RESUMO

Biofilms, which are resistant to conventional antimicrobial treatments, pose significant challenges in medical and industrial environments. This study introduces manganese complex-gold nanoparticles (Mn-DPA-AuNPs) as a hybrid strategy for biofilm inhibition and eradication. Upon exposure to green light, these nanoparticles significantly enhance the generation of reactive oxygen species (ROS), including hydrogen peroxide and superoxide. This activity substantially reduces the regrowth potential of the surviving bacteria within the biofilm, with marked efficacy noted in Pseudomonas aeruginosa PAO1. This study highlights the potential of integrating manganese complexes with gold nanoparticles to develop advanced antimicrobial agents against resistant biofilms, offering a promising approach to enhance microbial control in diverse settings.

RESUMO

BACKGROUND: Glucose-regulated protein 78 (GRP78), as a chaperone protein, can protect the endoplasmic reticulum of cells and is expressed to influence chemoresistance and prognosis in cancer. Deoxypodophyllotoxin (DPT) is a compound with antitumor effects on cancers. DPT inhibits the proliferation of osteosarcoma by inducing apoptosis, necrosis, or cell cycle arrest. OBJECT: This study was performed to demonstrate the molecular mechanism by which DPT attenuates osteosarcoma progression through GRP78. METHODS: Natural compound libraries and western blot (WB) were used to screen the inhibitors of osteosarcoma GRP78. The expression of mitochondria-related genes in cancer cells of the treatment group was detected by quantitative real-time PCR (qPCR) and WB. 3-(4,5)- Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and 5-ethynyl-2'- deoxyuridine (EDU) were used to discover the activity and proliferation of osteosarcoma cells treated with DPT. We constructed an in vivo mouse model of DPT drug therapy and carried out immunohistochemical detection of xenografts. The treated osteosarcoma cells were analyzed using bioinformatics and electron microscopy. The data were analyzed finally. RESULTS: DPT inhibited osteosarcoma cell survival and the growth of tumor xenografts. It promoted up-regulation of BCL2-associated X protein (Bax) and B-cell CLL/lymphoma 2 (Bcl-2), which serves to mediate and attenuate, respectively, the killing activities of DPT through mitochondria dysfunction. The effect of DPT against cancer cells could be attenuated by the overexpression of GRP78, characterized by the inactivation of the caspase cascade. The loss of GRP78 in osteosarcoma cells negatively mediated the basal level of autophagyassociated genes. DPT stimulated autophagy via the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT), a mechanistic target of rapamycin (mTOR) axis. The autophagy caused by DPT played an active role in the osteosarcoma of humans and blocked the apoptotic cascade. CONCLUSION: Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.

RESUMO

The aim of this study was to evaluate the accuracy of the JAMR upper-arm blood pressure monitor B23 in the general population according to the AAMI/ESH/ISO Universal Standard (ISO 81060-2 : 2018/AMD 1 : 2020). The study recruited participants who met the criteria of the AAMI/ESH/ISO Universal Standard in terms of their number, sex, age, limb size, and blood pressure (BP) distribution. The study involved measuring BP, including both SBP and DBP, using both the test device and a standard mercury sphygmomanometer in sequential measurements. Of 90 participants, 85 qualified participants were analyzed. A total of 255 sets of comparison data (three sets for each subject) were obtained and analyzed. For the validation criterion 1, the mean ±â€…SD of the differences between the JAMR B23 and mercury sphygmomanometer BP readings was -0.24 ±â€…6.52/-2.67 ±â€…5.6 mmHg (SBP/DBP). For criterion 2, the SD of the averaged BP (SBP/DBP) differences between the JAMR B23 and reference BP (SBP/DBP) per participant was 5.61/5.13 mmHg (the requirement was ≤6.95/6.43 mmHg by calculation). The JAMR B23 passed all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2 : 2018/AMD 1 : 2020) and can be recommended for clinical and self/home use in the general population.

RESUMO

Phthalate esters (PAEs) are emerging hazardous and toxic chemicals that are extensively used as plasticizers or additives. Diethyl phthalate (DEP) and dimethyl phthalate (DMP), two kinds of PAEs, have been listed as the priority pollutants by many countries. PAE hydrolases are the most effective enzymes in PAE degradation, among which family IV esterases are predominate. However, only a few PAE hydrolases have been characterized, and as far as we know, no crystal structure of any PAE hydrolases of the family IV esterases is available to date. HylD1 is a PAE hydrolase of the family IV esterases, which can degrade DMP and DEP. Here, the recombinant HylD1 was characterized. HylD1 maintained a dimer in solution, and functioned under a relatively wide pH range. The crystal structures of HylD1 and its complex with monoethyl phthalate were solved. Residues involved in substrate binding were identified. The catalytic mechanism of HylD1 mediated by the catalytic triad Ser140-Asp231-His261 was further proposed. The hylD1 gene is widely distributed in different environments, suggesting its important role in PAEs degradation. This study provides a better understanding of PAEs hydrolysis, and lays out favorable bases for the rational design of highly-efficient PAEs degradation enzymes for industrial applications in future.

Assuntos

Ácidos Ftálicos , Ácidos Ftálicos/química , Ácidos Ftálicos/metabolismo , Ésteres/química , Hidrólise , Cristalografia por Raios X , Catálise , Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases de Éster Carboxílico/genética

RESUMO

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

Assuntos

Predisposição Genética para Doença , Genótipo , Hepatite C , Polimorfismo de Nucleotídeo Único , Humanos , Masculino , Feminino , Estudos de Casos e Controles , Hepatite C/genética , Hepatite C/virologia , Hepatite C/imunologia , Pessoa de Meia-Idade , Adulto , Antígenos HLA-A/genética , Hepacivirus/genética , Hepacivirus/imunologia , Receptores KIR/genética , Idoso , Receptores KIR3DL2/genética

RESUMO

Insecticide resistance has been a problem in both the agricultural pests and vectors. Revealing the detoxification mechanisms may help to better manage insect pests. Here, we showed that arylalkylamine N-acetyltransferase 1 (AANAT1) regulates intestinal detoxification process through modulation of reactive oxygen species (ROS)-activated transcription factors cap"n"collar isoform-C (CncC): muscle aponeurosis fibromatosis (Maf) pathway in both the oriental fruit fly, Bactrocera dorsalis, and the arbovirus vector, Aedes aegypti. Knockout/knockdown of AANAT1 led to accumulation of biogenic amines, which induced a decreased in the gut ROS level. The reduced midgut ROS levels resulted in decreased expression of CncC and Maf, leading to lower expression level of detoxification genes. AANAT1 knockout/knockdown insects were more susceptible to insecticide treatments. Our study reveals that normal functionality of AANAT1 is important for the regulation of gut detoxification pathways, providing insights into the mechanism underlying the gut defense against xenobiotics in metazoans.

Assuntos

Arilalquilamina N-Acetiltransferase , Inativação Metabólica , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Arilalquilamina N-Acetiltransferase/metabolismo , Arilalquilamina N-Acetiltransferase/genética , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Aedes/genética , Aedes/metabolismo , Inseticidas/farmacologia , Trato Gastrointestinal/metabolismo

RESUMO

Mechanoluminescence, or the generation of light from materials under external force, is a powerful tool for biology and materials science. However, direct mechanoluminescence from polymers remains limited. Here, we report a novel design strategy for mechanoluminescent polymers that leverages the synergy between a masked 2-furylcarbinol mechanophore for mechanically triggered release and an adamantylidene-phenoxy-1,2-dioxetane chemiluminophore payload. Ultrasound-induced mechanochemical activation of polymers, in both organic and aqueous solutions, triggers a cascade reaction that ultimately results in bright green light emission. This novel strategy capitalizes on the modularity of the masked 2-furylcarbinol mechanophore system in combination with advances in the design of exceptionally bright and highly tunable adamantylidene-1,2-dioxetane chemiluminophores. We anticipate that this chemistry will enable diverse applications in optoelectronics, sensing, bioimaging, optogenetics, and many other areas.

RESUMO

Ovarian cancer (OC) is a gynecological malignancy that results in a global threat to women's lives. Lactic acid, a key metabolite produced from the glycolytic metabolism of glucose molecules, is correlated with tumor immune infiltration and platinum resistance. In our previous study, we found that endothelial cell-specific molecule 1 (ESM1) plays a key role in OC progression. This study revealed that lactate could upregulate ESM1, which enhances SCD1 to attenuate the antitumor CD8+ T-cell response. ESM1 and SCD1 expression levels were significantly greater in OC patients with high lactic acid levels than in those with low lactic acid levels. Further mechanistic studies suggested that the Wnt/ß-catenin pathway was inactivated after ESM1 knockdown and rescued by SCD1 overexpression. IC50 analysis indicated that the ESM1-SCD1 axis induces the resistance of OC cells to platinum agents, including cisplatin, carboplatin, and oxaliplatin, by upregulating P-gp. In conclusion, our study indicated that the induction of SCD1 by lactic acid-induced ESM1 can impede the CD8+ T-cell response against tumors and promote resistance to cisplatin by activating the Wnt/ß-catenin pathway in ovarian cancer. Consequently, targeting ESM1 may have considerable therapeutic potential for modulating the tumor immune microenvironment and enhancing drug sensitivity in OC patients.

Assuntos

Antineoplásicos , Linfócitos T CD8-Positivos , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Ácido Láctico , Proteínas de Neoplasias , Neoplasias Ovarianas , Proteoglicanas , Via de Sinalização Wnt , Feminino , Humanos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cisplatino/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Láctico/metabolismo , Proteoglicanas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/imunologia , Animais , Camundongos , Estearoil-CoA Dessaturase

RESUMO

Background: The calcium-binding protein 4 (CABP4) gene is a newly identified epilepsy-related gene that might be associated with a rare type of genetic focal epilepsy; that is, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro, mutant CABP4 causes an increased inward flow voltage of calcium ions and a significant increase in the electrical signal discharge in hippocampus neurons; however, the role of CABP4 in epilepsy has not yet been specifically described, and there is not yet a CABP4 mutant animal model recapitulating the epilepsy phenotype. Methods: We introduced a human CABP4 missense mutation into the C57BL/6J mouse genome and generated a knock-in strain carrying a glycine-to-aspartic acid mutation in the gene. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to evaluate the CABP4 expression level. Slice patch-clamp recording was carried out on pyramidal cells of prefrontal cortex layers II and III. Results: The CABP4G155D/+ mutant mice were viable and born at an expected Mendelian ratio. Surprisingly, the heterozygous (HE) mice did not display either an abnormal appearance or an overt seizure phenotype, and there was no statistically significant difference between the HE and wild-type (WT) mice in terms of overall messenger RNA (mRNA) and protein expression. However, the HE mutant mice showed an imbalance in the amount of protein expressed in the brain regions. Additionally, the patch-clamp recordings from the HE mouse layer II/III cortical pyramidal cells revealed an increase in the frequency of micro-excitatory post-synaptic currents (mEPSCs) but no change in the amplitude was observed. Conclusions: The findings of this study suggest that the CABP4 p.G155D mutation might be one of the mechanisms underlying seizure onset.

RESUMO

Ovarian cancer is one of the most common malignant tumors in women, and treatment options are limited. Despite efforts to adjust cancer treatment models and develop new methods, including tumor microenvironment (TME) therapy, more theoretical support is needed. Increasing attention is being given to antiangiogenic measures for TME treatment. Another important concept in ovarian cancer TME is angiogenesis, where tumor cells obtain nutrients and oxygen from surrounding tissues through blood vessels to support further expansion and metastasis. Many neovascularization signaling pathways become imbalanced and hyperactive during this process. Inhibiting these abnormal pathways can yield ideal therapeutic effects in patients, even by reversing drug resistance. However, these deep TME signaling pathways often exhibit crosstalk and correlation. Understanding these interactions may be an important strategy for further treating ovarian cancer. This review summarizes the latest progress and therapeutic strategies for these angiogenic signaling pathways in ovarian cancer.

Assuntos

Neovascularização Patológica , Neoplasias Ovarianas , Transdução de Sinais , Microambiente Tumoral , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Feminino , Neovascularização Patológica/metabolismo , Progressão da Doença , Animais , Inibidores da Angiogênese/uso terapêutico

RESUMO

BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

Assuntos

Proteínas de Transporte , Ácidos Graxos , Proteínas de Membrana , Proteínas de Neoplasias , Neoplasias Ovarianas , Proteínas de Ligação a Hormônio da Tireoide , Hormônios Tireóideos , Microambiente Tumoral , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Animais , Hormônios Tireóideos/metabolismo , Camundongos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Efeito Warburg em Oncologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células , Proteoglicanas

RESUMO

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

Assuntos

Neoplasias dos Ductos Biliares , Bortezomib , Colangiocarcinoma , PTEN Fosfo-Hidrolase , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Bortezomib/uso terapêutico , Bortezomib/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia

RESUMO

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/ß-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

Assuntos

Disfunção Cognitiva , Proteínas do Tecido Nervoso , Proteoma , Ribossomos , Sevoflurano , Comportamento Social , Animais , Masculino , Camundongos , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/toxicidade , Anestésicos Inalatórios/farmacologia , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo

RESUMO

BACKGROUND: Hylurgus ligniperda, an invasive species originating from Eurasia, is now a major forestry quarantine pest worldwide. In recent years, it has caused significant damage in China. While traps have been effective in monitoring and controlling pests, manual inspections are labor-intensive and require expertise in insect classification. To address this, we applied a two-stage cascade convolutional neural network, YOLOX-MobileNetV2 (YOLOX-Mnet), for identifying H. ligniperda and other pests captured in traps. This method streamlines target and non-target insect detection from trap images, offering a more efficient alternative to manual inspections. RESULTS: Two cascade convolutional neural network models were employed in two stages to detect both target and non-target insects from images captured in the same forest. Initially, You Only Look Once X (YOLOX) served as the target detection model, identifying insects and non-insects from the collected images, with non-insect targets subsequently filtered out. In the second stage, MobileNetV2, a classification network, classified the captured insects. This approach effectively reduced false positives from non-insect objects, enabled the inclusion of additional classification terms for multi-class insect classification models, and utilized sample control strategies to enhance classification performance. CONCLUSION: Application of the cascade convolutional neural network model accurately identified H. ligniperda, and Mean F1-score of all kinds of insects in the trap was 0.98. Compared to traditional insect classification, this method offers great improvement in the identification and early warning of forest pests, as well as provide technical support for the early prevention and control of forest pests. © 2024 Society of Chemical Industry.

Assuntos

Espécies Introduzidas , Redes Neurais de Computação , Animais , Insetos/fisiologia , Controle de Insetos/métodos , China

RESUMO

The gut microbiota of insects has been shown to regulate host detoxification enzymes. However, the potential regulatory mechanisms involved remain unknown. Here, we report that gut bacteria increase insecticide resistance by activating the cap "n" collar isoform-C (CncC) pathway through enzymatically generated reactive oxygen species (ROS) in Bactrocera dorsalis. We demonstrated that Enterococcus casseliflavus and Lactococcus lactis, two lactic acid-producing bacteria, increase the resistance of B. dorsalis to ß-cypermethrin by regulating cytochrome P450 (P450) enzymes and α-glutathione S-transferase (GST) activities. These gut symbionts also induced the expression of CncC and muscle aponeurosis fibromatosis. BdCncC knockdown led to a decrease in resistance caused by gut bacteria. Ingestion of the ROS scavenger vitamin C in resistant strain affected the expression of BdCncC/BdKeap1/BdMafK, resulting in reduced P450 and GST activity. Furthermore, feeding with E. casseliflavus or L. lactis showed that BdNOX5 increased ROS production, and BdNOX5 knockdown affected the expression of the BdCncC/BdMafK pathway and detoxification genes. Moreover, lactic acid feeding activated the ROS-associated regulation of P450 and GST activity. Collectively, our findings indicate that symbiotic gut bacteria modulate intestinal detoxification pathways by affecting physiological biochemistry, thus providing new insights into the involvement of insect gut microbes in the development of insecticide resistance.

Assuntos

Microbioma Gastrointestinal , Resistência a Inseticidas , Piretrinas , Espécies Reativas de Oxigênio , Tephritidae , Animais , Espécies Reativas de Oxigênio/metabolismo , Piretrinas/farmacologia , Piretrinas/metabolismo , Resistência a Inseticidas/genética , Tephritidae/microbiologia , Tephritidae/genética , Inseticidas/farmacologia , Inseticidas/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Lactococcus lactis/genética , Lactococcus lactis/metabolismo , Lactobacillales/genética , Lactobacillales/metabolismo , Lactobacillales/efeitos dos fármacos , Lactobacillales/fisiologia , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Enterococcus/genética , Enterococcus/metabolismo , Enterococcus/efeitos dos fármacos , Glutationa Transferase/genética , Glutationa Transferase/metabolismo

RESUMO

BACKGROUND: Aberrant expression of tumor protein D52 (TPD52) is associated with some tumors. The role of TPD52 in uterine corpus endometrial carcinoma (UCEC) remains uncertain. OBJECTIVE: We aimed to investigate the involvement of TPD52 in the pathogenesis of UCEC. METHODS: We employed bioinformatics analysis and experimental validation in our study. RESULTS: Our findings indicated that elevated TPD52 expression in UCEC was significantly associated with various clinical factors, including clinical stage, race, weight, body mass index (BMI), histological type, histological grade, surgical approach, and age (p < 0.01). Furthermore, high TPD52 expression was a predictor of poorer overall survival (OS), progress-free survival (PFS), and disease-specific survival (DSS) (p = 0.011, p = 0.006, and p = 0.003, respectively). TPD52 exhibited a significant correlation with DSS (HR: 2.500; 95% CI: 1.153-5.419; p = 0.02). TPD52 was involved in GPCR ligand binding and formation of the cornified envelope in UCEC. Moreover, TPD52 expression was found to be associated with immune infiltration, immune checkpoints, tumor mutation burden (TMB)/ microsatellite instability (MSI), and mRNA stemness indices (mRNAsi). The somatic mutation rate of TPD52 in UCEC was 1.9%. A ceRNA network of AC011447.7/miR-1-3p/TPD52 was constructed. There was excessive TPD52 protein expression. The upregulation of TPD52 expression in UCEC cell lines was found to be statistically significant. CONCLUSION: TPD52 is upregulated in UCEC and may be a useful patent for prognostic biomarkers of UCEC, which may have important value for clinical treatment and supervision of UCEC patients.

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a highly clinically heterogeneous neurodegenerative disorder primarily attributed to abnormal GGC repeat expansions in the NOTCH2NLC gene. This study aims to comprehensively explore its phenotypic characteristics and genotype-phenotype correlation. A literature search was conducted in PubMed, Embase, and the Cochrane Library from September 1, 2019, to December 31, 2022, encompassing reported NIID cases confirmed by pathogenic NOTCH2NLC mutations. Linear regressions and trend analyses were performed. Analyzing 635 cases from 85 included studies revealed that familial cases exhibited significantly larger GGC repeat expansions than sporadic cases (p < 0.001), and this frequency significantly increased with expanding GGC repeats (p trend < 0.001). Age at onset (AAO) showed a negative correlation with GGC repeat expansions (p < 0.001). The predominant initial symptoms included tremor (31.70%), cognitive impairment (14.12%), and muscle weakness (10.66%). The decreased or absent tendon reflex (DTR/ATR) emerged as a notable clinical indicator of NIID due to its high prevalence. U-fiber was observed in 79.11% of patients, particularly prominent in paroxysmal disease-dominant (87.50%) and dementia-dominant cases (81.08%). Peripheral neuropathy-dominant cases exhibited larger GGC repeat expansions (median = 123.00) and an earlier AAO (median = 33.00) than other phenotypes. Moreover, a significant genetic anticipation of 3.5 years was observed (p = 0.039). This study provides a comprehensive and up-to-date compilation of genotypic and phenotypic information on NIID since the identification of the causative gene NOTCH2NLC. We contribute a novel diagnostic framework for NIID to support clinical practice.

RESUMO

BACKGROUND: Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. METHODS: The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. RESULTS: Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. CONCLUSION: Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.

Assuntos

Cistadenocarcinoma Seroso , Janus Quinase 2 , Neoplasias Ovarianas , Fator de Transcrição STAT3 , Animais , Feminino , Humanos , Microambiente Tumoral , Simulação de Acoplamento Molecular , Angiogênese , Peixe-Zebra/metabolismo , Carcinogênese , Proliferação de Células , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Proteína 4 Semelhante a Angiopoietina/genética , Proteínas de Neoplasias , Proteoglicanas

RESUMO

Polymers that release functional small molecules in response to mechanical force are promising materials for a variety of applications including drug delivery, catalysis, and sensing. While many different mechanophores have been developed that enable the triggered release of a variety of small molecule payloads, most mechanophores are limited to one specific payload molecule. Here, we leverage the unique fragmentation of a 5-aryloxy-substituted 2-furylcarbinol derivative to design a novel mechanophore capable of the mechanically triggered release of two distinct cargo molecules. Critical to the mechanophore design is the incorporation of a self-immolative spacer to facilitate the release of a second payload. By varying the relative positions of each cargo molecule conjugated to the mechanophore, dual payload release occurs either concurrently or sequentially, demonstrating the ability to fine-tune the release profiles.

RESUMO

Polymers that release small molecules in response to mechanical force are promising for a variety of applications including drug delivery, catalysis, and sensing. While a number of mechanophores have been developed for the release of covalently bound payloads, existing strategies are either limited in cargo scope or, in the case of more general mechanophore designs, are restricted to the release of one or two cargo molecules per polymer chain. Herein, we introduce a nonscissile mechanophore based on a masked 2-furylcarbinol derivative that enables the preparation of multimechanophore polymers with ultrahigh payload capacity. We demonstrate that polymers prepared via ring-opening metathesis polymerization are capable of releasing hundreds of small-molecule payloads per polymer chain upon ultrasound-induced mechanochemical activation. This nonscissile masked 2-furylcarbinol mechanophore overcomes a major challenge in cargo loading capacity associated with previous 2-furylcarbinol mechanophore designs, enabling applications that benefit from much higher concentrations of delivered cargo.