m2) or CKD?EPI (?91.5 mL/min/m2) before chemotherapy indicates a strong tendency for c?AKI. In addition, we detected a high risk of c?AKI for females compared to their counterparts. Although eGFR 60 mL/min is considered the threshold level to accept patients as cisplatin?eligible, we recommend close follow?up of high?risk patients for cisplatin nephrotoxicity we detected in our models.
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ObjectiveTo explore the mechanism of Buzhong Yiqitang-containing serum in alleviating the cisplatin resistance in human non-small cell lung cancer (A549/DDP) cells via regulating the nuclear factor E2-related factor 2 (Nrf2)/reactive oxygen species (ROS) signaling pathway. MethodThe serum containing Buzhong Yiqitang was prepared and A549/DDP cells were cultured and randomly grouped: blank (10% blank serum), cisplatin (10% blank serum+20 mg·L-1 cisplatin), Buzhong Yiqitang (10% Buzhong Yiqitang-containing serum+20 mg·L-1 cisplatin), ML385 (10% blank serum+5 μmol·L-1 ML385+20 mg·L-1 cisplatin), Buzhong Yiqitang+ML385 (10% Buzhong Yiqitang-containing serum+5 μmol·L-1 ML385+20 mg·L-1 cisplatin), tertiary butylhydroquinone (TBHQ) (10% blank serum+5 μmol·L-1 TBHQ+20 mg·L-1 cisplatin), and Buzhong Yiqitang+TBHQ (10% Buzhong Yiqitang-containing serum+5 μmol·L-1 TBHQ+20 mg·L-1 cisplatin). The median inhibitory concentration (IC50) of cisplatin in each group was determined by the cell counting kit-8 (CCK-8) method and the resistance index (RI) was calculated. The apoptosis rate was detected by flow cytometry. The ROS content of each group was determined with the DCFH-DA fluorescence probe. Western blot was employed to determine the protein levels of Nrf2, cleaved cysteinyl aspartate-specific protease-3 (cleaved Caspase-3), cytochrome C (Cyt C), and B-cell lymphoma-2 (Bcl-2). ResultCompared with those in the cisplatin group, the IC50 and RI of A549/DDP cells to cisplatin in Buzhong Yiqitang, ML385, and Buzhong Yiqitang+ML385 groups decreased (P˂0.05). Compared with the blank group, the cisplatin, Buzhong Yiqitang, ML385, and Buzhong Yiqitang+ML385 groups showed increased apoptosis rate of A549/DDP cells (P˂0.05). Compared with the blank group, cisplatin promoted the expression of Nrf2 (P˂0.05). Compared with the cisplatin group, Buzhong Yiqitang, ML385, and Buzhong Yiqitang+ML385 inhibited the expression of Nrf2 (P<0.05), elevated the ROS level (P˂0.05), up-regulated the protein levels of cleaved Caspase-3 and Cyt C, and down-regulated the protein level of Bcl-2 (P<0.05), which were the most significant in the Buzhong Yiqitang+ML385 group. Compared with the cisplatin group, the TBHQ group showed increased IC50 and RI of cisplatin (P<0.05), decreased apoptosis rate of A549/DDP cells (P<0.05), up-regulated protein levels of Nrf2 and Bcl-2 (P<0.05), lowered level of ROS (P˂0.05), and down-regulated protein levels of cleaved Caspase-3 and Cyt C (P<0.05). Compared with the TBHQ group, Buzhong Yiqitang+TBHQ decreased the IC50 and RI of cisplatin in A549/DDP cells (P<0.05), increased the apoptosis rate (P<0.05), down-regulated the protein levels of Nrf2 and Bcl-2 (P<0.05), increased ROS (P˂0.05), and up-regulated the protein levels of cleaved Caspase-3 and Cyt C (P<0.05). ConclusionBuzhong Yiqitang induced apoptosis by inhibiting Nrf2/ROS pathway to alleviate cisplatin resistance in A549/DDP cells.
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Objective To investigate the transcriptome differences of ovarian cancer cells after cisplatin(DDP)resistance,and to find potential antagonists based on this screening.Methods DDP-resistant cell line A2780-DDP was constructed with A2780 cells as the research object.Through transcriptome sequencing anal-ysis,the key factors of DDP resistance were found and verified by quantitative real-time PCR(qPCR)and Western blot experiments.Through the screening of small molecule inhibitors,CCK-8 cell viability assay was used to find potential antagonists.Results A2780-DDP were successfully constructed,and it was found that there was no difference in cell proliferation after drug resistance,but the ability of cell invasion and migration was enhanced.Through transcriptome sequencing analysis,it was found that ITGB7 and Akt may be the key genes of A2780-DDP,and qPCR and Western blot showed that they were highly expressed in A2780-DDP.CCK-8 results showed that triptolide(TPL)and Olaparib had good inhibitory effects in DDP-resistant cell lines.Conclusion The ITGB7/Akt pathway plays an important role in DDP resistance,and potential DDP re-sistance antagonists such as TPL can provide new ideas for the treatment of ovarian cancer.
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Cisplatin resistance is an important factor in the poor treatment effect of ovarian cancer patients. MicroRNA (miRNA) can regulate cellular structural molecules, DNA repair, cell cycle, apoptosis and Wnt/β-catenin signaling pathway, autophagy, methylation and cancer stem cell, which are involved in the regulation of cisplatin resistance in ovarian cancer. Further understanding the mechanism of miRNA regulation of cisplatin resistance in ovarian cancer will help find new treatment options to optimize existing treatment plans and improve efficacy.
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Objective To investigate the effect of cisplatin treatment on the transcriptional level of human liver cancer cells by conducting transcriptome sequencing analysis after treating human liver cancer cell lines with differ-ent concentrations of cisplatin(CDDP).Methods Liver cancer cell lines HepG2 and Huh7 were incubated with cisplatin at different final concentrations of 0,20,50,100 and 200 μmol/L.After 12 hours,cell viability,immuno-fluorescence and RNA-sequencing(RNA-seq)were performed.Differential gene expression analysis(DEG),KEGG pathway analysis,and protein-protein interaction network analysis were conducted.Results Cisplatin de-creased cell viability and increased DNA damage in HepG2,Huh7 cells.Among the genes regulated after cisplatin treatment at different concentrations,59 genes were commonly up-regulated in both HepG2 and Huh7 cells,while 81 genes were commonly down-regulated.The commonly upregulated genes were mainly enriched in cancer initiation and progression pathways.The 81 commonly down-regulated genes were mainly enriched in Rap1 signaling pathway,Ras signaling pathway,signaling pathways regulating pluripotency of stem cells,axon guidance,and cell adhesion-related pathways.Survival analysis of key nodes in the protein-protein interaction network of commonly up-regulated and downregulated genes revealed a significant correlation between high expression of Jun proto-oncogene,AP-1 transcription factor subunit(JUN)and prolonged patient survival and a significant correlation between low ex-pression of growth arrest and DNA damage inducible alpha(GADD45A)and prolonged patient survival.Conclu-sions The study revealed common transcriptional changes in liver cancer cells under cisplatin treatment.Differential expression of JUN and GADD45A is a potential core mechanism to explain drug resistance.This conclusion provides some important prognostic indicators for clinical treatment.
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Objective To investigate whether omeprazole(OME)can enhance the sensitivity of epithelial ovarian cancer(EOC)cells to cisplatin(DDP)by inhibition of autophagy and to elucidate its possible mechanism.Methods Color in situ hy-bridization(CISH)and immunohistochemistry were applied to detect the expression of miR-214-3p and autophagy specific mark-ers p62 in EOC tissues,respectively.Pearson analysis showed the correlation between miR-214-3p and p62 expression levels in EOC.The half concentration(IC50)of DDP was determined by CCK-8 method.The mRNA expressions of miR-214-3p and multi-drug resistance gene 1(MDR1),the protein levels of p-gp and p62 were measured by using real-time quantitative PCR(qRT-PCR)and Western blot,respectively.Results In 43 cases,the expressions of miR-214-3p and p62 were 53.5%(23/43)and 60.5%(26/43)in patients with ovarian carcinoma,respectively.miR-214-3p was downregulated in platinum-relatively resistant OC tissue(P<0.05).On the contrary,p62 was upregulated in platinum-relatively resistant OC tissue(P<0.01).In ovarian cancer,the negative expression of miR-214-3p was closely related with p62(r=0.238,P<0.05).After OME(150 μmol/L)pre-treatment,varying degrees of decrease was observed in cisplatin IC50 OV2008 and C13K cells,especially cisplatin resistant strain C13K(P<0.01).After DDP treatment,qRT-PCR results revealed that the expression of miR-214-3p was decreased,the mRNA and protein expressions of MDR1 were greatly increased,and the protein levels of p62 were increased in C13K and OV2008 cells,compared to the blank control C13K and OV2008 cells(all P<0.01).Compared with the blank control C13K and OV2008 cells,the IC50 of DDP was decreased after pretreatment with OME(150 μmol/L).The sensitivity of C13K and OV2008 cells to DDP was increased after OME(150 μmol/L)pretreatment,the relative expression of miR-214-3p was significantly increased,the expression of MDR1 protein and mRNA was decreased,and the expression of p62 protein was decreased(all P<0.05).Conclu-sion OME pretreatment might enhance the sensitivity of ovarian cancer cells to DDP by downregulating miR-214-3p mediated autophagy.
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Objective To investigate the ameliorating effect of salidroside(SAL)on cisplatin(CIS)-induced damages of cochlear hair cells(CHC)and spiral ganglion neurons(SGNs)and its relationship with cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)/cAMP response element binding protein(CREB)pathway.Methods The cochlear basilar membranes of newborn C 57BL/6 mice were isolated and separated into control(C)group,CIS group,SAL group,SAL+SQ22536(cAMP inhibitor)group and SAL+H-89(PKA inhibitor)group,20 per group.Immunofluorescence staining was applied to observe the damages of CHC and SGNs.The kits were applied to detect the contents of ROS and cAMP in the basement membrane of the cochlea.Western blot was applied to detect the protein levels of PKA,p-CREB,CREB,Bcl-2,BDNF,and NF-M.Results CHC in CIS group were disorderly arranged and enlarged in size,SGNs had fragmented nuclei and lost neurites.SAL alleviated the damages of CHC and SGNs.Compared with the C group,the numbers of CHC and SGNs in the CIS group were less(P<0.05),the contents of ROS and cAMP,and the levels of PKA,BDNF,NF-M,Bcl-2 proteins and p-CREB/CREB were higher(P<0.05).Compared with the CIS group,the numbers of CHC and SGNs in the SAL group were higher(P<0.05),the content of ROS was lower(P<0.05),the content of cAMP,and the levels of PKA,BD-NF,NF-M,Bcl-2 proteins and p-CREB/CREB were higher(P<0.05).Both SQ22536 and H-89 reversed the pro-tective effects of SAL on CHC and SGNs.Conclusion SAL may promote the expression of anti-apoptotic proteins and neuroprotective factors by activating the cAMP/PKA/CREB pathway to alleviate the damages of CHC and SGNs caused by CIS.
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Objective To investigate the effect of inositol-requiring enzyme 1(IRE1)on cisplatin-induced ap-optosis of cochlear hair cells in mouse.Methods The cochlear basilar membranes of 500 healthy Kunming mice(3~5 days old)were isolated and cultured in vitro.After 24 hours,they were randomly divided into control group and cisplatin groups(4 μg/ml,8 μg/ml,16 μg/ml and 32 μg/ml),and cultured for another 24 hours.The loss of co-chlear hair cells was observed by fluorescein isothiocyanate(FITC)staining.The apoptosis of cochlear hair cells was observed by TRITC and Hoechst 33258 fluorescence staining.Western blot was used to detect the protein levels of p-IRE1α,p-JNK,Bax and caspase-3 in each group.Results Compared with control group,the hair cell loss and apoptosis rate of hair cells and the protein levels of p-IRE1α,p-JNK,Bax and caspase-3 were significantly increased in cisplatin groups(P<0.01).Furthermore,the expression of p-IRE1α was positively correlated with the expres-sion of Bax and caspase-3 and with the apoptosis rate of hair cells(P<0.05).Conclusion IREI may be involved in the regulation of cisplatin-induced apoptosis in cochlear hair cells.
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Background and purpose:Trastuzumab has a relatively low incidence of drug resistance,which can be used as an adjuvant treatment to improve clinical efficacy.It has been used to treat breast cancer in the past,but its application in other cancers has been less studied.This study aimed to explore the effects of trastuzumab assisted modified DOF fortnightly regimen on serum tumor markers and survival rate in cisplatin-resistant gastric cancer patients,in order to provide more references for the selection of clinical treatment methods for cisplatin-resistant gastric cancer.Methods:Eighty patients with cisplatin-resistant gastric cancer treated in Harison International Peace Hospital from January 2017 to January 2019 were selected as the study objects,and they were divided into observation group and control group according to random number table method.All of them received improved DOF fortnightly treatment,and trastuzumab adjuvant treatment was added to the observation group on this basis.The serum tumor markers[serum carcinoembryonic antigen(CEA),carbohydrate antigen 19-9(CA19-9),CA72-4],serum neovascular markers[vascular endothelial growth factor(VEGF),pigment epithelial derived factor(PEDF),angiopoietin-2(Ang-2)],biochemical indicators[N-terminal pro B type natriuretic peptide(NT proBNP),aspartate transaminase(AST),blood urea nitrogen(BUN),alanine aminotransferase(ALT)],adverse reactions and survival rate were compared between two groups.This study was approved by the Ethics Committee of Harison International Peace Hospital(number:20160511).Results:After treatment,CEA,CA19-9 and CA72-4 in both groups decreased,and CEA,CA19-9 and CA72-4 levels were lower in the observation group than in the control group with statistical significance(P<0.01).After treatment,VEGF,PEDF and Ang-2 in two groups decreased,and the difference was statistically significant(P<0.01).The levels of VEGF,PEDF and Ang-2 were compared between the two groups before and after treatment,and there was no significant difference(P>0.05).The levels of NT-proBNP,AST,BUN and ALT were compared between the two groups before and after treatment,and there was no statistically significant difference(P>0.05).The number of patients with fatigue,gastrointestinal reaction and myelosuppression and the total incidence of adverse reactions were compared between the two groups,and there was no statistically significant difference(P>0.05).At 5 years after treatment,11 cases(27.5%)survived and 29 cases(72.5%)died in the observation group.There were 3 cases(7.5%)of survival and 37 cases(92.5%)of death in the control group.The median survival was 2 years(95%CI:1.8-2.2)in the observation group and 1 year(95%CI:0.6-1.4)in the control group.The survival rate of 1-5 years was higher in the observation group than in the control group.The difference was statistically significant(log-rank χ2 = 13.853,P = 0.001).Conclusion:In the clinical treatment of cisplatin-resistant gastric cancer,trastuzumab assisted modified DOF fortnightly regimen suggests that it can reduce the expression levels of serum tumor markers,improve the 5-year survival rate of patients,and has certain drug safety.
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AIM:To study whether glycyrrhizic acid(GL)can resist the ototoxicity of cisplatin(CDDP)in mice and its molecular mechanism.METHODS:Male C57BL/6J mice were divided into 5 groups:control group,DMSO(5%)group,CDDP(4 mg/kg)group,CDDP+low-dose(50 mg/kg)GL group,and CDDP+high-dose(100 mg/kg)GL group(n=14).Auditory brainstem response(ABR)was used to detect hearing changes of mice.HE staining was used to observe the morphological change of cochlear stria vascular in mice.Evans blue(EB)staining was used to observe the per-meability change of the blood-labyrinth barrier(BLB).Immunohistochemical technique was used to detect the expression and distribution of adhesion protein VE-cadherin and tight junction protein ZO-1 on the cochlear stria.ELISA assay and immunofluorescence technology were employed to detect the expression of tumor necrosis factor-α(TNF-α)and interleu-kin-1β(1L-1β).RESULTS:In CDDP group,ABR waveforms of all frequencies were disturbed,the hearing threshold was significantly increased,and I wave latency was prolonged(P<0.05).In CDDP+GL group,ABR waveforms of various frequencies were well differentiated,the hearing threshold was significantly decreased,and the latency of I-wave was shortened(P<0.01).The disordered morphology and more vacuoles in the stria vascularis were observed by HE staining in CDDP group.The GL alleviated CDDP-induced damage in the stria vascularis.In EB staining,CDDP caused an increase in per-meability of BLB(P<0.01),which was improved by GL treatment(P<0.01).Immunohistochemical results showed that the expression of VE-cadherin and ZO-1 in CDDP group were decreased(P<0.01),which was restored in CDDP+GL group(P<0.01).The ELISA and immunofluorescence results showed that the expression of IL-1β and TNF-α was in-creased after CDDP treatment(P<0.01),which was restored in CDDP+GL group(P<0.01).CONCLUSION:The GL alleviates CDDP-induced hearing loss in mice by inhibiting CDDP-induced inflammation and reducing the permeability of BLB.
ABSTRACT
AIM:To investigate the therapeutic effect of menstrual blood-derived endometrial stem cells(MenSCs)on chemotherapy-induced intestinal mucositis and flora disorders in mice,and to explore the potential mecha-nism.METHODS:The mice were randomly divided into 3 groups including normal treatment,cisplatin(Cis)treatment and Cis+MenSC treatment,with 10 mice in each group.To induce intestinal mucositis,the mice were treated with Cis(2 mg·kg-1·d-1)by intraperitoneal injection for 5 consecutive days.Control mice for normal group were received equal vol-umes of normal saline.For Cis+MenSC treatment,MenSCs(1×106)was transplanted into the mice of Cis treated mice through tail vein.The performances and weight changes of mice were examined during the experiment.After the treat-ment,the small intestine and colon were isolated for subsequent HE staining,the ratio of F4/80 and IL-6 positive cells in small intestine were detected by immunohistochemical staining,and the expression of tight junction,inflammation and apoptosis related proteins was detected by Western blot.16S rDNA amplicon sequencing was performed to detect the diver-sity and richness of intestinal flora in mice.RESULTS:Compared to the Cis group,the MenSCs-treated mice showed sig-nificantly increased body weight,relieved intestinal lymphocytes infiltration,alleviated intestinal villous edema,and or-derly arranged glands in intestinal tissues.Further analysis indicated that MenSCs transplantation significantly up-regulat-ed the expression of intestinal tight junction related proteins ZO-1 and occludin in Cis-treated mice(P<0.05).Subse-quently,MenSCs transplantation significantly inhibited the macrophages infiltration in intestinal tissues(P<0.01),down-regulated the expression of pro-inflammatory factors IL-1 and IL-6 and pro-apoptotic protein Bax(P<0.01),while up-regu-lated anti-inflammatory factor IL-10 and anti-apoptotic protein Bcl-2(P<0.01).Additionally,further microflora sequenc-ing indicated that MenSCs transplantation prevented mice from Cis-induced intestinal flora disorder,and significantly re-duced the abundance of harmful bacteria such as isenbergiella tayi and Anaerotruncus colihominis(P<0.01).At the same time,the abundance of beneficial bacteria Lactobacillus apodemi was increased(P<0.05),thereby restoring the composi-tion and function of healthy intestinal flora.CONCLUSION:MenSCs transplantation alleviates the chemotherapy-in-duced damage of intestinal structure,relieves the symptoms of chemotherapy-induced mucositis and restores the homeosta-sis of intestinal flora in mice.