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1.
Mol Cell Biochem ; 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39269678

RESUMO

Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, often associated with severe complications and even death. In ALI, macrophages, alveolar epithelial cells and vascular endothelial cells in the lung are damaged to varying degrees and their function is impaired. Research in recent years has focused on the use of SIRT1 for the treatment of ALI. In this paper, we reviewed the role of SIRT1 in ALI in terms of its cellular and molecular mechanism, targeting of SIRT1 by non-coding RNAs and drug components, as well as pointing out the value of SIRT1 for clinical diagnosis and prognosis. Based on the current literature, SIRT1 exhibits diverse functionalities and possesses significant therapeutic potential. Targeting SIRT1 may provide new therapeutic ideas for the treatment of ALI.

2.
Sci Rep ; 14(1): 18845, 2024 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-39143232

RESUMO

Research on the potential association between life-ever gallstones and depressive symptoms is limited. This study aims to evaluate whether the presence of gallstone disease is associated with depressive symptoms. In this cross-sectional study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2017-March 2020 cycles. The presence of depressive symptoms and gallstone disease was assessed using questionnaire responses. Adjusted odds ratios (OR) were calculated using a multivariate logistic regression model, with adjustments made for age, sex, race, body mass index, history of cardiovascular disease, hypertension, arthritis, and pulmonary disease across different models. Subgroup and sensitivity analyses were conducted to ensure the stability of the results. This study included 6201 adults aged 20 years and above, with 539(8.7%) experiencing depressive symptoms. After adjusting for age, sex, race, body mass index, CVD history, hypertension, arthritis, pulmonary disease, depressive symptoms were possibly associated with life-ever gallstones (OR 1.37, 95% CI 0.91-2.08).When depressive symptoms were categorized as mild, moderate, moderately severe, and severe,life-ever gallstones was possibly associated with mild depressive symptoms (OR 1.12, 95% CI 0.81-1.56), moderate depressive symptoms (OR 1.37, 95% CI 0.89-2.12), moderately severe depressive symptoms (OR 1.93, 95% CI 0.93-3.99), and severe depressive symptoms (OR 0.67, 95% CI 0.16-2.88).As a continuous variable, life-ever gallstones was associated with the PHQ-9 score (OR 0.42, 95% CI 0.02-0.83). The results remained stable after multiple imputation for all missing data. This cross-sectional study demonstrates no significant association between life-ever gallstones and depressive symptoms in US adults.


Assuntos
Depressão , Cálculos Biliares , Humanos , Cálculos Biliares/epidemiologia , Cálculos Biliares/complicações , Cálculos Biliares/psicologia , Masculino , Feminino , Depressão/epidemiologia , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Idoso , Inquéritos Nutricionais , Adulto Jovem , Fatores de Risco , Razão de Chances
3.
J Pharm Anal ; 14(6): 100940, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39027912

RESUMO

Inhibiting the death receptor 3 (DR3) signaling pathway in group 3 innate lymphoid cells (ILC3s) presents a promising approach for promoting mucosal repair in individuals with ulcerative colitis (UC). Paeoniflorin, a prominent component of Paeonia lactiflora Pall., has demonstrated the ability to restore barrier function in UC mice, but the precise mechanism remains unclear. In this study, we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s. C57BL/6 mice were subjected to random allocation into 7 distinct groups, namely the control group, the 2 % dextran sodium sulfate (DSS) group, the paeoniflorin groups (25, 50, and 100 mg/kg), the anti-tumor necrosis factor-like ligand 1A (anti-TL1A) antibody group, and the IgG group. We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using Western blot and flow cytometry, respectively. Meanwhile, DR3-overexpressing MNK-3 cells and 2 % DSS-induced Rag1-/- mice were used for verification. The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier. Simultaneously, paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines (Interleukin-17A, Granulocyte-macrophage colony stimulating factor, and Interleukin-22). Alternatively, paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage independently of the adaptive immune system. We additionally confirmed that paeoniflorin-conditioned medium (CM) restored the expression of tight junctions in Caco-2 cells via coculture. In conclusion, paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner, and its mechanism is associated with the inhibition of the DR3 signaling pathway.

4.
Gene ; 928: 148786, 2024 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-39047959

RESUMO

Cysteine dioxygenase (CDO) is a rate-limiting enzyme in taurine biosynthesis. Taurine synthesis is limited in marine fish, and most taurine is provided by their diet. Although a nutritional study indicated that the transcription of ToCDO was significantly altered by treatment with 10.5 g/kg taurine in food, the regulatory mechanism of this biosynthesis has not been fully elucidated. In the present study, we identified the sequence features of Trachinotus ovatus cysteine dioxygenase (ToCDO), which consists of 201 amino acids. It is characterized by being a member of the cupin superfamily with two conserved cupin motifs located at amino acids 82-102 and 131-145 and with a glutamate residue substituted by a cysteine in its first motif. Moreover, phylogenetic analysis revealed that the similarity of the amino acid sequences between ToCDO and other species ranged from 84.58 % to 91.54 %. Furthermore, a high-performance liquid-phase assay of the activity of recombinantly purified ToCDO protein showed that ToCDO could catalyse the oxidation of cysteine to produce cysteine sulphite. Furthermore, the core promoter region of CDO was identified as -1182-+1 bp. Mutational analysis revealed that the HNF4α and NF-κB sites significantly and actively affected the transcription of CDO. To further investigate the binding of these two loci to the CDO promoter, an electrophoretic shift assay (EMSA) was performed to verify that HNF4α-1 and NF-κB-1 interact with the binding sites of the promoter and promote CDO gene expression, respectively. Additionally, cotransfection experiments showed that HNF4α or both HNF4α and NF-κB can significantly influence CDO promoter activity, and HNF4α was the dominant factor. Thus, HNF4α and NF-κB play important roles in CDO expression and may influence taurine biosynthesis within T. ovatus by regulating CDO expression.


Assuntos
Cisteína Dioxigenase , Fator 4 Nuclear de Hepatócito , NF-kappa B , Taurina , Animais , Taurina/metabolismo , Taurina/biossíntese , Cisteína Dioxigenase/genética , Cisteína Dioxigenase/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Regiões Promotoras Genéticas , Filogenia , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Sequência de Aminoácidos , Peixes/genética , Peixes/metabolismo
5.
J Org Chem ; 89(14): 9841-9852, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38917372

RESUMO

A novel methodology for the synthesis of nitrones via palladium-catalyzed redox cross-coupling of nitro compounds and alcohols is established. The protocol is a mild, convenient, ligand-free, and scalable synthesis method that can be compatible with various nitro compounds and alcohols. Nitrone is a significant multifunctional platform synthon which can be synthesized directly and efficiently via this tactic from commercially available and cheap raw materials.

6.
J Vis Exp ; (207)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38856215

RESUMO

This study showcases a comprehensive treatment protocol for high-risk hepatocellular carcinoma (HCC) patients, focusing on the combined use of Y-90 transarterial radioembolization (TARE) and Programmed Cell Death-1 (PD-1) inhibitors as neoadjuvant therapy. Highlighted through a case report, it offers a step-by-step reference for similar therapeutic interventions. A retrospective analysis was conducted on a patient who underwent hepatectomy following Y-90 TARE and PD-1 inhibitor treatment. Key demographic and clinical details were recorded at admission to guide therapy selection. Y-90 TARE suitability and dosage calculation were based on Technetium-99m (Tc-99m) macroaggregated albumin (MAA) perfusion mapping tests. Lesion coverage by Y-90 microspheres was confirmed through single photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging, and adverse reactions and follow-up outcomes were meticulously documented. The patient, with a 7.2 cm HCC in the right hepatic lobe (T1bN0M0, BCLC A, CNLC Ib) and an initial alpha-fetoprotein (AFP) level of 66,840 ng/mL, opted for Y-90 TARE due to high recurrence risk and initial surgery refusal. The therapy's parameters, including the lung shunting fraction (LSF) and non-tumor ratio (TNR), were within therapeutic limits. A total of 1.36 GBq Y-90 was administered. At 1 month post-therapy, the tumor shrank to 6 cm with partial necrosis, and AFP levels dropped to 21,155 ng/mL, remaining stable for 3 months. After 3 months, PD-1 inhibitor treatment led to further tumor reduction to 4 cm and AFP decrease to 1.84 ng/mL. The patient then underwent hepatectomy; histopathology confirmed complete tumor necrosis. At 12 months post-surgery, no tumor recurrence or metastasis was observed in follow-up sessions. This protocol demonstrates the effective combination of Y-90 TARE and PD-1 inhibitor as a bridging strategy to surgery for HCC patients at high recurrence risk, providing a practical guide for implementing this approach.


Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Terapia Neoadjuvante , Radioisótopos de Ítrio , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Terapia Neoadjuvante/métodos , Embolização Terapêutica/métodos , Radioisótopos de Ítrio/uso terapêutico , Masculino , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Idoso , Compostos Radiofarmacêuticos/uso terapêutico
7.
Transl Oncol ; 47: 101997, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38889522

RESUMO

The liver is the most common organ for the formation of colorectal cancer metastasis. Non-invasive prognostication of colorectal cancer liver metastasis (CRLM) may better inform clinicians for decision-making. Contrast-enhanced computed tomography images of 180 CRLM cases were included in the final analyses. Radiomics features, including shape, first-order, wavelet, and texture, were extracted with Pyradiomics, followed by feature engineering by penalized Cox regression. Radiomics signatures were constructed for disease-free survival (DFS) by both elastic net (EN) and random survival forest (RSF) algorithms. The prognostic potential of the radiomics signatures was demonstrated by Kaplan-Meier curves and multivariate Cox regression. 11 radiomics features were selected for prognostic modelling for the EN algorithm, with 835 features for the RSF algorithm. Survival heatmap indicates a negative correlation between EN or RSF risk scores and DFS. Radiomics signature by EN algorithm successfully separates DFS of high-risk and low-risk cases in the training dataset (log-rank test: p < 0.01, hazard ratio: 1.45 (1.07-1.96), p < 0.01) and test dataset (hazard ratio: 1.89 (1.17-3.04), p < 0.05). RSF algorithm shows a better prognostic implication potential for DFS in the training dataset (log-rank test: p < 0.001, hazard ratio: 2.54 (1.80-3.61), p < 0.0001) and test dataset (log-rank test: p < 0.05, hazard ratio: 1.84 (1.15-2.96), p < 0.05). Radiomics features have the potential for the prediction of DFS in CRLM cases.

8.
Zhen Ci Yan Jiu ; 49(5): 526-533, 2024 May 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38764125

RESUMO

Lumbar intervertebral disc herniation (LDH) is a common and frequently-occurring disease, which usually causes lumbar and leg pain. Studies have shown that acupuncture can improve the symptoms of LDH patients. In the present paper, we summarize the progress of researches on the mechanisms of acupuncture underlying improvement of symptoms of LDH in recent 10 years from 1) delaying the intervertibral disc degeneration (by down-regulating the expressions of matrix metalloproteinase ï¼»MMPï¼½-3 and MMP-4, up-regulating the expressions of diosaccharides and polyglycoprotein, inhibiting apoptosis and promoting mitochondrial autophagy of nucleus pulposus cells, etc.), 2) maintaining spinal column stability (by relieving rachiasmus and improving lumbar flexor and extensor muscle strength, lowering the degree of polyfidus edema and fat infiltration, and restoring the biomechanics of the spine), 3) regulating inflammation (by inhibiting the production of proinflammatory factors and increasing the production of anti-inflammatory factors, etc.), 4) regulating immune response (by promoting the activity of T cells and other immune cells, lowering serum levels of MMP-3, transforming growth factor-ß1 and prostaglandin E2, raising serum levels of IgA, IgG and IgM to improve immune function ), 5) modulating neural structure and function (by promoting myelin regeneration of sciatic nerve fibers, and reducing the edema of Schwann cells' cytoplasm and mitochondria, and improving neural ultrastructure, and sensory and motor functions of peripheral nerves, etc.), 6) relieving lumbar pain (by down-regulating expression of Ca2+/calmodulin-dependent protein kinase and activation of lumbar spinal cord glial cells, blocking nociceptive signal conduction, regulating the levels of pain-related factors, etc.), and 7) improving local microcirculation. These results may provide scientific evidence for acupuncture treatment of LDH.


Assuntos
Terapia por Acupuntura , Deslocamento do Disco Intervertebral , Humanos , Deslocamento do Disco Intervertebral/terapia , Animais , Vértebras Lombares
9.
Mol Neurobiol ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38740706

RESUMO

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

10.
PLoS One ; 19(5): e0301553, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38781254

RESUMO

BACKGROUND: Urinary incontinence (UI) might be linked to suicidal ideation, but we do not yet have all the relevant details. This study aimed to dig deeper into the connection between UI and suicidal ideation using data from the National Health and Nutrition Examination Survey (NHANES). METHODS: We examined 31,891 participants aged ≥ 20 years from NHANES 2005-2018 who provided complete information. We used standardized surveys to check for UI and signs of suicidal ideation. To better understand this relationship, we used statistical tools such as multivariable logistic regression, subgroup analysis, and sensitivity analyses. RESULTS: Among the 31,891 participants, 28.9% reported UI and 10.7% reported suicidal ideation. Those with UI exhibited a significantly greater incidence of suicidal ideation (15.5%) than did those without UI (8.8%, P < 0.001). After adjusting for various factors, including age, sex, marital status, socioeconomic status, educational level, lifestyle factors, and chronic comorbidities, UI remained significantly associated with suicidal ideation (OR:1.54, 95% CI = 1.39-1.7, P < 0.001). Among all types of UI, MUI participants were more likely to experience suicidal ideation. Compared with no UI, higher odds of suicidal ideation suffered from MUI (OR:2.11, 95%CI:1.83-2.44, P < 0.001), SUI (OR:1.4, 95%CI:1.19-1.65, P < 0.001), UUI(OR:1.37,95%CI:1.16-1.62, P < 0.001) after full adjustment. With the exception of individuals living with a partner, the remaining subgroups exhibited a positive correlation between urinary incontinence and suicidal ideation, considering that factors such as age, sex, and prevalent comorbidities such as hypertension, depression, and diabetes did not reveal any statistically significant interactions (all P > 0.05). Sensitivity analyses, incorporating imputed missing covariates, did not substantially alter the results (OR: 1.53, 95% CI: 1.4-1.68, P < 0.001). CONCLUSION: Urinary incontinence may correlate with increased suicidal ideation risk, priority screening for suicidal ideation and timely intervention are essential for individuals with urinary incontinence, but prospective studies are needed to verify the results.


Assuntos
Inquéritos Nutricionais , Ideação Suicida , Incontinência Urinária , Humanos , Incontinência Urinária/epidemiologia , Incontinência Urinária/psicologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Fatores de Risco , Estados Unidos/epidemiologia
11.
J Cell Physiol ; 239(5): e31237, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38468464

RESUMO

GINS1 regulates DNA replication in the initiation and elongation phases and plays an important role in the progression of various malignant tumors. However, the role of GINS1 in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we investigated the role and underlying mechanisms of GINS1 in contributing to HCC metastasis. We found that GINS1 was significantly upregulated in HCC tissues and cell lines, especially in HCC tissues with vascular invasion and HCC cell lines with highly metastatic properties. Additionally, high expression of GINS1 was positively correlated with the progressive clinical features of HCC patients, including tumor number (multiple), tumor size (>5 cm), advanced tumor stage, vascular invasion and early recurrence, suggesting that GINS1 upregulation was greatly involved in HCC metastasis. Moreover, Kaplan-Meier survival analysis revealed that high GINS1 expression predicted a poor prognosis. Both in vitro and in vivo, silencing of GINS1 inhibited proliferation, migration, invasion and metastasis, while overexpression of GINS1 induced opposite effects. Mechanistically, we found that ZEB1 was a crucial regulator of GINS1-induced epithelial-mesenchymal transition (EMT), and GINS1 promoted EMT and tumor metastasis through ß-catenin signaling. Overall, the present study demonstrated that GINS1 promoted ZEB1-mediated EMT and tumor metastasis via ß-catenin signaling in HCC.


Assuntos
Carcinoma Hepatocelular , Movimento Celular , Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Homeobox 1 de Ligação a E-box em Dedo de Zinco , beta Catenina , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , beta Catenina/metabolismo , beta Catenina/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
12.
Curr Neuropharmacol ; 22(10): 1672-1696, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38362904

RESUMO

Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Humanos , Animais , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Metabolismo Energético/fisiologia , Astrócitos/metabolismo , Neuroglia/metabolismo , Microglia/metabolismo , Reprogramação Metabólica
13.
Aging (Albany NY) ; 15(24): 14915-14929, 2023 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-38126999

RESUMO

BACKGROUND: Liver cancer (LC) is a rare malignancy. Circular RNA (circRNA) dysregulation is associated with LC metastasis. hsa_circ_0002980 was found to be unexpectedly downregulated in LC tissues; however, its specific function remains unclear. METHODS: hsa_circ_0002980 expression was confirmed using RT-qPCR. The effects of circ_0002980 on the proliferation, metastasis, and EMT-related proteins of LC cells were assessed using clone formation, flow cytometry, Transwell assays, and Western blotting. The relationship between circ_0002980 and miR-1303 or miR-1303 and CADM2 was analyzed using a dual-luciferase reporter assay. Thereafter, the influence of these three genes on LC cell progression was determined through rescue experiments. RESULTS: hsa_circ_0002980 expression was lower in LC. circ_0002980 overexpression inhibited the proliferation, migration, invasion, and EMT of LC cells. In addition, circ_0002980 specifically binds to miR-1303, and the accelerated effect of miR-1303 overexpression on LC progression was partially reversed by circ_0002980. Moreover, miR-1303 can also target CADM2, and CADM2-mediated prevention can also be attenuated by miR-1303 overexpression. CONCLUSIONS: In LC cells, circ_0002980 upregulation prevents cell proliferation, metastasis, and EMT by affecting the miR-1303/CADM2 axis. Therefore, this axis may be a novel therapeutic target in LC.


Assuntos
Neoplasias Hepáticas , MicroRNAs , RNA Circular , Humanos , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Circular/genética
14.
Urolithiasis ; 52(1): 15, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38117370

RESUMO

The aim of the study was to analyze the factors influencing the efficacy of ultrasound-guided extracorporeal shockwave lithotripsy (ESWL) in the treatment of ureteral stones. The clinical data of 8102 patients (6083 men and 2019 women) who presented with ureteral stones were retrospectively analyzed. All the patients were treated with ultrasound-guided ESWL. The stone-free rate (SFR) was calculated to evaluate the effect of ESWL. The characteristics of the patients and their stones, and the ESWL parameters applied were compared to identify the factors affecting the treatment outcomes. The SFR and that following one ESWL session were 94.6% (7663/8102) and 75.4% (6107/8102), respectively. Multivariate analysis showed that stone location (OR 0.656, p < 0.001), stone size (OR 1.103, p < 0.001), and degree of hydronephrosis (OR 1.952, p < 0.001) independently affected SFR; and age (OR 1.005, p = 0.022), stone location (OR 0.729, p < 0.001), stone size (OR 1.103, p < 0.001), degree of hydronephrosis (OR 1.387, p = 0.001), maximum energy level(OR 0.691, p < 0.001) independently affected SFR following one session. Ultrasound-guided ESWL is effective in all levels of ureteral stones. Large stone size and moderate hydronephrosis are correlated with treatment failure. Ultrasound-guided ESWL may be the first choice for distal ureteral stones.


Assuntos
Hidronefrose , Litotripsia , Cálculos Ureterais , Masculino , Humanos , Feminino , Estudos Retrospectivos , Litotripsia/efeitos adversos , Cálculos Ureterais/diagnóstico por imagem , Cálculos Ureterais/terapia , Ultrassonografia de Intervenção
15.
Mol Ther Nucleic Acids ; 34: 102047, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37869260

RESUMO

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

16.
Int Immunopharmacol ; 124(Pt B): 111018, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37801969

RESUMO

Crosstalk between the central nervous system and immune system by the neuroendocrine and autonomic nervous systems is critical during the inflammatory response. Exposure to endotoxin alters the activity of hypothalamic homeostatic systems, resulting in changed transmitter release within the brain. This study investigated the effects and cellular molecular mechanisms of neurogenic and exogenous orexin-A (OXA) in LPS-induced acute lung injury (ALI). We found the production of OXA in the hypothalamus and lungs was both decreased following LPS infection. LPS-induced lung injury including the destruction of the structure, inflammatory cell infiltration, and pro-inflammatory cytokines generation was aggravated in mice in which orexin neurons were lesioned with the neurotoxin orexin-saporin (orexin-SAP). Administration of exogenous OXA greatly improved lung pathology and reduced inflammatory response. Orexin receptors were found in cultured mouse bone marrow-derived macrophages (BMDMs) and lung macrophages (LMs), adoptive transfer of OXA-treated macrophages showed alleviative lung injury compared to adoptive transfer of macrophages without OXA treatment. Mechanistically, it is the induction of autophagy via JNK activation that is responsible for OXA to suppress macrophage-derived pro-inflammatory cytokine production. These findings highlight the importance of neuro-immune crosstalk and indicate that OXA may be a potential therapeutic agent in the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Autofagia , Citocinas , Pulmão/patologia , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Orexinas/uso terapêutico , Orexinas/farmacologia
17.
Phytomedicine ; 121: 155116, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37776619

RESUMO

BACKGROUND: Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC. METHODS: To investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor). RESULTS: Our results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC. CONCLUSION: Astragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.


Assuntos
Colite , PPAR gama , Animais , Camundongos , Azoximetano/toxicidade , Sulfato de Dextrana/efeitos adversos , Espécies Reativas de Oxigênio , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/metabolismo , Carcinogênese , Transformação Celular Neoplásica , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
18.
Transl Cancer Res ; 12(5): 1145-1164, 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37304536

RESUMO

Background: Liver cancer remains one of the tricky malignancies nowadays. GINS complex subunit 3 (GINS3), part of the GINS tetrameric complex, is significantly upregulated in many cancers, including liver hepatocellular carcinoma (LIHC). With the development of liver cancer treatment, immune and molecular targeted therapy gradually becomes a promising treatment. However, the key target for liver cancer is still indistinct. Herein, the underneath mechanism of GINS3 was investigated to verify its role as a biomarker in LIHC. Methods: Genomic expression, genetic alteration, and methylation analyses were obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), The University of Alabama at Birmingham CANcer (UALCN), and Human Protein Atlas (HPA), cBioPortal, and MethSurv databases. Subsequently, the diagnostic and prognostic role of GINS3 in LIHC were analyzed based on data from receiver operating characteristic (ROC), Kaplan-Meier plotter (KM-plotter), and univariate and multivariate cox regression analyses. The functional analyses were conducted with GeneMANIA and STRING databases, gene-gene, and protein-protein interaction (PPI) networks, Gene Ontology (GO) term, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Tumor Immune Estimation Resource (TIMER), Tumor-Immune System Interaction Database (TISIDB), and Gene Expression Profiling Interactive Analysis (GEPIA) were utilized to explore the internal connection with the immune escape. Results: Through the analyses of genomic expression, GINS3 was significantly upregulated in LIHC and positively correlated with higher T classification. ROC analysis indicated GINS3 as a potential biomarker in the diagnosis of LIHC. KM-plotter, univariate and multivariate cox regression analyses both associated GINS3 with poor prognosis in LIHC patients. GINS3 genetic alteration, gene-gene interaction, PPI networks, and enrichment analysis further revealed that GINS3 played a pivotal role in the progression of LIHC. Furthermore, hypermethylation of GINS3 at different cytosine-guanine (CpG) sites was correlated with better or worse overall survival (OS) in LIHC and GINS3 was also closely correlated with m6A modification. Moreover, results supported that GINS3 could influence the tumor microenvironment and relate to the immune checkpoints. Conclusions: Taken together, comprehensive analyses from this study supported GINS3 as a novel targeted biomarker in LIHC.

19.
Discov Oncol ; 14(1): 72, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37204526

RESUMO

Breast cancer is the tumor with the highest incidence in women worldwide. According to research, the poor prognosis of breast cancer is closely related to abnormal glucose metabolism in tumor cells. Changes in glucose metabolism in tumor cells are an important feature. When sufficient oxygen is available, cancer cells tend to undergo glycolysis rather than oxidative phosphorylation, which promotes rapid proliferation and invasion of tumor cells. As research deepens, targeting the glucose metabolism pathway of tumor cells is seen as a promising treatment. Non-coding RNAs (ncRNAs), a recent focus of research, are involved in the regulation of enzymes of glucose metabolism and related cancer signaling pathways in breast cancer cells. This article reviews the regulatory effect and mechanism of ncRNAs on glucose metabolism in breast cancer cells and provides new ideas for the treatment of breast cancer.

20.
Front Hum Neurosci ; 17: 1154798, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37007681

RESUMO

Objective: To study the brain network mechanism of cognitive control in the elderly with brain aging. Materials and methods: 21 normal young people and 20 elderly people were included in this study. Mini-mental State Examination and functional near-infrared spectroscopy (fNIRS) synchronous judgment test (including forward tests and reverse judgment tests) were performed on all subjects. To observe and compare differences in brain region activation and brain functional connectivity between subjects and forward and reverse trials by recording functional connectivity (FC) in different task paradigms and calculating bilateral prefrontal and primary motor cortical (PMC) areas. Results: In the forward and reverse judgment tests, the reaction time of the elderly group was significantly longer than the young group (P < 0.05), and there was no significant difference in the correct rate. In the homologous regions of interest (ROI) data, the FC of PMC and prefrontal cortex (PFC) in the elderly group was significantly decreased (P < 0.05). In the heterologous ROI data, except for left primary motor cortex (LPMC)-left prefrontal cortex (LPFC), the other PMC and PFC of the elderly group were significantly lower than the young group (P < 0.05) while processing the forward judgment test. However, the heterologous ROI data of LPMC-right prefrontal cortex (RPFC), LPMC-LPFC and RPFC-LPFC in the elderly group were significantly lower than the young group (P < 0.05) while processing the reverse judgment test. Conclusion: The results suggest that brain aging affected degeneration of whole brain function, which reduce the speed of information processing and form a brain network functional connection mode different from that of young people.

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