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Proteomics offers a robust method for quantifying proteins and elucidating their roles in cellular functions, surpassing the insights provided by transcriptomics. The Clinical Proteomic Tumor Analysis Consortium database, enriched with comprehensive cancer proteomics data including phosphorylation and ubiquitination profiles, alongside transcriptomics data from the Genomic Data Commons, allow for integrative molecular studies of cancer. The ProteoCancer Analysis Suite (PCAS), our newly developed R package and Shinyapp, leverages these resources to facilitate in-depth analyses of proteomics, phosphoproteomics, and transcriptomics, enhancing our understanding of the tumor microenvironment through features like immune infiltration and drug sensitivity analysis. This tool aids in identifying critical signaling pathways and therapeutic targets, particularly through its detailed phosphoproteomic analysis. To demonstrate the functionality of the PCAS, we conducted an analysis of GAPDH across multiple cancer types, revealing a significant upregulation of protein levels, which is consistent with its important biological and clinical significance in tumors, as indicated in our prior research. Further experiments were used to validate the findings performed using the tool. In conclusion, the PCAS is a powerful and valuable tool for conducting comprehensive proteomic analyses, significantly enhancing our ability to uncover oncogenic mechanisms and identify potential therapeutic targets in cancer research.
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Neoplasias , Proteômica , Humanos , Proteômica/métodos , Neoplasias/metabolismo , Neoplasias/genética , Microambiente Tumoral/genética , Software , Biologia Computacional/métodos , Proteoma/metabolismoRESUMO
Exosomes are considered as promising biomarkers for early cancer diagnosis and prognosis. However, the majority of the research studies focused on a single type of exosomal biomarkers, which cannot comprehensively reflect the state of cancer for accurate diagnosis. To address this problem, we presented a ship-shaped microfluidic device containing a microcolumn array for simultaneous in situ detection of exosomal surface proteins and miRNAs. Exosomes were first captured in the microchannels modified with CD63 protein aptamer. Exosomal surface proteins and miRNAs were simultaneously detected in four parallel channels to avoid the interference of fluorescent signals using specific aptamers labeled by Cy5 and catalytic hairpin assembly (CHA) based signal amplification strategy. The limit of detection for multiplexed markers in exosomes was 83 exosomes per µL, which is comparable to previously reported methods. Through quantitative analysis of two disease-specific surface proteins and miRNAs derived from different cancer cells and clinical serum samples, different cancer subtypes as well as cancer patients and healthy people could be significantly distinguished. These results suggest that this simple, highly sensitive, and more accurate analytical strategy by simultaneous in situ profiling of different types of exosomal biomarkers has potential applications in cancer diagnosis and stage monitoring.
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Exossomos , MicroRNAs , Neoplasias , Humanos , MicroRNAs/análise , Exossomos/química , Microfluídica , Proteínas de Membrana , Neoplasias/metabolismo , Oligonucleotídeos/metabolismoRESUMO
BACKGROUND: Infected pancreatic necrosis (IPN) accounts for 30% mortality in severe acute pancreatitis (SAP). Early prediction of IPN occurrence is critical for prophylactic measures to be taken. This study aimed to evaluate the predicting value for IPN of combined markers at early stages of SAP. METHODS: The clinical records of 324 SAP patients admitted within 48 h after disease onset were retrospectively analyzed. As potential predictors, the neutrophil to lymphocyte ratio (NLR), blood procalcitonin (PCT) concentration on the 1st, 4th, and 7th day post admission, as well as modified computerized tomography severity index (MCTSI) on the 5-7th day post admission, were extracted. Correlations between these features with IPN were analyzed using logistic regression, and predictive values were estimated using the receiver operating characteristic curve analyses. RESULTS: NLR, PCT, body mass index, and MCTSI were significantly higher in the IPN group (p < 0.001) compared to the control, among which NLR, PCT, and MCTSI were identified as independent predictors for IPN in logistic regression model. Combination of these parameters yielded significant predicting values with an area under curve of 0.92, sensitivity of 97.2%, and specificity of 77.2% in receiver operating characteristic curve analysis. CONCLUSION: Combination of NLR, PCT, MCTSI might facilitate the prediction of IPN occurrence in SAP patients.
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Pancreatite Necrosante Aguda , Humanos , Pancreatite Necrosante Aguda/diagnóstico por imagem , Pró-Calcitonina , Doença Aguda , Neutrófilos , Estudos Retrospectivos , Curva ROC , Linfócitos , Tomografia Computadorizada por Raios X , Prognóstico , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The classical role of PIWIL2 is to regulate reproduction by binding to piRNA, but its tumor-related function has received increasing attention in recent years. This study aims to explore its role in the progression of thyroid cancer (TC). METHODS: First, we measured and analyzed the levels of PIWIL2 and miR-146a-3p in TC tissue and adjacent tissues as well as several TC cell lines. We demonstrated the clinical significance of PIWIL2 and miR-146a-3p through the survival rate. Based on these results, we selected TPC-1 and KTC-3 cell lines for our cell experiments. We treated these cell lines with PIWIL2 lentivirus, PIWIL2 siRNA, miR-146a-3p mimic, or miR-146a-3p inhibitor and measured cell proliferation, cell cycle, apoptosis, migration, and invasion. We used PCR and Western blot to quantify the mRNA and protein levels of PIWIL2, while we used luciferase reporter assay and RNA binding protein immunoprecipitation to explore the relationship between miR-146a-3p and PIWIL2. Finally, we developed a xenograft tumor model to confirm the effects of the miR-146a-3p/PIWIL2 axis on TC progression in vivo. RESULTS: We identified that PIWIL2 and miR-146a-3p exhibit opposite expression alterations in TC tissues and that PIWIL2 serves as a 'sponge' by adsorbing miR-146a-3p. Up-regulating PIWIL2 decelerated the proliferation, metastasis, and cell cycle progression of TPC-1 and KTC-3 cells, but accelerated the apoptosis of TC cells, while miR-146a-3p exhibited opposite effects. Finally, overexpressing PIWIL2 restrained the progression of TC in nude mice, which can be reversed by increasing miR-146a-3p expression. Inhibiting PIWIL2, on the other hand, promoted the progression of TC in vivo, which can be reversed by inhibiting miR-146a-3p. CONCLUSION: PIWIL2 may inhibit the progression of TC by sponging miR-146a-3p, providing new insights into the early treatment, recrudescence treatment, and metastasis treatment of TC.
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MicroRNAs , Neoplasias da Glândula Tireoide , Humanos , Animais , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Neoplasias da Glândula Tireoide/genética , Apoptose , Modelos Animais de Doenças , MicroRNAs/genética , Proteínas Argonautas/genéticaRESUMO
BACKGROUND Acute pancreatitis, a sudden inflammation of the pancreas, can result in severe complications. The presence and volume of ascites, an abnormal accumulation of fluid in the abdomen, has been linked to disease severity. Our study investigates ascites volume, quantified via abdominal CT scans, as a potential predictive tool for disease severity. MATERIAL AND METHODS In this retrospective analysis, patients diagnosed with acute pancreatitis were evaluated. Patients were categorized into groups with and without ascites, with comparisons made regarding clinical characteristics. We further compared the mean ascitic volume against various outcome parameters in patients with ascites. Ascites volume and other predictive systems were assessed through receiver operating characteristic (ROC) curves, with the area under the ROC curve (AUC) for different predictive systems being analyzed. RESULTS The ascites group had higher severity scores and related serological indexes (P<0.05 for all). Among patients with ascites, a significant correlation was observed between ascites volume and outcome parameters (P<0.05 for all). The area under the ROC curve for predicting severe acute pancreatitis was 0.896, with 93% sensitivity and 79% specificity. Ascites volume yielded the highest diagnostic odds ratio (53.1; 95% confidence interval: 13.2,199.6). CONCLUSIONS Early-stage acute pancreatitis patients with ascites are indicative of severe illness and poor prognosis. An increase in ascites volume correlates with adverse clinical outcomes, thus highlighting the significance of ascites volume as a prognostic marker. This underscores the importance of abdominal CT in measuring ascites volume to predict disease severity.
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Ascite , Pancreatite , Humanos , Ascite/diagnóstico por imagem , Estudos Retrospectivos , Índice de Gravidade de Doença , Doença Aguda , Pancreatite/complicações , Tomografia Computadorizada por Raios X/métodos , Abdome , Curva ROC , Prognóstico , Valor Preditivo dos TestesRESUMO
Cranioplasty is a common neurosurgical procedure; however, the optimal material choice remains controversial. At the time of this writing, autologous bone, the preferred choice for primary cranioplasty, has a high incidence of complications such as infection and resorption, thus requiring frequent use of synthetic materials. Therefore, this study aimed to compare the clinical benefits of titanium mesh (Ti), polyetheretherketone (PEEK), and composite bone cement (CBC) in cranioplasty to provide a clear selection basis for clinicians and patients. This study retrospectively collected data from 207 patients who underwent cranioplasty with Ti (n=129), PEEK (n=54), and CBC (n=24) between January 2018 and December 2020 at Henan Provincial People's Hospital. Postoperative follow-up information after 6 months was used to compare the long-term effects of the 3 materials on the patients. There were no significant differences in the overall complication rate after cranioplasty among the 3 materials. However, subcutaneous effusion was more frequent with PEEK (24.07%) and CBC (20.83%) than with Ti (2.33%). Second, there were no significant differences in the increase in Glasgow Outcome Scale and Karnofsky Performance Status scores after cranioplasty among the 3 materials. Finally, we found that PEEK had the highest patient satisfaction and hospitalization cost, whereas the opposite was true for Ti. Although the surgical outcomes of the 3 implant materials were similar, an examination of clinical outcomes such as patient satisfaction showed significant differences, deepening people's perceptions of the 3 materials.
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Implantes Dentários , Procedimentos de Cirurgia Plástica , Humanos , Estudos Retrospectivos , Cimentos Ósseos , Titânio , Telas Cirúrgicas/efeitos adversos , Polietilenoglicóis , Cetonas , Crânio/cirurgia , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND Acute pancreatitis (AP) is a common acute abdominal disease. Rapid evaluation of the severity is important for AP prognosis and treatment. Free triiodothyronine (fT3) level is associated with the prognosis of AP patients. This study aimed to investigate the fT3 level in patients with acute pancreatitis; early warning signs of inflammation, including interleukin-6 (IL-6) and interleukin-10 (IL-10); and the correlation of fT3 level with illness severity. MATERIAL AND METHODS Enrolled AP patients (N=312) were divided into an SAP group (N=92) and a non-SAP group (N=220) according to the Revision of Atlanta classification. Blood or tissue samples and baseline clinical characteristics were recorded. The t test and chi-square test were used to evaluate differences between the 2 groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to investigate protective factors. One-way repeated measures analysis of variance was used to evaluate the prognosis of SAP patients. RESULTS In our study, compared with APACHII score (AUC 0.829 [95% CIs 0.769-0.889]) and Ranson score (AUC 0.629 [95% CIs 0.542-0.715]), our predictive model (AUC 0.918 [95% CIs 0.875-0.961]) showed better prognostic performance in predicting poor patient outcomes. In the SAP group, changes in fT3 level were significantly associated with prognosis (P<0.05). CONCLUSIONS The predictive model can improve the diagnostic accuracy and prediction of the severity of disease. FT3 level could be used as an independent risk factor to predict the mortality of SAP patients.
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Interleucina-10/sangue , Interleucina-6/sangue , Pancreatite/sangue , Pancreatite/fisiopatologia , Tri-Iodotironina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
MicroRNAs (miRNAs) are a group of endogenous, small (â¼22 nts in length) noncoding RNA molecules that function specifically by base pairing with the mRNA of genes and regulate gene expression at the post-transcriptional level. Alterations in miR-32 expression have been found in numerous diseases and shown to play a vital role in cell proliferation, apoptosis, oncogenesis, invasion, metastasis and drug resistance. MiR-32 has been documented as an oncomiR in the majority of related studies but has been also verified as a tumour suppressor miRNA in conflicting reports. Moreover, it has a crucial role in metabolic and cardiovascular disorders. This review provides an in-depth look into the most recent finding regarding miR-32, which is involved in the expression, regulation and functions in different diseases, especially tumours. Additionally, this review outlines novel findings suggesting that miR-32 may be useful as a noninvasive biomarker and as a targeted therapeutic in several diseases.
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Doenças Cardiovasculares/metabolismo , Doenças Metabólicas/metabolismo , MicroRNAs/fisiologia , Neoplasias/metabolismo , Animais , Biomarcadores/metabolismo , HumanosRESUMO
BACKGROUND/AIMS: This study aimed to report the clinical efficacy of continuous renal replacement therapy (CRRT) in combination with ultrasound-guided percutaneous transhepatic gallbladder drainage (PTGD) (CRRT+PTGD) in the treatment of acute severe biliary pancreatitis (ASBP). METHODS: Between January 2010 and January 2016, 40 cases of patients with ASBP who received routine CRRT (CRRT group) and 40 of those who received CRRT+PTGD (CRRT+PTGD group) at the Affiliated Hospital of Qingdao University (Qingdao, China) were retrospectively reviewed. Clinical (including abdominal pain remission time, gastrointestinal decompression time, Intensive Care Unit (ICU) hospital stay, respirator treatment time, and mortality rate), laboratory (white blood cells [WBC], platelet [PLT], procalcitonin [PCT], C-reactive protein [CRP], total bilirubin [TBIL], alanine aminotransferase [ALT], albumin [ALB], and blood lactic acid [Lac]) parameters, various critical disease scores, and incidence of complications after the treatment were compared between the two groups. RESULTS: Compared with those in the routine CRRT group, patients in the CRRT+PTGD group exhibited significant remission of clinical symptoms (i.e. shorter abdominal pain remission time, gastrointestinal decompression time, respirator treatment time and ICU hospital stay) (all P<0.05), change of laboratory parameters (WBC, PLT, PCT, CRP, TBIL, ALT) (P<0.05), and improvement of various critical disease scores (P<0.05). Moreover, the variation of most of the above parameters after versus before the treatment was greater in the CRRT+PTGD group than in the CRRT group (all P<0.05). CONCLUSION: CRRT in combination with PTGD is more effective in the treatment of ASBP than CRRT alone.
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Drenagem/métodos , Vesícula Biliar/cirurgia , Pancreatite/terapia , Terapia de Substituição Renal/métodos , Doença Aguda , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The electrodeposition of nanocrystalline NiFe alloy coatings and associated nucleation/growth processes are investigated on the glassy carbon (GC) electrode in 1-butyl-3-methylimidazolium-hydrogen sulfate ([BMIM]HSO4) ionic liquid (IL). Cyclic voltammetric data suggest that the co-electrodeposition of NiFe alloys is quasi-reversible. Moreover, chronoamperometry results indicate that the electrodeposition proceeds via a simultaneous nucleation and three-dimensional growth mechanism. In addition, the effects of electrodeposition potential and electrolyte temperature on the coating thickness and Fe content are also studied. The microstructure and composition of the NiFe alloy coatings on Cu substrate are investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD) and energy-dispersive spectroscopy (EDS). SEM observations show that these electrodeposits present a dense and compact structure, EDS analysis indicates that the coatings are composed of Ni and Fe, XRD pattern shows the coatings are crystalline with a face-centred cubic (fcc) structure. Tafel plots reveal that the NiFe alloy prepared from [BMIM]HSO4 IL presents better corrosion resistance than that of pure Ni.
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A novel strategy for the preparation of an aptamer based organic-inorganic hybrid affinity monolithic column was developed successfully using gold nanoparticles (GNPs) as an intermediary for a sandwich structure to realize the functional modification of the surface of the monolithic matrix. This monolithic matrix was facilely pre-synthesized via one-step co-condensation. Due to the high surface-to-volume ratio of GNPs and the large specific surface area of the hybrid matrix, the average coverage density of aptamers on the hybrid monolith reached 342 pmol µL(-1). With the combination of an aptamer based hybrid affinity monolithic column and enzymatic chromogenic assay, the quantitation and detection limits of thrombin were as low as 5 nM and 2 nM, respectively. These results indicated that the GNPs attached monolith provided a novel technique to immobilize aptamers on an organic-inorganic hybrid monolith and it could be used to achieve highly selective recognition and determination of trace proteins.
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Aptâmeros de Peptídeos , Ouro , Nanopartículas Metálicas , Proteínas/análise , Limite de Detecção , Trombina/análiseRESUMO
Background: Severe acute pancreatitis (SAP) is an inflammatory disorder affecting the gastrointestinal system. Intestinal injury plays an important role in the treatment of severe acute pancreatitis. In this study, we mainly investigated the role of S1PR2 in regulating macrophage pyroptosis in the intestinal injury of severe acute pancreatitis. Methods: The SAP model was constructed using cerulein and lipopolysaccharide, and the expression of S1PR2 was inhibited by JTE-013 to detect the degree of pancreatitis and intestinal tissue damage in mice. Meanwhile, the level of pyroptosis-related protein was detected by western blot, the level of related mRNA was detected by PCR, and the level of serum inflammatory factors was detected by ELISA. In vitro experiments, LPS+ATP was used to construct the pyroptosis model of THP-1. After knockdown and overexpression of S1PR2, the pyroptosis proteins level was detected by western blot, the related mRNA level was detected by PCR, and the level of cell supernatant inflammatory factors were detected by ELISA. A rescue experiment was used to verify the sufficient necessity of the RhoA/ROCK pathway in S1PR2-induced pyroptosis. Meanwhile, THP-1 and FHC were co-cultured to verify that cytokines released by THP-1 after damage could regulate FHC damage. Results: Our results demonstrated that JTE-013 effectively attenuated intestinal injury and inflammation in mice with SAP. Furthermore, we observed a significant reduction in the expression of pyroptosis-related proteins within the intestinal tissue of SAP mice upon treatment with JTE-013. We confirmed the involvement of S1PR2 in THP-1 cell pyroptosis in vitro. Specifically, activation of S1PR2 triggered pyroptosis in THP-1 cells through the RhoA/ROCK signaling pathway. Moreover, it was observed that inflammatory factors released during THP-1 cell pyroptosis exerted an impact on cohesin expression in FHC cells. Conclusion: The involvement of S1PR2 in SAP-induced intestinal mucosal injury may be attributed to its regulation of macrophage pyroptosis.
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Modelos Animais de Doenças , Macrófagos , Pancreatite , Piroptose , Receptores de Esfingosina-1-Fosfato , Animais , Camundongos , Humanos , Macrófagos/metabolismo , Macrófagos/imunologia , Pancreatite/metabolismo , Pancreatite/imunologia , Pancreatite/patologia , Pancreatite/induzido quimicamente , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Masculino , Transdução de Sinais , Camundongos Endogâmicos C57BL , Proteína rhoA de Ligação ao GTP/metabolismo , Células THP-1 , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , Intestinos/imunologia , Citocinas/metabolismo , Lipopolissacarídeos , Pirazóis , PiridinasRESUMO
Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, dissociable Siamese nanoparticles (SIANPs) are developed for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promotes dendritic cell maturation and CD8+ T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. This study represents a two-pronged approach for orchestrating immune responses, and paves a new way for employing epi-drugs in cancer immunotherapy.
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Imunoterapia , Nanopartículas , Microambiente Tumoral , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Adenina/análogos & derivados , Adenina/química , Adenina/farmacologia , Piperidinas/química , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/metabolismo , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Pirimidinas/química , Pirimidinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Pirazóis/química , Pirazóis/farmacologiaRESUMO
The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.
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PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS-STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK-STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with immune checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS-STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Inibidores de Histona Desacetilases/farmacologia , Janus Quinases , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fatores de Transcrição STAT , Transdução de Sinais , Nucleotidiltransferases/genéticaRESUMO
Background: In this study, we examined the functions and mechanisms by which naringenin protects against SAP (severe acute pancreatitis)-related intestinal injury by modulating the AhR/NLRP3 signaling pathway. Material and methods: Fifteen healthy male C57BL/6 mice were randomly divided into SAP (n = 12) and normal (n = 3) groups. Mice in the SAP group received caerulein and lipopolysaccharide intraperitoneal injections and were then randomly assigned to the SAP, NAR, CH223191, and Dexamethasone (DEX) groups. Pathological changes in the pancreatic and intestinal mucosa were observed by Hematoxylin & Eosin (H&E) staining. In vitro, RAW264.7 cells were exposed to lipopolysaccharide and treated with naringenin. The levels of NLRP3, AhR, IL-1ß, TNF, and IL-6 in the SAP model and RAW264.7 cells were evaluated by enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry. The nuclear translocation of AhR was shown by immunofluorescence. AutoDockTools was used to predict the conformations of naringenin-AhR binding, and PyMol 2.4 was used to visualize the conformations. Results: Mouse pancreatic and intestinal injury was alleviated by treatment with naringenin. Naringenin inhibited the activation of the NLRP3 inflammasome and inhibited damage to intestinal tight junctions. Moreover, naringenin increased AhR nuclear translocation and activated the AhR pathway. Conclusion: Naringenin can reduce SAP-associated intestinal injury by inhibiting the activation of the NLRP3 inflammasome via the AhR signaling pathway.
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Proline and serine-rich coiled-coil 1 (PSRC1) has been reported to function as an oncogene in several cancers by regulating mitosis, while there are few reports on the role of PSRC1 in lower-grade glioma (LGG). Thus, this study collected 22 samples and 1126 samples from our institution and several databases, respectively, to explore the function of PSRC1 in LGG. First, the analysis of clinical characteristics showed that PSRC1 was always highly expressed in more malignant clinical characteristics of LGG, such as higher WHO grade, recurrence type, and IDH wild type. Second, the prognosis analysis revealed that the high expression of PSRC1 was an independent risk factor contributing to the shorter overall survival of LGG patients. Third, the analysis of DNA methylation showed that the expression of PSRC1 was associated with its 8 DNA methylation sites, overall negatively regulated by its DNA methylation level in LGG. Fourth, the analysis of immune correlation revealed that the expression of PSRC1 was positively correlated with the infiltration of 6 immune cells and the expression of 4 well-known immune checkpoints in LGG, respectively. Finally, co-expression analysis and KEGG analysis showed the 10 genes most related to PSRC1 and the signaling pathways involved by PSRC1 in LGG, respectively, such as MAPK signaling pathway and focal adhesion. In conclusion, this study identified the pathogenic role of PSRC1 in the pathological progression of LGG, expanding the molecular understanding of PSRC1, and provided a biomarker and potential immunotherapeutic target for the treatment of LGG.
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Neoplasias Encefálicas , Glioma , Humanos , Metilação de DNA , Imunoterapia , Glioma/genética , Glioma/terapia , Bases de Dados Factuais , Sistema de Sinalização das MAP Quinases , FosfoproteínasRESUMO
[This corrects the article DOI: 10.3389/fphar.2023.1090261.].
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Extracellular matrix protein 2 (ECM2), which regulates cell proliferation and differentiation, has recently been reported as a prognostic indicator for multiple cancers, but its value in lower grade glioma (LGG) remains unknown. In this study, LGG transcriptomic data of 503 cases in The Cancer Genome Atlas (TCGA) database and 403 cases in The Chinese Glioma Genome Atlas (CGGA) database were collected to analyze ECM2 expression patterns and the relationship with clinical characteristics, prognosis, enriched signaling pathways, and immune-related markers. In addition, a total of 12 laboratory samples were used for experimental validation. Wilcoxon or Kruskal-Wallis tests demonstrated highly expressed ECM2 in LGG was positively associated with malignant histological features and molecular features such as recurrent LGG and isocitrate dehydrogenase (IDH) wild-type. Also, Kaplan-Meier (KM) curves proved high ECM2 expression could predict shorter overall survival in LGG patients, as multivariate analysis and meta-analysis claimed ECM2 was a deleterious factor for LGG prognosis. In addition, the enrichment of immune-related pathways for ECM2, for instance JAK-STAT pathway, was obtained by Gene Set Enrichment Analysis (GSEA) analysis. Furthermore, positive relationships between ECM2 expression with immune cells infiltration and cancer-associated fibroblasts (CAFs), iconic markers (CD163), and immune checkpoints (CD274, encoding PD-L1) were proved by Pearson correlation analysis. Finally, laboratory experiments of RT-qPCR and immunohistochemistry showed high expression of ECM2, as well as CD163 and PD-L1 in LGG samples. This study identifies ECM2, for the first time, as a subtype marker and prognostic indicator for LGG. ECM2 could also provide a reliable guarantee for further personalized therapy, synergizing with tumor immunity, to break through the current limitations and thus reinvigorating immunotherapy for LGG. AVAILABILITY OF DATA AND MATERIALS: Raw data from all public databases involved in this study are stored in the online repository (chengMD2022/ECM2 (github.com)).