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1.
Gastroenterology ; 166(1): 178-190.e16, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37839499

RESUMO

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Delayed manifestation of symptoms and lack of specific diagnostic markers lead patients being diagnosed with PDAC at advanced stages. This study aimed to develop a circular RNA (circRNA)-based biomarker panel to facilitate noninvasive and early detection of PDAC. METHODS: A systematic genome-wide discovery of circRNAs overexpressed in patients with PDAC was conducted. Subsequently, validation of the candidate markers in the primary tumors from patients with PDAC was performed, followed by their translation into a plasma-based liquid biopsy assay by analyzing 2 independent clinical cohorts of patients with PDAC and nondisease controls. The performance of the circRNA panel was assessed in conjunction with the plasma levels of cancer antigen 19-9 for the early detection of PDAC. RESULTS: Initially, a panel of 10 circRNA candidates was identified during the discovery phase. Subsequently, the panel was reduced to 5 circRNAs in the liquid biopsy-based assay, which robustly identified patients with PDAC and distinguished between early-stage (stage I/II) and late-stage (stage III/IV) disease. The areas under the curve of this diagnostic panel for the detection of early-stage PDAC were 0.83 and 0.81 in the training and validation cohorts, respectively. Moreover, when this panel was combined with cancer antigen 19-9 levels, the diagnostic performance for identifying patients with PDAC improved remarkably (area under the curve, 0.94) for patients in the validation cohort. Furthermore, the circRNA panel could also efficiently identify patients with PDAC (area under the curve, 0.85) who were otherwise deemed clinically cancer antigen 19-9-negative (<37 U/mL). CONCLUSIONS: A circRNA-based biomarker panel with a robust noninvasive diagnostic potential for identifying patients with early-stage PDAC was developed.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , RNA Circular/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Estadiamento de Neoplasias , Detecção Precoce de Câncer , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Antígeno CA-19-9 , Adenocarcinoma/patologia
2.
Mol Carcinog ; 63(11): 2145-2157, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39282961

RESUMO

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.


Assuntos
Apoptose , Neoplasias Colorretais , Sinergismo Farmacológico , Photinia , Extratos Vegetais , Proantocianidinas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Proantocianidinas/farmacologia , Proantocianidinas/química , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Photinia/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Frutas/química , Sobrevivência Celular/efeitos dos fármacos
3.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569514

RESUMO

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), triggered by various pathogenic factors inside and outside the lungs, leads to diffuse lung injury and can result in respiratory failure and death, which are typical clinical critical emergencies. Severe acute pancreatitis (SAP), which has a poor clinical prognosis, is one of the most common diseases that induces ARDS. When SAP causes the body to produce a storm of inflammatory factors and even causes sepsis, clinicians will face a two-way choice between anti-inflammatory and anti-infection objectives while considering the damaged intestinal barrier and respiratory failure, which undoubtedly increases the difficulty of the diagnosis and treatment of SAP-ALI/ARDS. For a long time, many studies have been devoted to applying glucocorticoids (GCs) to control the inflammatory response and prevent and treat sepsis and ALI/ARDS. However, the specific mechanism is not precise, the clinical efficacy is uneven, and the corresponding side effects are endless. This review discusses the mechanism of action, current clinical application status, effectiveness assessment, and side effects of GCs in the treatment of ALI/ARDS (especially the subtype caused by SAP).


Assuntos
Lesão Pulmonar Aguda , Pancreatite , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Sepse , Humanos , Glucocorticoides/uso terapêutico , Doença Aguda , Pancreatite/complicações , Síndrome do Desconforto Respiratório/patologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/complicações , Sepse/complicações
4.
J Cell Mol Med ; 25(4): 1851-1866, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33438315

RESUMO

Long non-coding RNAs (lncRNAs) contribute to disease pathogenesis and drug treatment effects. Both emodin and dexamethasone (DEX) have been used for treating severe acute pancreatitis-associated acute lung injury (SAP-ALI). However, lncRNA regulation networks related to SAP-ALI pathogenesis and drug treatment are unreported. In this study, lncRNAs and mRNAs in the lung tissue of SAP-ALI and control rats, with or without drug treatment (emodin or DEX), were assessed by RNA sequencing. Results showed both emodin and DEX were therapeutic for SAP-ALI and that mRNA and lncRNA levels differed between untreated and treated SAP-ALI rats. Gene expression profile relationships for emodin-treated and control rats were higher than DEX-treated and -untreated animals. By comparison of control and SAP-ALI animals, more up-regulated than down-regulated mRNAs and lncRNAs were observed with emodin treatment. For DEX treatment, more down-regulated than up-regulated mRNAs and lncRNAs were observed. Functional analysis demonstrated both up-regulated mRNA and co-expressed genes with up-regulated lncRNAs were enriched in inflammatory and immune response pathways. Further, emodin-associated lncRNAs and mRNAs co-expressed modules were different from those associated with DEX. Quantitative polymerase chain reaction demonstrates selected lncRNA and mRNA co-expressed modules were different in the lung tissue of emodin- and DEX-treated rats. Also, emodin had different effects compared with DEX on co-expression network of lncRNAs Rn60_7_1164.1 and AABR07062477.2 for the blue lncRNA module and Nrp1 for the green mRNA module. In conclusion, this study provides evidence that emodin may be a suitable alternative or complementary medicine for treating SAP-ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Emodina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Pancreatite/complicações , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores , Biópsia , Biologia Computacional/métodos , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ontologia Genética , Mediadores da Inflamação/metabolismo , Masculino , Ratos
5.
Pharmacol Res ; 163: 105311, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33246170

RESUMO

Kidney injury is one of the main complications of obstructive jaundice (OJ) and its pathogenesis has not been clarified. As an independent risk factor for OJ associated with significant morbidity and mortality, it can be mainly divided into two types of morphological injury and functional injury. We called these dysfunctions caused by OJ-induced kidney injury as OJKI. However, the etiology of OJKI is still not fully clear, and research studies on how OJKI becomes a facilitated factor of OJ are limited. This article reviews the underlying pathological mechanism from five aspects, including metabolisms of bile acids, hemodynamic disturbances, oxidative stress, inflammation and the organic transporter system. Some nephrotoxic drugs and measures that can enhance or reduce the renal function with potential intervention in perioperative periods to alleviate the incidence of OJKI were also described. Furthermore, a more in-depth study on the pathogenesis of OJKI from multiple aspects for exploring more targeted treatment measures were further put forward, which may provide new methods for the prevention and treatment of clinical OJKI and improve the prognosis.


Assuntos
Icterícia Obstrutiva/complicações , Nefropatias/etiologia , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Humanos , Icterícia Obstrutiva/tratamento farmacológico , Icterícia Obstrutiva/metabolismo , Icterícia Obstrutiva/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/fisiopatologia
6.
J Mol Cell Cardiol ; 143: 1-14, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32278833

RESUMO

BACKGROUND: It has been noted that dysregulation of microRNAs (miRNAs) contributes to the formation of abdominal aortic aneurysm (AAA), a vascular disease associated with progressive aortic dilatation and degradation, and pathological infiltration and activation of inflammatory cells, such as macrophages. Our microarray data revealing that miR-144-5p was the top 1 downregulated miRNA in mouse AAA tissues as compared to normal aortas motivated us to explore its role in AAA development. METHODS: We profiled miRNA and mRNA expression in Angiotensin II (Ang II)- (n = 3) and saline-infused abdominal aortas (n = 4) via Agilent microarrays, and further validated the data with real-time QPCR. In vivo, miR-144-5p or control agomirs were given to Apoe-/- mice with Ang II infusion-induced AAA. In vitro, mouse RAW 264.7 macrophages and human THP-1 macrophage-like cells were transfected with miR-144-5p or control agomirs/antagomirs, and oxidized Low Density Lipoprotein (ox-LDL) was used to stimulate M1 macrophage polarization. RESULTS: Based on the microarray and real-time QPCR validation data, we identified miR-144-5p as a novel downregulated miRNA in AAA tissues. Overexpression of miR-144-5p by utilizing its specific agomirs in vivo significantly attenuated Ang II-induced aortic dilatation and elastic degradation in Apoe-/- mice and improved their survival. AAA incidence was reduced by miR-144-5p as well. MiR-144-5p polarized macrophages to M2 type in Ang II-infused aortas. Further, the expression levels of two predictive targets for miR-144-5p, Toll Like Receptor 2 (TLR2) and ox-LDL Receptor 1 (OLR1), were higher in AAA specimens, and negatively correlated to miR-144-5p (Pearson correlation coefficient r < -0.9, P < .01). These two molecules were then confirmed as novel miR-144-5p targets via dual-luciferase assay. MiR-144-5p agomirs suppressed ox-LDL-induced upregulation of M1 macrophage markers, including interleukin 1ß (IL1ß), tumor necrosis factor α (TNFα), prostaglandin-endoperoxide synthase 2 (PTGS2) and nitric oxide synthase 2 (NOS2), in macrophages probably by targeting TLR2. MiR-144-5p also inhibited the signaling transduction of pathways downstream to TLR2 and OLR1, including NF-κB and ERK1/2 pathways, whose abnormal activation contributed AAA formation. CONCLUSION: Our work suggests miR-144-5p as a novel regulator for AAA pathology. Management of miR-144-5p and its targets TLR2 and OLR1 provides therapeutic potential for limiting AAA formation.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Inflamação/complicações , Macrófagos/metabolismo , MicroRNAs/genética , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Linhagem Celular , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Inflamação/etiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Células RAW 264.7 , Interferência de RNA , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
7.
J Cell Physiol ; 235(12): 9336-9346, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32342520

RESUMO

Abdominal aortic aneurysm (AAA) is a potentially lethal disease featured by focal dilatation in the aorta. The transition of vascular smooth muscle cells (SMCs) from a contractile/differentiated to a synthetic/dedifferentiated phenotype is considered to contribute to AAA formation and expansion. Our previous gene microarray data showed that Ventricular Zone Expressed PH Domain Containing 1 (VEPH1) expression increased in angiotensin II (Ang II)-infused aortic tissues. This study was thus performed to further explore the role of VEPH1. Herein, we first demonstrate that VEPH1 increases in the SMCs of Ang II-treated abdominal aortas. As in vivo, Ang II also upregulated VEPH1 expression in cultured hAoSMCs. The dedifferentiation of human aortic SMCs (hAoSMCs) was induced by a 24-hr stimulation of Ang II (1 µM)-the expression of contractile SMC markers, MYH11 and α-smooth muscle actin (α-SMA) decreased and that of synthetic markers, proliferating cell nuclear antigen and Vimentin increased. Inhibition of VEPH1 prevented Ang II-induced pathological dedifferentiation of hAoSMCs as indicated by the restored expression of MYH11 and α-SMA. In contrast, the forced overexpression of VEPH1 aggravated Ang II's effects. Furthermore, we demonstrated that VEPH1 and transforming growth factor-ß1 (TGF-ß1), a key regulator responsible for vascular SMC differentiation, negatively regulated each other's transcription. In contrast to VEPH1 silencing, its overexpression inhibited recombinant TGF-ß1-induced increases in MYH11 and α-SMA and suppressed Smad3 phosphorylation and nuclear accumulation. Collectively, our study demonstrates that VEPH1 elevation promotes the synthetic phenotype switching of AoSMCs and suppressed the TGF-ß1/Smad3 signaling pathway. Identification of VEPH1 as a pathogenic molecule for AAA formation provides novel insights into this disease.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Angiotensina II/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Miócitos de Músculo Liso/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
8.
Lab Invest ; 100(12): 1564-1574, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32612287

RESUMO

Abdominal aortic aneurysm (AAA) is a potential lethal disease that is defined by an irreversible dilatation (>50%) of the aorta. During AAA expansion, the aortic wall is often remodeled, which is featured by extracellular matrix (ECM) degeneration, medial and adventitial inflammation, depletion and phenotypic switching of vascular smooth muscle cells (SMCs). Recent studies have suggested microRNAs as vital regulators for vascular SMC function. Our earlier work demonstrated an anti-AAA role of miR-126-5p in ApoE-/- mice infused with angiotensin (Ang) II. The present study aimed to further elucidate its role in AAA pathogenesis with a focus on aortic SMC phenotypic switching. Ventricular zone expressed PH domain containing 1 (VEPH1) was identified as a novel negative regulator for vascular SMC differentiation by our group, and its expression was negatively correlated to miR-126-5p in mouse abdominal aortas based on the present microarray data. In vivo, in addition attenuating Ang II infusion-induced aortic dilation and elastin degradation, miR-126-5p agomirs also significantly reduced the expression of VEPH1. In vitro, to induce synthetic transition of human aortic smooth muscle cells (hAoSMCs), cells were stimulated with 1 µM Ang II for 24 h. Ectopic overexpression of miR-126-5p restored the differentiation of hAoSMCs-the expression of contractile/differentiated SMC markers, MYH11, and α-SMA, increased, whilst that of synthetic/dedifferentiated SMC markers, PCNA and Vimentin, decreased. Both mus and homo VEPH1 genes were validated as direct targets for miR-126-5p. VEPH1 re-expression impaired miR-126-5p-induced differentiation of hAoSMCs. In addition, Ang II-induced upregulation in matrix metalloproteinase (MMP)-9 and MMP2, two key proteases responsible for ECM degradation, in mouse aortas and hAoSMCs was reduced by miR-126-5p overexpression as well. Collectively, these results reveal an important, but previously unexplored, role of miR-126-5p in inhibiting AAA development-associated aortic SMC dedifferentiation.


Assuntos
Angiotensina II/metabolismo , Aorta Abdominal , MicroRNAs , Músculo Liso Vascular , Proteínas do Tecido Nervoso/metabolismo , Animais , Aorta Abdominal/citologia , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo
9.
Arch Biochem Biophys ; 683: 108325, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142888

RESUMO

Monocyte infiltration and macrophage polarization are widely considered as pivotal steps for the initiation and progression of atherosclerosis. Previous studies suggested that zanthoxylum piperitum had strong analgesic and anti-inflammatory effects. However, it remains unclear whether zanthoxylum piperitum inhibits inflammation via macrophage function. In the present study, we investigated the effects of xanthoplanine (the total alkaloid extract of zanthoxylum piperitum) on macrophage function. CCK-8 kit was performed to determine cell viability and the preferred concentration of xanthoplanine. We assayed the effects of xanthoplanine on markers of macrophage polarization and inflammation via quantitative PCR and enzyme-linked immunosorbent assay, and measured the production of reactive oxygen species (ROS) by flow cytometry. Immunoblots, co-immunoprecipitation, immunofluorescence and Luciferase activity were performed to investigate the molecular mechanism of STAT signaling pathway in response to xanthoplanine. We found that xanthoplanine (50 and 100 µM) significantly reduced M1 polarization and promoted M2 polarization. The contents of inflammatory cytokines measured by ELISA were markedly decreased in macrophages pretreated with xanthoplanine, compared with those induced by LPS and IFN-γ. In parallel, xanthoplanine alleviated the production of ROS in macrophages induced by LPS and IFN-γ. Moreover, xanthoplanine alleviated STAT5 phosphorylation and blocked STAT5 nuclear translocation without alterations in CrkL expression, subsequently interrupting the interaction between p-STAT5 and CrkL. Likewise, xanthoplanine prominently attenuated the transcription activity of STAT5 induced by LPS and IFN-γ but did not affect the transcription activity of STAT1 and STAT3. Xanthoplanine attenuated M1 phenotypic switch and macrophage inflammation via blocking the formation of CrkL-STAT5 complex.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Polaridade Celular , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT5/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Sobrevivência Celular , Células HEK293 , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Xantopterina , Zanthoxylum/metabolismo
10.
Biochem Pharmacol ; 228: 116509, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39214450

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, primarily due to the intrinsic development of chemoresistance. The most apparent histopathological feature associated with chemoresistance is the alterations in extracellular matrix (ECM) proteins. Natural dietary botanicals such as berberine (BBR) and emodin (EMO) have been shown to possess chemo-preventive potential by regulating ECM in various cancers. Herein, we further investigated the potential synergistic effects of BBR and EMO in enhancing anticancer efficacy by targeting ECM proteins in pancreatic cancer. Genomewide transcriptomic profiling identified that LAMB3 was significantly upregulated in PDAC tissue and highly associated with poor overall survival (OS, hazard ratio [HR], 2.99, 95 % confidence interval [CI], 1.46-6.15; p = 0.003) and progress-free survival (PFS, HR, 2.59; 95 % CI, 1.30-5.18; p = 0.007) in PDAC. A systematic series of functional experiments in BxPC-3 and MIA-PaCa-2 cells revealed that the combination of BBR and EMO exhibited synergistic anti-tumor potential, as demonstrated by cell proliferation, clonogenicity, migration, and invasion assays (p < 0.05-0.001). The combination also altered the expression of key proteins involved in apoptosis, EMT, and EGFR/ERK1,2/AKT signaling. These findings were further supported by patient-derived organoids (PDOs), where the combined treatment resulted in fewer and smaller organoids compared to each compound individually (p < 0.05-0.001). Our results suggest that BBR combined with EMO exerts synergistic anti-cancer effects by modulating the EGFR-signaling pathway through interference with LAMB3 in PDAC.


Assuntos
Berberina , Sinergismo Farmacológico , Emodina , Receptores ErbB , Neoplasias Pancreáticas , Transdução de Sinais , Berberina/farmacologia , Berberina/uso terapêutico , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Emodina/farmacologia , Emodina/uso terapêutico , Receptores ErbB/metabolismo , Receptores ErbB/genética , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Animais , Feminino , Masculino
11.
Phytomedicine ; 135: 156086, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39326133

RESUMO

BACKGROUND: Aronia berry extracts (ABE) have recently been reported to possess significant anti-cancer effects in various malignancies, including colorectal cancer (CRC), due to their high polyphenolic content. However, the molecular mechanism(s) underlying the anti-cancer effects of ABE in CRC remain unclear, which is important to consider when considering their use as complementary medicine approaches in cancer. METHODS: We performed genome-wide transcriptomic profiling and pathway enrichment analysis to identify specific growth signaling pathways associated with ABE treatment in CRC cells. In addition, a series of systematic and comprehensive cell culture studies were performed to investigate the anti-cancer effects of ABE in SW480 and HCT116 CRC cell lines. Subsequently, these findings were validated in patient-derived 3D organoids (PDOs) models. RESULTS: Transcriptomic profiling analysis identified p53 signaling as one of the key enriched pathways mediating the anti-cancer activity of ABE. Analysis of public datasets revealed that Chk1, a key regulator of p53, was one of the critical targets of ABE in CRC. Chk1 and p53 activation was shown to be downregulated with ABE treatment, leading to the induction of cell cycle arrest (p = 0.003-0.014) and enhanced DNA damage (p = 0.015-0.026). Furthermore, these findings were validated in PDOs, where the ABE treatment resulted in significantly fewer and smaller PDOs in a concentration-dependent manner (p = 0.045 - <0.001). CONCLUSIONS: We firstly provide evidence for the role of the p53 signaling pathway as a mediator of the anti-cancer activity of ABE, which provides a rationale for its use as a safe and effective integrative medicine approach in CRC.

12.
Cancers (Basel) ; 16(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38730579

RESUMO

TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines.

13.
Pharmaceuticals (Basel) ; 17(7)2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-39065761

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE's potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC.

14.
Drug Des Devel Ther ; 18: 2043-2061, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863767

RESUMO

Background: Despite its extensive utilization in Chinese hospitals for treating acute pancreatitis (AP) and related acute respiratory distress syndrome (ARDS), the active components and mechanisms underlying the action of Qingyi Granule (QYKL) remain elusive. Methods: This study consists of four parts. First, we used Mendelian randomization (MR) to investigate the causal relationship between AP, cytokine, and ARDS. Next, 321 patients were collected to evaluate the efficacy of QYKL combined with dexamethasone (DEX) in treating AP. In addition, we used UHPLC-QE-MS to determine the chemical constituents of QYKL extract and rat serum after the oral administration of QYKL. The weighted gene coexpression network analysis (WGCNA) method was used to find the main targets of AP-related ARDS using the GSE151572 dataset. At last, a AP model was established by retrograde injection of 5% sodium taurocholate. Results: MR showed that AP may have a causal relationship with ARDS by mediating cytokine storms. Retrospective study results showed early administration of QYKL was associated with a lower incidence of ARDS, mortality, admissions to the intensive care unit, and length of stay in AP patients compared to the Control group. Furthermore, we identified 23 QYKL prototype components absorbed into rat serum. WGCNA and differential expression analysis identified 1558 APALI-related genes. The prototype components exhibited strong binding activity with critical targets. QYKL has a significant protective effect on pancreatic and lung injury in AP rats, and the effect is more effective after combined treatment with DEX, which may be related to the regulation of the IL-6/STAT3 signaling pathway. Conclusion: By integrating MR, retrospective analysis, and systematic pharmacological methodologies, this study systematically elucidated the therapeutic efficacy of QYKL in treating AP-related ARDS, establishing a solid foundation for its medicinal use.


Assuntos
Medicamentos de Ervas Chinesas , Pancreatite , Síndrome do Desconforto Respiratório , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Síndrome do Desconforto Respiratório/tratamento farmacológico , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Animais , Ratos , Humanos , Estudos Retrospectivos , Masculino , Ratos Sprague-Dawley , Dexametasona/farmacologia , Dexametasona/administração & dosagem , Doença Aguda , Feminino , Pessoa de Meia-Idade
15.
MedComm (2020) ; 5(10): e710, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39309691

RESUMO

Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.

16.
Cell Rep Med ; 5(7): 101645, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39019012

RESUMO

Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.


Assuntos
Compostos de Anilina , Proteínas de Ciclo Celular , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metformina , Mutação , Quinase 1 Polo-Like , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Pirazinas , Transdução de Sinais , Tirosina Quinase 3 Semelhante a fms , Metformina/farmacologia , Metformina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Humanos , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Transdução de Sinais/efeitos dos fármacos , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Camundongos , Mutação/genética , Linhagem Celular Tumoral , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT5/metabolismo , Fator de Transcrição STAT5/genética , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Serina-Treonina Quinases TOR/metabolismo
17.
Pharmaceuticals (Basel) ; 16(3)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36986483

RESUMO

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.

18.
Front Pharmacol ; 14: 1253520, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37745052

RESUMO

Background: Clinical decision support tools (CDSs) have been demonstrated to enhance the accuracy of antibiotic prescribing among physicians. However, their effectiveness in reducing inappropriate antibiotic use for respiratory tract infections (RTI) is controversial. Methods: A literature search in 3 international databases (Medline, Web of science and Embase) was conducted before 31 May 2023. Relative risk (RR) and corresponding 95% confidence intervals (CI) were pooled to evaluate the effectiveness of intervention. Summary effect sizes were calculated using a random-effects model due to the expected heterogeneity (I 2 over 50%). Results: A total of 11 cluster randomized clinical trials (RCTs) and 5 before-after studies were included in this meta-analysis, involving 900,804 patients met full inclusion criteria. Among these studies, 11 reported positive effects, 1 reported negative results, and 4 reported non-significant findings. Overall, the pooled effect size revealed that CDSs significantly reduced antibiotic use for RTIs (RR = 0.90, 95% CI = 0.85 to 0.95, I 2 = 96.10%). Subgroup analysis indicated that the intervention duration may serve as a potential source of heterogeneity. Studies with interventions duration more than 2 years were found to have non-significant effects (RR = 1.00, 95% CI = 0.96 to 1.04, I 2 = 0.00%). Egger's test results indicated no evidence of potential publication bias (p = 0.287). Conclusion: This study suggests that CDSs effectively reduce inappropriate antibiotic use for RTIs among physicians. However, subgroup analysis revealed that interventions lasting more than 2 years did not yield significant effects. These findings highlight the importance of considering intervention duration when implementing CDSs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432584, Identifier: PROSPERO (CRD42023432584).

19.
Inquiry ; 60: 469580231151783, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36722617

RESUMO

The study aimed to evaluate the change in accessibility of essential anticancer medicines, from 2015 to 2018 in a pilot province for health care reform in China. Data on access to 23 essential anticancer medicines was obtained from 6 provincial tertiary hospitals. A comprehensive analysis was applied to explore these trends. The total utilization of anticancer medicines had increased by an average of 2.57 times (P < .001) during the study period, of which targeted anticancer medicines had the fastest growth rate of 6.45 times (P < .001). The prices of all targeted medicines and original brands (OBs) were showing a downward trend, with the average change rate of -32% and -28% respectively (both P < .001). In contrast, the price of non-targeted medicines and lowest-price generics (LPG) increased by an average of 98% (P < .001) and 117% (P < .004) respectively. All targeted anticancer medicines were found to be unaffordable under this standard of this study, but the affordability of these medicines is on the rise. The study suggested positive changes in the utilization, price, and affordability of the most essential anticancer medicines. In the future, comprehensive strategies need to be conducted to further increase the affordability of targeted anticancer medicines.


Assuntos
Medicamentos Essenciais , Humanos , Estudos Longitudinais , China , Reforma dos Serviços de Saúde , Centros de Atenção Terciária
20.
Front Public Health ; 11: 1114085, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37089481

RESUMO

Background: The outbreak of COVID-19 in early 2020 presented a major challenge to the healthcare system in China. This study aimed to quantitatively evaluate the impact of COVID-19 on health services utilization in China in 2020. Methods: Health service-related data for this study were extracted from the China Health Statistical Yearbook. The Auto-Regressive Integrated Moving Average model (ARIMA) was used to forecast the data for the year 2020 based on trends observed between 2010 and 2019. The differences between the actual 2020 values reported in the statistical yearbook and the forecast values from the ARIMA model were used to assess the impact of COVID-19 on health services utilization. Results: In 2020, the number of admissions and outpatient visits in China declined by 17.74 and 14.37%, respectively, compared to the ARIMA model's forecast values. Notably, public hospitals experienced the largest decrease in outpatient visits and admissions, of 18.55 and 19.64%, respectively. Among all departments, the pediatrics department had the greatest decrease in outpatient visits (35.15%). Regarding geographical distribution, Beijing and Heilongjiang were the regions most affected by the decline in outpatient visits (29.96%) and admissions (43.20%) respectively. Conclusion: The study's findings suggest that during the first year of the COVID-19 pandemic, one in seven outpatient services and one in six admissions were affected in China. Therefore, there is an urgent need to establish a green channel for seeking medical treatment without spatial and institutional barriers during epidemic prevention and control periods.


Assuntos
COVID-19 , Criança , Humanos , COVID-19/epidemiologia , Pandemias , Atenção à Saúde , China/epidemiologia , Assistência Ambulatorial
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