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PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.
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Long noncoding RNA MYLK antisense RNA 1 (MYLK-AS1) is the crux in multiple diseases. Therefore, the purpose of this study was to investigate the possible mechanism of MYLK-AS1. A total of 62 colon cancer (CC) specimens and paired adjacent normal tissues were collected, and the expression of MYLK-AS1, microRNA (miR)-101-5p/cell division cycle 42 (CDC42) was detected. CC cell lines were transfected with MYLK-AS1, miR-101-5p, CDC42-related plasmids, and the biological functions and markers of epithelial-mesenchymal transition (EMT) were analyzed. The binding relationship between MYLK-AS1, miR-101-5p, and CDC42 was evaluated. In CC tissues and cell lines, MYLK-AS1 and CDC42 were highly expressed, and miR-101-5p was lowly expressed. Inhibition of MYLK-AS1 or upregulation of miR-101-5p can inhibit CC cell growth and EMT. miR-101-5p inhibited CDC42/N-wasp axis activation in CC cells by targeting CDC42. Knockdown of CDC42 or upregulation of miR-101-5p partially reversed the effects caused by upregulation of MYLK-AS1. MYLK-AS1, which is significantly upregulated in CC, may be a molecular sponge for miR-101-5p, and MYLK-AS1 promotes the activation of the CDC42/N-wasp axis in CC cells by targeting CDC42 through miR-101-5p, which in turn promotes tumor development. MYLK-AS1 may be a potential biomarker and target for CC therapy.
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Neoplasias del Colon , MicroARNs , ARN Largo no Codificante , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Transición Epitelial-Mesenquimal/genética , Neoplasias del Colon/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proteínas de Unión al Calcio/metabolismo , Quinasa de Cadena Ligera de Miosina/genética , Quinasa de Cadena Ligera de Miosina/metabolismoRESUMEN
Retraction of 'Construction of a temperature-responsive terpolymer coating with recyclable bactericidal and self-cleaning antimicrobial properties' by Bailiang Wang et al., Biomater. Sci., 2016, 4, 1731-1741, https://doi.org/10.1039/C6BM00587J.
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Traditional total mesorectal excision (TME) for rectal cancer requires partial resection of Denonvilliers' fascia (DVF), which leads to injury of pelvic autonomic nerve and postoperative urogenital dysfunction. It is still unclear whether entire preservation of DVF has better urogenital function and comparable oncological outcomes. We conducted a randomized clinical trial to investigate the superiority of DVF preservation over resection (NCT02435758). A total of 262 eligible male patients were randomized to Laparoscopic TME with DVF preservation (L-DVF-P group) or resection procedures (L-DVF-R group), 242 of which completed the study, including 122 cases of L-DVF-P and 120 cases of L-DVF-R. The initial analysis of the primary outcomes of urogenital function has previously been reported. Here, the updated analysis and secondary outcomes including 3-year survival (OS), 3-year disease-free survival (DFS), and recurrence rate between the two groups are reported for the modified intention-to-treat analysis, revealing no significant difference. In conclusion, L-DVF-P reveals better postoperative urogenital function and comparable oncological outcomes for male rectal cancer patients.
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Neoplasias del Recto , Humanos , Masculino , Estudios de Seguimiento , Neoplasias del Recto/cirugía , Pelvis/cirugía , Vías Autónomas , FasciaRESUMEN
Expression of concern for 'Bacterial infection microenvironment-responsive enzymatically degradable multilayer films for multifunctional antibacterial properties' by Qingqing Yao et al., J. Mater. Chem. B, 2017, 5, 8532-8541, https://doi.org/10.1039/C7TB02114C.
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Retraction of 'A self-defensive antibacterial coating acting through the bacteria-triggered release of a hydrophobic antibiotic from layer-by-layer films' by Bailiang Wang et al., J. Mater. Chem. B, 2017, 5, 1498-1506, https://doi.org/10.1039/C6TB02614A.
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Objective: The problems and challenges encountered by Chinese medical institutions in implementing the national centralized drug procurement was investigated and analyzed in order to provide reference for the regulatory agencies to formulate policies. Methods: A questionnaire survey was conducted to collect the problems encountered by 329 Chinese medical institutions in implementing the national centralized drug procurement and the corresponding suggestions provided by relevant experts. Statistical analysis was performed to identify differences in the themes and the number of collected problems, further revealing the relevance to the region in which the medical institutions is located. Result: 1360 problems and suggestions were collected from 329 Chinese medical institutions that located in North (19.15%), Northeast (5.78%), East (33.43%), Central (10.03%), South (9.73%), Southwest (14.89%), and Northwest China (6.99%). There was statistically significant difference in the number of collected problems and suggestions between regions (p < 0.001). Furthermore, the content of gathered problems and suggestions involves in 15 themes including system construction, organizational system and work responsibilities, reasonable measurement and reporting of procurement volume et al. These themes that these medical institutions are focusing on are mainly centered on the supply guarantee (15%), reasonable measurement and reporting of procurement volume (11.40%) and guarantee measures for clinical priority use (9.48%) of drugs with national centralized procurement. Meanwhile, we found that problems regarding the supply guarantee of drugs with national centralized procurement displayed significant difference between regions (p = 0.0096). Conclusion: Chinese medical institutions are facing great challenges in implementing the national centralized drug procurement. The scientific study and judgment of the current situation and the construction of corresponding solution require a precise classification of the problems encountered by medical institutions in the process of implementing the national centralized drug procurement policy, which is of great practical significance for deepening the reform of the medical and health system.
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Expression of concern for 'Bacterial self-defense antibiotics release from organic-inorganic hybrid multilayer films for long-term anti-adhesion and biofilm inhibition properties' by Qingwen Xu, Nanoscale, 2017, 9, 19245-19254, https://doi.org/10.1039/C7NR07106J.
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This commentary presents a virtual special issue on the global growth of community psychology (CP), particularly, but not exclusively, as reflected in the American Journal of Community Psychology (AJCP). CP exists in at least 50 countries all over the world, in many of those for over 25 years. Yet, aside from several early Israeli articles, AJCP rarely published work from or about countries outside the US and Canada until the early 2000s, when the number of international articles began to rise sharply. The focus of CP developed differently in different continents. CP in Australia and New Zealand initially followed North America's emphasis on improving social service systems, but has since focused more on environmental and indigenous cultural and decolonial issues that are as salient in those countries as in North America, but have drawn much more attention. CP came later to most of Asia, where it also tended to follow the North American path, but starting in Japan, India, and Hong Kong and now in China and elsewhere, it is establishing its own way. The other two global hotspots for CP for over 40 years have been Europe and Latin America. The level and focus of CP in Europe varies in each country, with some focused on applied developmental psychology and/or community services and others advancing critical and liberation psychology. CP in Latin America evolved from social psychology, but like CP in Sub-Saharan Africa, is also more explicitly political due to a history of political oppression, social activism, and the limitations of individualistic psychology to focus on social change, overcoming poverty, and interventions by (not just for) community members. Despite those differences, CP literature over the past 23 years suggests an increasingly common interest in social justice, multinational collaborations, and decoloniality. There is still a need for more truly (bidirectional) cross-cultural, comparative work for mutual learning, sharing of ideas, methods, and intervention practices, and for CP to develop in countries and communities throughout the globe where it could have the greatest impact.
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Psicología Social , Psicología , Estados Unidos , Humanos , América Latina , América del Norte , Europa (Continente) , CanadáRESUMEN
Objective To identify the key targets and molecular mechanisms of Sangbaipi decoction in the treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) by using network pharmacology. Methods The active components of Sangbaipi Decoction were searched in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, with the corresponding targets predicted. The related targets of AECOPD were searched within gene banks, OMIM and Drugbank.The names of prediction targets and disease targets were standardized by UniProt, and the intersection targets were selected. TCM component target network diagram was drawn and analyzed by Cytoscape 3.6.0. The common targets were imported into the metascape database for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking was carried out by using auto dock tools software. Results A total of 126 active ingredients in Sangbaipi decoction, 1351 predicted corresponding targets and 2296 disease-related targets were detected. The main active ingredients include quercetin, luteolin, kaempferol, wogonin ß. The core targets of sitosterol involve tumor necrosis factor (TNF), interleukin-6 (IL-6), tumor protein p53 (TP53), mitogen activated protein kinase 8 (MAPK8) and MAPK14. A total of 2720 signals were obtained from GO enrichment analysis and 334 signal pathways were obtained from KEGG enrichment analysis. The molecular docking results showed that the main active components can bind to the core target, at a stable the binding conformation. Conclusion Sangbaipi decoction may have anti-inflammatory, anti-oxidant and other biological effects through multiple active ingredients, multiple targets and signal pathways, thus effectively treating AECOPD.
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Antioxidantes , Factor de Necrosis Tumoral alfa , Simulación del Acoplamiento Molecular , Biología Computacional , Ontología de GenesRESUMEN
OBJECTIVE: To determine the morbidity, mortality, and pathologic outcomes of transanal total mesorectal resection (taTME) versus laparoscopic total mesorectal excision (laTME) among patients with rectal cancer with clinical stage I to III rectal cancer below the peritoneal reflection. BACKGROUND: Studies with sufficient numbers of patients allowing clinical acceptance of taTME for rectal cancer are lacking. Thus, we launched a randomized clinical trial to compare the safety and efficacy of taTME versus laTME. METHODS: A randomized, open-label, phase 3, noninferiority trial was performed at 16 different hospitals in 10 Chinese provinces. The primary endpoints were 3-year disease-free survival and 5-year overall survival. The morbidity and mortality within 30 days after surgery, and pathologic outcomes were compared based on a modified intention-to-treat principle; this analysis was preplanned. RESULTS: Between April 13, 2016, and June 1, 2021, 1115 patients were randomized 1:1 to receive taTME or laTME. After exclusion of 26 cases, modified intention-to-treat set of taTME versus laTME groups included 544 versus 545 patients. There were no significant differences between taTME and laTME groups in intraoperative complications [26 (4.8%) vs 33 (6.1%); difference, -1.3%; 95% confidence interval (CI), -4.2% to 1.7%; P =0.42], postoperative morbidity [73 (13.4%) vs 66 (12.1%); difference, 1.2%; 95% CI, -2.8% to 5.2%; P =0.53), or mortality [1 (0.2%) vs 1 (0.2%)]. Successful resection occurred in 538 (98.9%) versus 538 (98.7%) patients in taTME versus laTME groups (difference, 0.2%; 95% CI, -1.9% to 2.2%; P >0.99). CONCLUSIONS: Experienced surgeons can safely perform taTME in selected patients with rectal cancer.
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Laparoscopía , Neoplasias del Recto , Cirugía Endoscópica Transanal , Humanos , Complicaciones Posoperatorias/etiología , Cirugía Endoscópica Transanal/efectos adversos , Tempo Operativo , Neoplasias del Recto/cirugía , Laparoscopía/efectos adversos , Morbilidad , Recto/cirugía , Resultado del TratamientoRESUMEN
The concept of "Aging in place" has not been fully validated among older immigrant groups living in diverse cultures. The study used a qualitative research approach and interviewed Chinese immigrant older adults across three Chinese enclave communities in New York City to identify whether Chinatowns are a place for Chinese immigrants to age and explore their experience of aging in Chinatowns. The findings showed that Chinese immigrants did consider Chinatown as the place, which conveyed practical, linguistic, social, emotional and cultural meaning. Aging in Chinatown, older adults sought independence, security, and autonomy through various social resources. However, older adults, especially newly arrived immigrants, have faced obstacles that undermine their aging experience. Older immigrants' unique aging experience has provided profound insight in understanding migration and AIP, which help develop proper policies and programs to support the AIP initiative.
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Emigrantes e Inmigrantes , Humanos , Anciano , Envejecimiento , Pueblo Asiatico , Ciudad de Nueva YorkRESUMEN
Background: Colorectal cancer (CRC) has few or no symptoms and is often diagnosed at its end stage. Boeravinone B (BB) is a natural rotenoid which induces an antioxidative effect and has been used in cancer prevention. In this study, we scrutinized the chemoprotective effect of BB against 1,2dimethyl hydrazine (DMH) induced CRC in rats. Methods: Subcutaneous administration of DMH (40 mg/kg) was used for the induction of CRC in rats, followed by oral administration of BB. The body weight, tumor volume, tumor incidence, and total number of tumors were estimated in all rat groups rats except the normal group. Antioxidant parameters, phase I and II enzymes, and inflammatory cytokines and parameters were estimated at the completion of the study. Results: DMH induced group rats exhibited a tumor incidence of 100% along with several tumors/polyps per tumorbearing rat, while BB treatment remarkably suppressed the incidence of tumors and suppressed polyps per tumor bearing rat. BB treatment significantly (P<0.001) altered the level of antioxidant parameters, phase I and phase II enzymes, and cytokines such as TNF-α, IL-1ß, IL-4, IL-6, and IL-10, and treatment significantly (P<0.001) suppressed the level of inflammatory cytokines, including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS). Conclusions: BB treatment considerably suppresses colon cancer via its antioxidant and anti-inflammatory mechanism.
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The effectiveness of the multidisciplinary nursing model in the nursing of chronic kidney disease (CKD) by using meta-analysis is explored. Relevant literatures that are in line with the multidisciplinary nursing model for CKD intervention are searched and screened from domestic and foreign literature databases such as Wanfang Medical Center, CNKNET, VIP, and PubMed, and Meta-analysis is conducted with RevMan 5.2 software. A total of 6 literatures are included, and the publication bias of the included literatures is low. Meta-analysis shows that the multidisciplinary group had a better Hb compliance rate, Hb level, Scr, eGFR, SBP, and DBP than the traditional group. The experimental results show that multidisciplinary nursing intervention can improve the nursing effect of patients with CKD and help to improve Hb, Scr, blood pressure, and glomerular filtration function of patients.
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Insuficiencia Renal Crónica , Presión Sanguínea , Humanos , Insuficiencia Renal Crónica/terapiaRESUMEN
Background: To summarise data from previous reports and perform a meta-analysis to compare the short-term surgical outcomes and post-operative recovery between single-incision and multi-port laparoscopic distal gastrectomy (MLDG) for gastric cancer. Methods: A systematic literature search was performed using PubMed and Embase databases and relevant data were extracted. Short-term surgical outcomes and post-operative recovery of single-incision laparoscopic distal gastrectomy (SLDG) and MLDG for gastric cancer were compared using a fixed or random-effect model. Results: In total, we identified five relevant studies involving 983 participants for this systematic review and meta-analysis, and 45.8% (450/983) of patients underwent SLDG. The results demonstrated that mean operation time (weighted mean difference [WMD]:-3.22, 95% confidence interval [CI]: 14.64,8.19, P = 0.580; I2 = 75.6%), intra-operative blood loss (WMD:-19.77, 95% CI: 40.20,0.65, P = 0.058; I2 = 85.0%) and lymph node yield (WMD:-0.71, 95% CI: 1.47, 0.05, P = 0.068; I2 = 0%) of SLDG were comparable to those of MLDG for gastric cancer. In addition, SLDG had a similar incidence of post-operative complications compared with MLDG (odds ratio: 0.82, 95% CI: 0.55-1.22, P = 0.326; I2 = 0%). There was no significant difference between the two surgical procedures for the conversion to open surgery (OR: 0.32, 95%CI: 0.03-3.15, P = 0.331; I2 = 0%), the length of hospital stay (WMD:-0.05, 95% CI: 0.65, 0.55, P = 0.876; I2 = 44.1%), the time to first flatus (WMD:-0.24, 95% CI: 0.58, 0.10, P = 0.169; I2 = 85.3%) and the time to oral intake (WMD:-0.05, 95% CI: 0.20, 0.10, P = 0.500; I2 = 0%). Conclusion: Single-incision laparoscopic gastrectomy may be technically feasible and safe for gastric cancer. However, it did not show a more obvious advantage over MLDG.
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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. METHODS: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+â£/- cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. RESULTS: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. CONCLUSIONS: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.
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Anoctamina-1 , Riñón Poliquístico Autosómico Dominante , Canales Catiónicos TRPP , Animales , Anoctamina-1/genética , Anoctamina-1/metabolismo , Cilios/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Proteínas de Neoplasias , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/metabolismo , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismoRESUMEN
Introduction: In some cases, laparoscopic cholecystectomy (LC) may be very difficult and easily converted to laparotomy, causing many complications to patients and prolonging the prognosis time. Thus, to evaluate the difficulty of LC before operation is extremely important. Aim: To explore the risk factors of difficult cholecystectomy (DC) and to establish a risk prediction model of DC. Material and methods: The data of 201patients who underwent cholecystectomy from 1 January 2018 to 10 November 2019 were analysed retrospectively. The highest quartile (P75) of cholecystectomy operation time was used as a cutting point of DC (≥ P75) and NLC (< P75). Logistic regression was used to analyse the influencing factors of DC, and its risk model was constructed for prediction. Results: Multivariate logistic regression analysis showed that body mass index (BMI) > 25 kg/m2, white blood cell (WBC) > 10 × 109/l, calculus incarcerated in neck of gallbladder, frequency of acute cholecystitis in the last 2 months > 4 times, thickness of gallbladder wall > 0.5 cm, and maximum diameter of gallstone > 2 cm were independent risk factors for DC. The prediction efficiency of the logistic regression equation was 0.879 (χ 2 = 1.457, p > 0.05). Conclusions: Based on analysis of risk factors, a logistic risk prediction model for difficult cholecystectomy was established. This model can be used to predict the difficulty of cholecystectomy.
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Background/Aims: The increased mortality of gastric cancer (GC) is mainly attributed to the development of chemoresistance. Circular RNAs, as the novel type of biomarkers in GC, have attracted wide attention. The purpose of this study was to investigate the functional role of circ_0081143 in GC with doxorubicin (DR) resistance and its potential action mechanism. Methods: The expression of circ_0081143, miR-129-2-3p and YES proto-oncogene 1 (YES1) in GC tissues and cells was measured by quantitative real-time polymerase chain reaction. The half maximal inhibitory concentration value was calculated based on the MTT cell viability assay. Cell proliferation and apoptosis were monitored by MTT and flow cytometry assays. Transwell assays were employed to check cell migration and invasion. The protein levels of YES1 and apoptosis-related proteins were detected by western blotting. The interaction between miR-129-2-3p and circ_0081143 or YES1 was verified by dual-luciferase reporter and pull-down assays. A tumorigenicity assay was conducted to verify the role of circ_0081143 in vivo. Results: Circ_0081143 was highly expressed in DR-resistant GC tumor tissues and cells. Depletion of circ_0081143 reduced DR resistance and inhibited DR-resistant GC cell proliferation, migration and invasion. Circ_0081143 targeted miR-129-2-3p and inhibited the role of miR-129-2-3p. In addition, YES1 was a target of miR-129-2-3p, and its function was suppressed by miR-129-2-3p. Importantly, circ_0081143 positively modulated the expression of YES1 through mediating miR-129-2-3p. Circ_0081143 knockdown weakened the DR-resistant GC tumor growth in vivo. Conclusions: Circ_0081143 knockdown weakened DR resistance and blocked the development of DR-resistant GC by regulating the miR-129-2-3p/YES1 axis. Our data suggest that circ_0081143 is a promising target for the treatment of GC with DR resistance.
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MicroARNs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , ARN Circular/genética , Proliferación Celular/genética , Doxorrubicina/farmacología , Proteínas Proto-Oncogénicas c-yes/genéticaRESUMEN
Intestinal ischemia/reperfusion (I/R) injury (IIRI) is associated with high prevalence and mortality rate. Recently, mesenchymal stem cell (MSC) therapy attracted more attentions. However, the function and regulatory mechanism of MSC-derived exosomal miRNAs during IIRI remain largely uninvestigated. The in vitro and in vivo IIRI models were established. MSC were characterized by immunofluorescent staining and flow cytometry. Purified exosomes were characterized by transmission electron microscopy (TEM), flow cytometry, and western blot. The expression of key molecules was detected by western blot and qRT-PCR. CCK-8, TUNEL, and transepithelial electrical resistance (TER) assays were employed to assess cell viability, apoptosis, and intestinal integrity, respectively. Pre-miR-34A m6 modification was evaluated by methylated RNA immunoprecipitation (MeRIP)-qPCR. RNA pull-down and RIP were used to validate the direct association between pre-miR-34A and IGF2BP3. MSC-derived exosomal miR-34a-5p alleviated OGD/R-induced injury. In addition, MSC ameliorated OGD/R-induced injury through METTL3 pathway. Mechanistic study revealed that miR-34a-5p was modulated by METTL3/IGF2BP3-mediated m6A modification in MSC. The in vitro and in vivo functional experiments revealed that MSC secreted exosomal miR-34a-5p and ameliorated IIRI through METTL3/IGF2BP3-mediated m6A modification of pre-miR-34A. MSC promoted the secretion of exosomal miR-34a-5p and improved intestinal barrier function through METTL3/IGF2BP3-mediated pre-miR-34A m6A modification.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , Daño por Reperfusión , Apoptosis/genética , Exosomas/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , Metiltransferasas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismoRESUMEN
Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment.