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1.
Adv Sci (Weinh) ; : e2300878, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37162268

RESUMO

Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au-cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor-associated antigens release through ATO-induced ferroptosis and photothermal-induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1-6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long-term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti-programmed death-ligand 1 (PD-L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.

2.
Heliyon ; 9(5): e15451, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37131441

RESUMO

Cardiomyocyte apoptosis has been characterized as one of the major mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy. MicroRNA-21-5p (miR-21-5p) was reported to mitigate ischemia-induced cardiomyocyte apoptosis and cardiac injury. However, to our knowledge, the functional role of miR-21-5p in DOX-induced cardiomyopathy is unclear. In this study, we explored the role of miR-21-5p in DOX-induced cardiac injury. The expression level of miR-21-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Dual luciferase reporter assay was used to verify the potential target gene of miR-21-5p. The apoptosis rate of NRCMs was detected by TUNEL staining assay. Western blot analysis was used to detect the protein expression levels of Bax, Bcl-2, Caspase3, cleaved-Caspase3 and BTG2. For animal studies, mice were injected with AAV9-miR-21-5p or AAV9-Empty viruses, and treated with DOX at a dose of 5 mg/kg per week through intraperitoneally administration. After 4 weeks of DOX treatment, mice were subjected to echocardiography to measure the left ventricular ejection fraction (EF) and fractional shortening (FS). Results showed that miR-21-5p was upregulated in both DOX-treated primary cardiomyocytes and mouse heart tissues. Interestingly, enhanced miR-21-5p expression inhibited DOX-induced cardiomyocyte apoptosis and oxidative stress, while decreased miR-21-5p expression promoted cardiomyocyte apoptosis and oxidative stress. Furthermore, cardiac overexpression of miR-21-5p protected against DOX-induced cardiac injury. The mechanistic study indicated that BTG2 was a target gene of miR-21-5p. The anti-apoptotic effect of miR-21-5p could be inhibited by BTG2 overexpression. Conversely, inhibition of BTG2 rescued the pro-apoptotic effect of miR-21-5p inhibitor. Taken together, our study showed that miR-21-5p could prevent DOX-induced cardiomyopathy by downregulating BTG2.

3.
Oncogene ; 2023 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-37156839

RESUMO

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5highCAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5highCAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.

4.
Plant Physiol Biochem ; 198: 107701, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37105019

RESUMO

Chromium (Cr) in the soil is one of the major pollutants for agricultural production. This study examined the efficiency of sunflower plants to remediate Cr-contaminated soils using a plant growth regulator, 5-aminolevolinic acid (ALA). At six leaf stage, sunflower plants were exposed to soil-applied Cr (0.15 g kg-1), manganese (Mn, 0.3 g kg-1) and trisodium (S,S)-ethylenediamine-N,N'-disuccinic acid (EDDS, 2.5 mmol kg-1), ALA (10 mg L-1) was sprayed. After ALA treatment, the plants were harvested for further biochemical analyses. Results showed that EDDS and Mn improved the Cr accumulation but restrained plant growth. Conversely, ALA improved the growth of Cr-stressed plants by promoting chlorophyll concentration in the top fully expanded leaves. The bioaccumulation quantity and removal efficiency of sunflowers treated by Cr + EDDS + ALA was improved by 47.92% and 47.94%, respectively, as compared to the Cr treatment. This was further supported by qRT-PCR analysis, where the expression of heavy metal transport genes such as ZIP6 and NRAMP6 and subsequently Cr accumulation in sunflower tissues increased by EDDS, Mn, and ALA application. However, compared with other treatments, ALA ameliorated cellular injury from Cr-stress by uptake or movement of Cr prevention, modulation of antioxidant enzymes, and elimination of reactive oxygen species. Our study suggested that ALA as an ideal option for the phytoremediation of Cr-contaminated soils.


Assuntos
Helianthus , Metais Pesados , Poluentes do Solo , Cromo/toxicidade , Helianthus/metabolismo , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/metabolismo , Metais Pesados/metabolismo , Solo , Poluentes do Solo/toxicidade , Poluentes do Solo/análise , Biodegradação Ambiental
5.
Molecules ; 28(8)2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-37110540

RESUMO

The conversion of lignocellulose into valuable chemicals has been recognized as the key technology in green chemistry. However, selective degradation of hemicellulose and cellulose with the production of lignin is still a challenge. Therefore, a two-step process has been developed to degrade corncob into xylose and glucose under mild conditions. At first, the corncob was treated with the lower concentration of zinc chloride aqueous solution (30-55 w%) at 95 °C with a short reaction time (8-12 min) and 30.4 w% (selectivity = 89%) of xylose obtained with a solid residue of the composite of cellulose and lignin. Next, the solid residue was treated with a high concentration of zinc chloride aqueous solution (65-85 w%) at 95 °C for about 10 min, and 29.4 w% (selectivity = 92%) of glucose can be obtained. Combining the two steps, the total yield of xylose is 97%, while glucose is 95%. In addition, high pure lignin can be obtained simultaneously, which was confirmed using HSQC studies. Furthermore, for the solid residue of the first-step reaction, a ternary deep eutectic solvent (DES) (choline chloride/oxalic acid/1,4-butanediol, ChCl/OA/BD) has been used to separate the cellulose and lignin efficiently, and high-quality cellulose (Re-C) and lignin (Re-L) were obtained. Furthermore, it provides a simple method to disassemble the lignocellulose for monosaccharides, lignin, and cellulose.


Assuntos
Glucose , Lignina , Lignina/química , Glucose/metabolismo , Xilose/química , Biomassa , Celulose/química , Solventes/química , Hidrólise
6.
Water Res ; 236: 119953, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37060877

RESUMO

Extracellular antibiotic resistance genes (eARGs) are important emerging environmental pollutants in wastewater treatment plants (WWTPs). Nutritional substrate deficiency (i.e., starvation) frequently occurs in WWTPs owing to annual maintenance, water quality fluctuation, and sludge storage; and it can greatly alter the antibiotic resistance and extracellular DNA content of bacteria. However, the fate and corresponding transmission risk of eARGs in activated sludge under starvation stress remain largely unknown. Herein, we used metagenomic sequencing to explore the effects of starvation scenarios (carbon, nitrogen, and/or phosphorus deficiency) and environmental conditions (alternating anaerobic-aerobic, anaerobic, anoxic, and aerobic) on the distribution, mobility, and hosts of eARGs in activated sludge. The results showed that 30 days of starvation reduced the absolute abundances of eARGs by 40.9%-88.2%, but high-risk dual and multidrug resistance genes persisted. Starvation, particularly the simultaneous lack of carbon, nitrogen, and phosphorus under aerobic conditions, effectively alleviated eARGs by reducing the abundance of extracellular mobile genetic elements (eMGEs). Starvation also altered the profile of bacterial hosts of eARGs and the bacterial community composition, the latter of which had an indirect positive effect on eARGs via changing eMGEs. Our findings shed light on the response patterns and mechanisms of eARGs in activated sludge under starvation conditions and highlight starvation as a potential strategy to mitigate the risk of previously neglected eARGs in WWTPs.


Assuntos
Esgotos , Águas Residuárias , Esgotos/microbiologia , Genes Bacterianos , Antibacterianos/farmacologia , Bactérias/genética , Resistência Microbiana a Medicamentos/genética , Carbono
7.
Front Pharmacol ; 14: 1138762, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37007020

RESUMO

Introduction: It has been proven that hydrogen has obvious anti-inflammatory effects in animal experiments and clinical practice. However, the early dynamic process of the inflammatory response caused by lipopolysaccharide (LPS) and the anti-inflammatory effect of hydrogen has not been definitively reported. Methods: Inflammation in male C57/BL6J mice or RAW264.7 cells was induced with LPS, for which hydrogen was immediately administered until samples were taken. Pathological changes in lung tissue were assessed using hematoxylin and eosin (HE) staining. Levels of inflammatory factors in serum were determined using liquid protein chip. The mRNA levels of chemotactic factors in lung tissues, leukocytes, and peritoneal macrophages were measured by qRT-PCR. The expression levels of IL-1α and HIF-1α were measured by immunocytochemistry. Results: Hydrogen alleviated LPS-induced inflammatory infiltration in the lung tissues of mice. Among the 23 inflammatory factors screened, LPS-induced upregulation of IL-1α etc. was significantly inhibited by hydrogen within 1 hour. The mRNA expression of MCP-1, MIP-1α, G-CSF, and RANTES was inhibited obviously by hydrogen at 0.5 and 1 h in mouse peritoneal macrophages. In addition, hydrogen significantly blocked LPS or H2O2-induced upregulation of HIF-1α, and IL-1α in 0.5 h in RAW264.7 cells. Discussion: The results suggested that hydrogen is potentially inhibitive against inflammation by inhibiting HIF-1α and IL-1α release at early occurrence. The target of the inhibitive LPS-induced-inflammatory action of hydrogen is chemokines in macrophages in the peritoneal cavity. This study provides direct experimental evidence for quickly controlling inflammation with the translational application of a hydrogen-assisted protocol.

8.
Alcohol Clin Exp Res ; 2023 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-36871955

RESUMO

BACKGROUND AND PURPOSE: Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists. METHODS: C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells. RESULTS: Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells. CONCLUSIONS: Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.

9.
Cell Host Microbe ; 31(3): 389-404.e7, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36893735

RESUMO

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C. albicans)-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin decreased C. albicans-specific Th17 cells in the liver and reduced ethanol-induced liver disease in mice. Transgenic mice expressing T cell receptors (TCRs) reactive to Candida antigens developed more severe ethanol-induced liver disease than transgene-negative littermates. Adoptively transferring Candida-specific TCR transgenic T cells or polyclonal C. albicans-primed T cells exacerbated ethanol-induced liver disease in wild-type mice. Interleukin-17 (IL-17) receptor A signaling in Kupffer cells was required for the effects of polyclonal C. albicans-primed T cells. Our findings indicate that ethanol increases C. albicans-specific Th17 cells, which contribute to alcohol-associated liver disease.


Assuntos
Candida albicans , Células Th17 , Camundongos , Animais , Candida , Camundongos Transgênicos , Etanol/toxicidade
10.
Dig Dis Sci ; 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36807831

RESUMO

BACKGROUND: Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are two of the most common etiologies of chronic liver disease worldwide. Changes in intestinal permeability and increased gut microbial translocation have been posited as important contributors to inflammation in both ALD and NAFLD. However, gut microbial translocation has not been compared between the two etiologies and can lead to better understanding of the differences in their pathogenesis to liver disease. METHODS: We compared serum and liver markers in the following five models of liver disease to understand the differences in the role of gut microbial translocation on liver disease progression caused by ethanol versus Western diet: (1) 8-week chronic ethanol feeding model. (2) 2-week chronic-plus-binge (National Institute on Alcohol Abuse and Alcoholism (NIAAA)) ethanol feeding model. (3) 2-week chronic-plus-binge (NIAAA) ethanol feeding model in microbiota-humanized gnotobiotic mice colonized with stool from patients with alcohol-associated hepatitis. (4) 20-week Western-diet-feeding model of NASH. (5) 20-week Western-diet-feeding model in microbiota-humanized gnotobiotic mice colonized with stool from NASH patients. RESULTS: Translocation of bacterial lipopolysaccharide to the peripheral circulation was seen in both ethanol-induced and diet-induced liver disease, but translocation of bacteria itself was restricted to only ethanol-induced liver disease. Moreover, the diet-induced steatohepatitis models developed more significant liver injury, inflammation, and fibrosis compared with ethanol-induced liver disease models, and this positively correlated with the level of lipopolysaccharide translocation. CONCLUSIONS: More significant liver injury, inflammation, and fibrosis are seen in diet-induced steatohepatitis, which positively correlates with translocation of bacterial components, but not intact bacteria.

11.
Mikrochim Acta ; 190(3): 85, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36749408

RESUMO

Constructing of heterostructures can significantly improve the photoelectrical (PEC) response signal by promoting the migration and suppressing the recombination of photogenerated carries. A bifunctional PEC sensing platform was designed for simultaneous high-performance detection of mucin-1 (MUC1) and carcinoembryonic antigen (CEA), which was based on generated Z-scheme heterostructured Ag3PO4/Ag/TiO2 nanorod arrays (NAs) and enzyme-mediated catalytic precipitation by alkaline phosphatase (ALP) and Au/hollow Co3O4 polyhedron. The proposed aptasensor displayed linear ranges of 1.0-100 ng mL-1 and 0.1-50 ng mL-1 for MUC1 and CEA with limit of detections of 0.430 and 0.058 ng mL-1, respectively. This strategy offers potential applications for early diagnosis, monitoring progression, and even evaluating the prognosis of breast cancer in practice.


Assuntos
Biomarcadores Tumorais , Nanotubos , Antígeno Carcinoembrionário , Técnicas Eletroquímicas , Limite de Detecção , Nanotubos/química , Prata/química
12.
Trials ; 24(1): 72, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36726138

RESUMO

BACKGROUND: The high incidence of intraoperative glucose dysregulations in liver transplantation (LT) is related to the lack of highly orchestrated control of intraoperative blood glucose. Glucose monitoring based on a single arterial blood gas test can only provide a simple glucose profile and is insufficient in monitoring intraoperative glycemic variability (GV), which is not conducive to controlling GV and may have a lag in the management of hyper/hypoglycemia. Continuous glucose monitor (CGM), which has been successfully applied in the management of chronic disease in diabetes, provides more detailed blood glucose records and reflect GV parameters such as coefficient of variation (CV%). However, its effectiveness and accuracy for guiding blood glucose management in major surgeries remains unclear. METHODS: This is a single-center, randomized, controlled, superiority trial. One hundred and eighty patients scheduled for orthotopic LT will be recruited and randomized into two groups. All patients are monitored for intraoperative glucose using CGM combined with arterial blood gas (ABG). In the intervention group (group CG), ABG will be performed when CGM value is < 6.1 mmol/L or > 10.0 mmol/L, or the rate of change of CGM value > 1.67 mmol/(L·min). In the control group (group G), intraoperative ABG tests will be performed every 2 h, and the frequency of ABG tests will be adjusted based on the previous arterial glucose result. Patients in both groups will have their blood glucose adjusted according to arterial glucose values and a uniform protocol. Surgical and other anesthetic management is completed according to standard LT practices. DISCUSSION: This study intends to investigate the effectiveness of CGM-based intraoperative glucose management and its impact on the prognosis of LT patients by comparing the GV, mean glucose values, and the incidence of hypo/hypoglycemic events guided by the above two glucose monitoring methods. TRIAL REGISTRATION: This study is registered at www.chictr.org.cn on January 4, 2022, under the registration number ChiCTR2200055236.


Assuntos
Diabetes Mellitus Tipo 1 , Transplante de Fígado , Humanos , Glicemia , Automonitorização da Glicemia/métodos , Estudos Prospectivos , Transplante de Fígado/efeitos adversos , Hipoglicemiantes , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Hepatol Commun ; 7(2): e0029, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36706195

RESUMO

Chronic alcohol consumption is associated with intestinal fungal dysbiosis, yet we understand little about how alterations of intestinal fungi (mycobiota) contribute to the pathogenesis of alcohol-associated liver disease. By reanalyzing internal transcribed spacer 2 amplicon sequencing of fecal samples from a cohort of 66 patients with alcohol use disorder for presence (as opposed to relative abundance) of fungal species, we observed that the presence of Malassezia restricta was associated with increased markers of liver injury. M. restricta exacerbates ethanol-induced liver injury both in acute binge and chronic ethanol-feeding models in mice. Using bone marrow chimeric mice, we found that the disease exacerbating effect by M. restricta was mediated by C-type lectin domain family 4, member N on bone marrow-derived cells. M. restricta induces inflammatory cytokines and chemokines in Kupffer cells through C-type lectin domain family 4, member N signaling. Targeting fungal pathobionts might be a therapeutic strategy for alcohol-associated liver disease.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Hepatopatias Alcoólicas , Animais , Camundongos , Etanol/efeitos adversos , Hepatopatias Alcoólicas/microbiologia , Lectinas Tipo C/genética
14.
Org Lett ; 25(2): 364-368, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36625525

RESUMO

Herein, host-guest complexation between pagoda[n]arenes (n = 4, P4; n = 5, P5) and tropylium cation (G) was investigated in detail. It was found that both P4 and P5 showed surprisingly strong binding affinities toward the tropylium cation with association constants of more than 107 M-1 for the 1:1 host-guest complexes. The theoretical calculations showed different host-guest complexion ways for complexes G@P4 and G@P5 and the strong π···π interactions and multiple C-H···π interactions play a very important role in the formation of these stable complexes, respectively. Moreover, the switchable processes of guest binding and release in the complexes can be effectively controlled by redox stimuli, and they can be also visible by the color and fluorescence changes.

15.
J Control Release ; 354: 294-304, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36638843

RESUMO

Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis.


Assuntos
Aterosclerose , Nanopartículas , Camundongos , Animais , Micelas , Heparina de Baixo Peso Molecular/farmacologia , Portadores de Fármacos/química , Sirolimo , Nanopartículas/química , Aterosclerose/tratamento farmacológico , Lipídeos
16.
Cell Death Differ ; 30(2): 560-575, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36539510

RESUMO

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias Pancreáticas , Animais , Camundongos , Imunoterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteases Específicas de Ubiquitina
17.
Tohoku J Exp Med ; 259(3): 189-198, 2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36476587

RESUMO

Photoaging is mainly caused by the exposure of the skin to ultraviolet (UV) radiation. Among them, damage to human dermal fibroblast (HDF) cells caused by ultraviolet A (UVA) is the main cause of skin aging. Researchers have dedicated to identifying natural compounds from plants to fight against UV radiation-induced photoaging. We previously found that extracts from wild chrysanthemum could prevent acute damage and photoaging induced by UV irradiation. As one of the most abundant ingredients in wild chrysanthemum extract, handelin was hypothesized to have the potential to prevent UVA-induced photoaging of skin fibroblast. In the present study, we report the great potential of handelin in combating UVA-induced photoaging of fibroblasts. We firstly demonstrated that handelin was safe for skin fibroblast as high as a concentration of 0.0125 µM, showing no toxicity on the cells and improved cell viability. Furthermore, handelin can reduce UVA-induced cellular senescence, indicated by a reduced proportion of senescence-associated beta-galactose positive cells and the expression of P21. We then verified that handelin pretreatment markedly attenuated the production of reactive oxygen species (ROS) generation after UVA irradiation. Meanwhile, we found that handelin enhances autophagy after UVA irradiation, and autophagy is involved in the quality control of intracellular proteins after UV-induced damage (partially indirectly via ROS). Therefore, these results suggest that handelin has a very high potential as an effective ingredient against UVA-induced skin aging. Moreover, this provides an important basis for further research on the photoprotective mechanism of handelin.


Assuntos
Envelhecimento da Pele , Humanos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Autofagia , Fibroblastos , Células Cultivadas
18.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361825

RESUMO

The anterior cingulate cortex (ACC) is particularly critical for pain information processing. Peripheral nerve injury triggers neuronal hyper-excitability in the ACC and mediates descending facilitation to the spinal dorsal horn. The mechanically gated ion channel Piezo1 is involved in the transmission of pain information in the peripheral nervous system. However, the pain-processing role of Piezo1 in the brain is unknown. In this work, we found that spared (sciatic) nerve injury (SNI) increased Piezo1 protein levels in inhibitory parvalbumin (PV)-expressing interneurons (PV-INs) but not in glutaminergic CaMKⅡ+ neurons, in the bilateral ACC. A reduction in the number of PV-INs but not in the number of CaMKⅡ+ neurons and a significant reduction in inhibitory synaptic terminals was observed in the SNI chronic pain model. Further, observation of morphological changes in the microglia in the ACC showed their activated amoeba-like transformation, with a reduction in process length and an increase in cell body area. Combined with the encapsulation of Piezo1-positive neurons by Iba1+ microglia, the loss of PV-INs after SNI might result from phagocytosis by the microglia. In cellular experiments, administration of recombinant rat TNF-α (rrTNF) to the BV2 cell culture or ACC neuron primary culture elevated the protein levels of Piezo1 and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3). The administration of the NLRP3 inhibitor MCC950 in these cells blocked the rrTNF-induced expression of caspase-1 and interleukin-1ß (key downstream factors of the activated NLRP3 inflammasome) in vitro and reversed the SNI-induced Piezo1 overexpression in the ACC and alleviated SNI-induced allodynia in vivo. These results suggest that NLRP3 may be the key factor in causing Piezo1 upregulation in SNI, promoting an imbalance between ACC excitation and inhibition by inducing the microglial phagocytosis of PV-INs and, thereby, facilitating spinal pain transmission.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Ratos , Animais , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/metabolismo , Parvalbuminas/metabolismo , Giro do Cíngulo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuralgia/metabolismo , Regulação para Cima , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ratos Sprague-Dawley , Interneurônios/metabolismo
19.
Front Oncol ; 12: 898966, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387239

RESUMO

Colorectal diseases are threatening human health, especially inflammatory bowel disease (IBD) and colorectal cancer (CRC). IBD is a group of chronic, recurrent and incurable disease, which may affect the entire gastrointestinal tract, increasing the risk of CRC. Eukaryotic gene expression is a complicated process, which is mainly regulated at the level of gene transcription and mRNA translation. Protein translation in tissue is associated with a sequence of steps, including initiation, elongation, termination and recycling. Abnormal regulation of gene expression is the key to the pathogenesis of CRC. In the early stages of cancer, it is vital to identify new diagnostic and therapeutic targets and biomarkers. This review presented current knowledge on aberrant expression of eIFs, eEFs and eRFs in colorectal diseases. The current findings of protein synthesis on colorectal pathogenesis showed that eIFs, eEFs and eRFs may be potential targets for CRC treatment.

20.
Front Oncol ; 12: 1038925, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439516

RESUMO

Background: Spindle and kinetochore-associated complex subunits 1-3 (SKA1-3) stabilize the kinetochore-attached spindle microtubules in metaphase. Due to the dysregulation in multiple cancers, SKA1-3 is considered a predictor for the prognosis of the patients. However, the potential clinical applications of SKA1-3, particularly in hepatocellular carcinoma (HCC) prognosis and progression, have completely unknown yet. Methods: For the analysis of SKA1-3 expression and applications in clinics in HCC patients, several databases, such as STRING, UALCAN, GEO, and TCGA, were searched. In addition, the underlying mechanisms of SKA for the regulation of HCC occurrence, development, and progression were also explored. Results: Compared to the normal controls, HCC patients showed dramatically elevated SKA1-3 expression at the mRNA level, and the values of the area under the curve (AUC) were 0.982, 0.887, and 0.973, respectively. Increased SKA1-3 expression levels were associated with the clinical stage, age, body mass index, tumor grade, tissue subtype, and Tp53 mutation status in HCC patients. The analyses of Kyoto Encyclopedia of Genes and Genome (KEGG) and Gene ontology (GO) demonstrated that SKA1-3 are enriched mainly in the Fanconi anemia, homologous recombination, spliceosome, DNA replication, and cell cycle signaling pathways. The hub genes, such as CDK1, CCNB1, CCNA2, TOP2A, BUB1, AURKB, CCNB2, BUB1B, NCAPG, and KIF11, were identified in protein-protein interactions (PPIs). The expression levels of hub genes were increased in HCC patients and predictive of a poor prognosis. Finally, the expression levels of SKA1-3 were determined using the GEO database. Conclusions: SKA1-3 are potential prognostic biomarkers of and targets for HCC. In addition, SKA1-3 may affect HCC prognosis via the Fanconi anemia pathway, homologous recombination, spliceosome, DNA replication, and cell cycle signaling pathway.

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