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1.
Cereb Cortex ; 34(7)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38981852

RESUMO

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.


Assuntos
Astrócitos , Transtornos da Memória , Metanfetamina , Microglia , Minociclina , Memória Espacial , Animais , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Transtornos da Memória/induzido quimicamente , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos , Masculino , Minociclina/farmacologia , Camundongos Endogâmicos C57BL , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Estimulantes do Sistema Nervoso Central/toxicidade
2.
Wideochir Inne Tech Maloinwazyjne ; 19(1): 1-10, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38974765

RESUMO

Introduction: The Pfannenstiel incision is often used in gynecological Cesarean section; however, there is limited research on the use of the Pfannenstiel incision for specimen extraction in laparoscopic surgery for the treatment of colorectal cancer. Aim: To evaluate the safety of using the Pfannenstiel incision for specimen extraction in laparoscopic surgery for colorectal cancer patients. Material and methods: PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP and WanFangData were searched for studies published up to March 10, 2023; a random-effects model (RCT) and a fixed-effect model were used to evaluate the safety. Operative time, length of extraction skin incision, overall complications, superficial wound infection, organ/space surgical site infection and incisional hernia were evaluated. Results: A total of 5 studies were included in this research. There were no significant advantages in operation time, length of the incision, overall complications, superficial wound infection and organ/space surgical site in the Pfannenstiel group compared to the no Pfannenstiel group. However, the Pfannenstiel incision has a tendency to increase the length of the incision (SMD = 0.05; 95% CI = -0.22 to 0.33; p = 0.71) and the results of the remaining five (operative time,overall complications,incisional hernia, incisional infection and organ/space surgical site infection) are slightly skewed toward the Pfannenstiel incision. It is worth mentioning that incisional hernia (IH) may have an advantage in the Pfannenstiel group compared to the no Pfannenstiel group. Four studies were not at clear risk of bias and two studies were at risk of bias. Conclusions: Our study concludes that the Pfannenstiel incision has a good safety record and it is a good option for extracting specimens during laparoscopic surgery for colon cancer. The Pfannenstiel incision used for laparoscopic surgical specimen extraction has a significantly lower incidence of incisional hernia over no Pfannenstiel.

3.
Theranostics ; 14(10): 4107-4126, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994023

RESUMO

Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Glioblastoma , Microambiente Tumoral , Macrófagos Associados a Tumor , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/genética , Humanos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Animais , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Camundongos , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Macrófagos/metabolismo
4.
Front Oncol ; 14: 1395549, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38898957

RESUMO

Objective: To investigate the application value of complete laparoscopy and Da Vinci robot esophagogastric anastomosis double muscle flap plasty in radical resection of proximal gastric cancer. Method: A retrospective descriptive study was used. The clinicopathological data of 35 patients undergoing radical operation for proximal gastric cancer admitted to Liaoning Cancer Hospital from January 2020 to December 2023 were collected. Variables evaluated: 1. Transoperative,2. Postoperative, 3. Follow-up. In relation to follow-up, esophageal disease status reflux, anastomosis, nutritional status score, serum hemoglobin, tumor recurrence, and metastasis were investigated. The trans and postoperative variables were obtained from the clinical records and the patients were followed up in outpatient department and by telephone. Result: Among the 35 patients, 17 underwent robotic surgery and 18 underwent laparoscopic surgery. There were 29 males and 6 females. 1) Transoperative: Robotic surgery: The operation time was (305.59 ± 22.07) min, the esophagogastric anastomosis double muscle flap plasty time was (149.76 ± 14.91) min, the average number of lymph nodes cleared was 30, and the average intraoperative blood loss was 30 ml. Laparoscopic surgery: The mean operation time was 305.17 ± 26.92min, the operation time of esophagogastric anastomosis double muscle flap was (194.06 ± 22.52) min, the average number of lymph nodes cleared was 24, and the average intraoperative blood loss was 52.5 ml. 2) Postoperative: Robotic surgery: the average time for patients to have their first postoperative anal emission was 3 days, the average time to first postoperative feeding was 4 days, and the average length of hospitalization after surgery was 8 days. Laparoscopic surgery: the average time for patients to have their first postoperative anal emission was 5 days, the average time to first postoperative feeding was 6 days, the average length of hospitalization after surgery was 10 days. 3) Follow-up: The follow-up time ranged from 1 to 42 months, with a median follow-up time of 24 months. Conclusion: Complete Da Vinci robot and laparoscopic esophagogastric anastomosis double muscle flap plasty for radical resection of proximal gastric cancer can minimize surgical incision, reduce abdominal exposure, accelerate postoperative recovery of patients, and effectively prevent reflux esophagitis and maintain good hemoglobin concentration and nutritional status. The advantages of robotic surgery is less intraoperative bleeding and faster post-surgical recovery, but it is relatively more expensive.

5.
Clin Imaging ; 112: 110209, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38833916

RESUMO

PURPOSE: This meta-analysis aimed to compare the diagnostic effectiveness of [18F]FDG PET/CT with that of [18F]FDG PET/MRI in terms of identifying liver metastasis in patients with primary cancer. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched, and studies evaluating the diagnostic efficacy of [18F]FDG PET/CT and [18F]FDG PET/MRI in patients with liver metastasis of primary cancer were included. We used a random effects model to analyze their sensitivity and specificity. Subgroup analyses and corresponding meta-regressions focusing on race, image analysis, study design, and analysis methodologies were conducted. Cochrane Q and I2 statistics were used to assess intra-group and inter-group heterogeneity. RESULTS: Seven articles with 343 patients were included in this meta-analysis. The sensitivity of [18F]FDG PET/CT was 0.82 (95 % CI: 0.63-0.96), and that of [18F]FDG PET/MRI was 0.91 (95 % CI: 0.82-0.98); there was no significant difference between the two methods (P = 0.32). Similarly, both methods showed equal specificity: 1.00 (95 % CI: 0.95-1.00) for [18F]FDG PET/CT and 1.00 (95 % CI: 0.96-1.00) for [18F]FDG PET/MRI, and thus, there was no significant difference between the methods (P = 0.41). Furthermore, the subgroup analyses revealed no differences. Meta-regression analysis revealed that race was a potential source of heterogeneity for [18F]FDG PET/CT (P = 0.01), while image analysis and contrast agent were found to be potential sources of heterogeneity for [18F]FDG PET/MRI (P = 0.02). CONCLUSIONS: [18F]FDG PET/MRI has similar sensitivity and specificity to [18F]FDG PET/CT for detecting liver metastasis of primary cancer in both the general population and in subgroups. [18F]FDG PET/CT may be a more cost-effective option. However, the conclusions of this meta-analysis are tentative due to the limited number of studies included, and further research is necessary for validation.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(3): 768-773, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-38926965

RESUMO

OBJECTIVE: To analyze the prognostic value of del(1p32) in patients with newly diagnosed multiple myeloma (MM). METHODS: The clinical data of 341 newly diagnosed MM attended in Jiangsu Province Hospital were retrospective analyzed. Clinical characteristic combined with genetic features, especially del(1p32), were analyzed for survival and prognostic of patients. RESULTS: Among the 341 patients with newly diagnosed MM, 24(7.0%) patients were del(1p32) positive. The progression-free survival (PFS) and overall survival (OS) were significantly shorter in MM patients with del(1p32) than those without del(1p32) (PFS: P < 0.001;OS: P < 0.001). The COX proportional-hazards model showed that del (1p32) was an independent risk factor for PFS and OS of patients with MM. The patients with both 1q21 gain/amplification and del(1p32), as "double-hit chromosome 1", have worse prognosis than those with only 1q21 gain/amplification or only del(1p32) (PFS: P < 0.001; OS: P < 0.001). CONCLUSION: Del(1p32) is an independent risk factor for PFS and OS of patients with MM. Del(1p32) detection should be widely used in the prognostic analysis for newly diagnosed MM patients.


Assuntos
Cromossomos Humanos Par 1 , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Prognóstico , Estudos Retrospectivos , Cromossomos Humanos Par 1/genética , Fatores de Risco , Deleção Cromossômica , Modelos de Riscos Proporcionais , Masculino , Feminino , Pessoa de Meia-Idade
9.
J Oral Pathol Med ; 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802299

RESUMO

BACKGROUND: circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF. METHODS: Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH). RESULTS: circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002. CONCLUSION: circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF.

10.
Mol Ther ; 32(6): 1875-1894, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38549378

RESUMO

Chimeric antigen receptor-T (CAR-T) cell has been developed as a promising agent for patients with refractory or relapsed lymphoma and leukemia, but not all the recipients could achieve a long-lasting remission. The limited capacity of in vivo expansion and memory differentiation post activation is one of the major reasons for suboptimal CAR-T therapeutic efficiency. Nitric oxide (NO) plays multifaceted roles in mitochondrial dynamics and T cell activation, but its function on CAR-T cell persistence and anti-tumor efficacy remains unknown. Herein, we found the continuous signaling from CAR not only promotes excessive NO production, but also suppressed S-nitrosoglutathione reductase (GSNOR) expression in T cells, which collectively led to increased protein S-nitrosylation, resulting in impaired mitochondrial fitness and deficiency of T cell stemness. Intriguingly, enforced expression of GSNOR promoted memory differentiation of CAR-T cell after immune activation, rendered CAR-T better resistance to mitochondrial dysfunction, further enhanced CAR-T cell expansion and anti-tumor capacity in vitro and in a mouse tumor model. Thus, we revealed a critical role of NO in restricting CAR-T cell persistence and functionality, and defined that GSNOR overexpression may provide a solution to combat NO stress and render patients with more durable protection from CAR-T therapy.


Assuntos
Imunoterapia Adotiva , Mitocôndrias , Receptores de Antígenos Quiméricos , Animais , Camundongos , Mitocôndrias/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Humanos , Imunoterapia Adotiva/métodos , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Linfócitos T/metabolismo , Linfócitos T/imunologia , Óxido Nítrico/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Ativação Linfocitária , Transdução de Sinais
11.
Cancer Sci ; 115(4): 1196-1208, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38288901

RESUMO

Fms-like tyrosine kinase-3 (FLT3) is a commonly mutated gene in acute myeloid leukemia (AML). The two most common mutations are the internal-tandem duplication domain (ITD) mutation and the tyrosine kinase domain (TKD) mutation. FLT3-ITD and FLT3-TKD exhibit distinct protein stability, cellular localization, and intracellular signaling. To understand the underlying mechanisms, we performed proximity labeling with TurboID to identify proteins that regulate FLT3-ITD or -TKD differently. We found that BRCA1/BRCA2-containing complex subunit 36 (BRCC36), a specific K63-linked polyubiquitin deubiquitinase, was exclusively associated with ITD, not the wild type of FLT3 and TKD. Knockdown of BRCC36 resulted in decreased signal transducers and activators of transcription 5 phosphorylation and cell proliferation in ITD cells. Consistently, treatment with thiolutin, an inhibitor of BRCC36, specifically suppressed cell proliferation and induced cell apoptosis in ITD cells. Thiolutin efficiently affected leukemia cell lines expressing FLT3-ITD cell viability and exhibited mutual synergies with quizartinib, a standard clinical medicine for AML. Furthermore, mutation of the lysine at 609 of ITD led to significant suppression of K63 polyubiquitination and decreased its stability, suggesting that K609 is a critical site for K63 ubiquitination specifically recognized by BRCC36. These data indicate that BRCC36 is a specific regulator for FLT3-ITD, which may shed light on developing a novel therapeutic approach for AML.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Transdução de Sinais/fisiologia , Mutação , Estabilidade Proteica
12.
Adv Mater ; 36(18): e2311869, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38266188

RESUMO

Iron-based catalysts are widely used in Fenton-like water pollution control technology due to their high efficiency, but their practical applications are limited by complex preparation conditions and strong blockage of Fe2+/Fe3+ cycle during the reaction. Here, a new iron-molybdenum bimetallic carbon-based catalyst is designed and synthesized using cellulose hydrogel for adsorption of Fe and Mo bimetals as a template, and the effective iron cycle in water treatment is realized. The integrated materials (Fe2.5Mo@CNs) with "catalytic/cocatalytic" performance have higher Fenton-like activation properties and universality than the equivalent quantity iron-carbon-based composite catalysts (Fe@CNs). Through the different characterization methods, experimental verifications and theoretical calculations show that the unique Fe3Mo3N structure promotes the adsorption of persulfate and reduces the energy barrier of the reaction, further completing the double enhancement of radicals (such as SO4·-) and nonradicals (1O2 and electron transport process). The integrated "catalytic/cocatalytic" combined material is expected to provide a new promotion strategy for Fenton-like water pollution control.

13.
J Biol Chem ; 300(1): 105513, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38042483

RESUMO

α1,6-Fucosyltransferase (Fut8) catalyzes the transfer of fucose to the innermost GlcNAc residue of N-glycan to form core fucosylation. Our previous studies showed that lipopolysaccharide (LPS) treatment highly induced neuroinflammation in Fut8 homozygous KO (Fut8-/-) or heterozygous KO (Fut8+/-) mice, compared with the WT (Fut8+/+) mice. To understand the underlying mechanism, we utilized a sensitive inflammation-monitoring mouse system that contains the human interleukin-6 (hIL6) bacterial artificial chromosome transgene modified with luciferase (Luc) reporter cassette. We successfully detected LPS-induced neuroinflammation in the central nervous system by exploiting this bacterial artificial chromosome transgenic monitoring system. Then we examined the effects of l-fucose on neuroinflammation in the Fut8+/- mice. The lectin blot and mass spectrometry analysis showed that l-fucose preadministration increased the core fucosylation levels in the Fut8+/- mice. Notably, exogenous l-fucose attenuated the LPS-induced IL-6 mRNA and Luc mRNA expression in the cerebral tissues, confirmed using the hIL6-Luc bioluminescence imaging system. The activation of microglial cells, which provoke neuroinflammatory responses upon LPS stimulation, was inhibited by l-fucose preadministration. l-Fucose also suppressed the downstream intracellular signaling of IL-6, such as the phosphorylation levels of JAK2 (Janus kinase 2), Akt (protein kinase B), and STAT3 (signal transducer and activator of transcription 3). l-Fucose administration increased gp130 core fucosylation levels and decreased the association of gp130 with the IL-6 receptor in Fut8+/- mice, which was further confirmed in BV-2 cells. These results indicate that l-fucose administration ameliorates the LPS-induced neuroinflammation in the Fut8+/- mice, suggesting that core fucosylation plays a vital role in anti-inflammation and that l-fucose is a potential prophylactic compound against neuroinflammation.


Assuntos
Fucose , Inflamação , Lipopolissacarídeos , Animais , Humanos , Camundongos , Receptor gp130 de Citocina , Fucose/farmacologia , Fucose/metabolismo , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/genética , Lipopolissacarídeos/toxicidade , Doenças Neuroinflamatórias , RNA Mensageiro
15.
Front Cardiovasc Med ; 10: 1253619, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37881722

RESUMO

Introduction: Acute myocardial infarction (AMI) remains a critical disease, characterized by a high fatality rate in several countries. In clinical practice, the incidence of AMI is increased in patients with chronic kidney disease (CKD). However, the early diagnosis of AMI in the above group of patients is still poor. Methods: In the present study, a total of 829 patients with CKD, defined by an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 or 60-90 ml/min/1.73 m2 for patients with mildly reduced kidney function, who attended the Sichuan Provincial People's Hospital (SPPH) between January 2018 and November 2022 were enrolled. All patients underwent coronary angiography due to the presence of typical or atypical symptoms of AMI. Patients were divided into the following two groups: The training cohort, including 255 participants with AMI and 242 without AMI; and the testing cohort, including 165 and 167 subjects with and without AMI, respectively. Furthermore, a forward stepwise regression model and a multivariable logistic regression model, named SPPH-AMI-model, were constructed to select significant predictors and assist the diagnosis of AMI in patients with CKD, respectively. Results: The following factors were evaluated in the model: Smoking status, high sensitivity cardiac troponin I, serum creatinine and uric acid levels, history of percutaneous coronary intervention and electrocardiogram. Additionally, the area under the curve (AUC) of the receiver operating characteristic curve were determined in the risk model in the training set [AUC, 0.78; 95% confidence interval (CI), 0.74-0.82] vs. the testing set (AUC, 0.74; 95% CI, 0.69-0.79) vs. the combined set (AUC, 0.76; 95% CI, 0.73-0.80). Finally, the sensitivity and specificity rates were 71.12 and 71.21%, respectively, the percentage of cases correctly classified was 71.14%, while positive and negative predictive values of 71.63 and 70.70%, respectively, were also recorded. Discussion: The results of the current study suggested that the SPPH-AMI-model could be currently considered as the only risk scoring system for the early diagnosis of AMI in patients with CKD. This method could help clinicians and emergency physicians to quickly and accurately diagnose AMI in patients with CKD to promote the immediate and effective treatment of these patients.

16.
Cell Rep Methods ; 3(9): 100591, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37725985

RESUMO

Single-cell sequencing (SCS) is a crucial tool to reveal the genetic and functional heterogeneity of tumors, providing unique insights into the clonal evolution, microenvironment, drug resistance, and metastatic progression of cancers. Microfluidics is a critical component of many SCS technologies and workflows, conferring advantages in throughput, economy, and automation. Here, we review the current landscape of microfluidic architectures and sequencing techniques for single-cell omics analysis and highlight how these have enabled recent applications in oncology research. We also discuss the challenges and the promise of microfluidics-based single-cell analysis in the future of precision oncology.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Microfluídica , Medicina de Precisão , Oncologia , Automação , Microambiente Tumoral/genética
17.
Heliyon ; 9(9): e19219, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37662721

RESUMO

Circular RNAs (circRNAs) are important non-coding RNAs (ncRNAs) involved in the development of multiple human diseases, especially cancers. circRNA_0084043 is significantly involved in the progression of melanoma. However, whether circRNA_0084043 is associated with glioma remains unknown. In this study, the upregulation of circRNA_0084043 in glioma and the association between circRNA_0084043 and glioma grade were identified. Our results showed that circRNA_0084043 is significantly involved in the proliferative, migratory, and invasive capacities of glioma cells. The results obtained from starBase, luciferase reporter assays, RNA immunoprecipitation assays, and RNA pull-down assays demonstrated that circRNA_0084043 acts as a direct sponge for miR-577. TargetScan algorithm was used to identify potential miR-577 targets, it was found that sorting nexin 5 (SNX5) is a candidate bound to miR-577. Finally, cell experiments testified that circRNA_0084043 enhanced growth, migration and invasion of glioma through the regulation of miR-577-mediated SNX5. Taken together, we concluded that circRNA_0084043 in the miR-577/SNX5 axis can be used as a candidate target for glioma therapy.

18.
J Med Chem ; 66(17): 11965-11984, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37597216

RESUMO

A series of heterocyclic ring-fused derivatives of 20(S)-protopanaxadiol (PPD) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these compounds, 33 (SH491, IC50 = 11.8 nM) showed the highest potency with 100% inhibition at 0.1 µM and 44.4% inhibition at an even lower concentration of 0.01 µM, which was much more potent than the lead compound PPD (IC50 = 10.3 µM). Cytotoxicity tests indicated that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation was not due to their cytotoxicity. Interestingly, SH491 also exhibited a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. Mechanistic studies revealed that SH491 inhibits the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, CTSK, MMP-9, and ATPase v0d2. In vivo, SH491 could dramatically decrease the ovariectomy-induced osteoclast activity and relieve osteoporosis obviously. Thus, these PPD derivatives could be served as promising leads for the development of novel antiosteoporosis agents.


Assuntos
Adenosina Trifosfatases , Osteoporose , Feminino , Humanos , Osteoclastos , Osteogênese , Osteoporose/tratamento farmacológico
19.
Immunol Invest ; 52(6): 735-748, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37409941

RESUMO

BACKGROUND: CAR-T is emerging as an effective treatment strategy for hematologic malignancies, however its effectiveness for treating solid tumors, such as Hepatocellular Carcinoma (HCC) is limited. Here, we screened a variety of CAR-T cells that target c-Met to investigate their potential to induce HCC cell death in vitro. METHODS: Human T cells were transduced to express CARs by lentiviral vector transfection. c-Met expression in human HCC cell lines and CARs expression were monitored by flow cytometry. Tumor cell killing was evaluated by Luciferase Assay System Kit. The concentrations of cytokine were tested by Enzyme-linked immunosorbent assays. Knock down and overexpression studies targeting c-Met were conducted to assess the targeting specificity of CARs. RESULTS: We found that CAR T cells expressing a minimal amino-terminal polypeptide sequence comprising the first kringle (kringle 1) domain (denoted as NK1 CAR-T cells), efficiently killed HCC cell lines that expressed high levels of the HGF receptor c-Met. Furthermore, we report that while NK1 CAR-T cells were efficient at targeting SMMC7221 cells for destruction, and its potency was significantly attenuated in parallel experiments with cells stably expressing short hairpin RNAs (shRNAs) that suppressed c-Met expression. Correspondingly, overexpression of c-Met in the embryonic kidney cell line HEK293T led to their enhanced killing by NK1 CAR-T cells. CONCLUSION: Our studies demonstrate that a minimal amino-terminal polypeptide sequence comprising the kirngle1 domain of HGF is highly relevant to the design of effective CAR-T cell therapies that kill HCC cells expressing high levels of c-Met.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Células HEK293 , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Linhagem Celular Tumoral , Imunoterapia Adotiva , Citocinas/metabolismo , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fator de Crescimento de Hepatócito/metabolismo
20.
Bio Protoc ; 13(11): e4691, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37323638

RESUMO

Agrobacterium rhizogenes is a soil bacteria with extensive infectivity, which can infect almost all dicotyledonous plants and a few monocotyledonous plants to induce root nodules. This is caused by the root-inducing plasmid, which contains genes responsible for the autonomous growth of root nodules and crown gall base synthesis. Structurally, it is similar to the tumor-inducing plasmid in that it mainly contains the Vir region, the T-DNA region, and the functional region of crown gall base synthesis. Its T-DNA is integrated into the nuclear genome of the plant with the assistance of Vir genes, causing hairy root disease in the host plant and the formation of hairy roots. The roots produced by Agrobacterium rhizogenes-infested plants are characterized by a fast growth rate, high degree of differentiation, physiological, biochemical, and genetic stability, and ease of manipulation and control. In particular, the hairy root system is an efficient and rapid research tool for plants that have no affinity for transformation by Agrobacterium rhizogenes and low transformation efficiency. The establishment of germinating root culture system for the production of secondary metabolites in the original plants through the genetic transformation of natural plants mediated by root-inducing plasmid in Agrobacterium rhizogenes has become a new technology combining plant genetic engineering and cell engineering. It has been widely used in a variety of plants for different molecular purposes, such as pathological analysis, gene function verification, and secondary metabolite research. Chimeric plants obtained by induction of Agrobacterium rhizogenes that can be expressed instantaneously and contemporarily are more rapidly obtained, compared to tissue culture and stably inheritable transgenic strains. In general, transgenic plants can be obtained in approximately one month.

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