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6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.
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Doença Hepática Induzida por Substâncias e Drogas , Neutropenia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Polimorfismo Genético , Neutropenia/genética , Resultado do Tratamento , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológicoRESUMO
A new noncentrosymmetric crystal Na12(NbO)3(PO4)7 was successfully synthesized in the niobium phosphate system. Its structure characterizes isolated and highly distorted NbO6 octahedra joining with isolated PO4 groups to form a unit of a (Nb6P6O12) hexagonal star by sharing O atoms. In (Nb6P6O12) hexagonal stars, all Nb and P atoms are in a hexagonal star-like arrangement and all Na atoms are also in a hexagonal star-like arrangement, except for Na(3) and Na(10) atoms. Notably, it exhibits a strong phase-matched second harmonic response: 3 × KDP, which is rare in known niobium phosphate systems. Meanwhile, it also has a wide optically transparent window (0.29-4.44 µm) and a high laser-induced damage threshold (3.5 GW/cm2). More importantly, Na12(NbO)3(PO4)7 is a congruent melting compound that has the potential to be grown into large-sized single crystals by the Czochralski method. These excellent properties make it a promising candidate as a mid-infrared nonlinear optical crystal.
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Receptor-mediated vesicular transport has been extensively developed to penetrate the blood-brain barrier (BBB) and has emerged as a class of powerful brain-targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low-density lipoprotein receptor-related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein-coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)-loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti-angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94-positive brain diseases.
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Neoplasias Encefálicas , Nanocápsulas , Camundongos , Animais , Células Endoteliais/metabolismo , Biomimética , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas de Membrana/metabolismo , Barreira Hematoencefálica/metabolismoRESUMO
OBJECTIVES: The importance of thioesterase domains on bacillomycin D synthesis and the ability of different thioesterase domains to selectively recognize and catalyze peptide chain hydrolysis and cyclization were studied by deleting and substituting thioesterase domains. RESULTS: No bacillomycin D analogs were found in the thioesterase-deleted strain fmbJ-ΔTE, indicating that the TE domain was essential for bacillomycin D synthesis. Then the thioesterase in bacillomycin D synthetases was replaced by the thioesterase in bacillomycin F, iturin A, mycosubtilin, plipastatin and surfactin synthetases. Except for fmbJ-S-TE, all others were able to synthesize bacillomycin D homologs because a suitable recombination site was selected, which maintained the integrity of NRPSs. In particular, the yield of bacillomycin D in fmbJ-IA-TE, fmbJ-M-TE and fmbJ-P-TE was significantly increased. CONCLUSION: This study expands our understanding of the TE domain in bacillomycin D synthetases and shows that thioesterase has excellent potential in the chemical-enzymatic synthesis of natural products or their analogs.
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Bacillomycin D is a cyclic antimicrobial lipopeptide that has excellent antifungal effects, but its application is limited due to its low yield. At present, it is not clear whether fatty acids regulate the synthesis of bacillomycin D. Therefore, the effects of nine fatty acids on the yield of bacillomycin D produced by Bacillus amyloliquefaciens fmbJ were studied. The results showed that sodium propionate, propionic acid, and butyric acid could increase the yield of bacillomycin D by 44, 40, and 10%, respectively. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression levels of bacillomycin D synthesis gene, signaling factors and genes related to fatty acid metabolism, so as to explore the mechanism of sodium propionate regulating bacillomycin D synthesis. In conclusion, sodium propionate could accelerate the tricarboxylic acid cycle and promoted spore formation, cell movement, the secretion of extracellular protease and the transcription of bacillomycin D synthesis gene by upregulating the expression of signal factors degU, degQ, sigH, sigM and spo0A and ultimately promoted the synthesis of bacillomycin D. In this study, the mechanism of sodium propionate increasing bacillomycin D production was explored from multiple perspectives, which provided theoretical support for the large-scale production of bacillomycin D and was expected to promote its wide application in food, agriculture and medicine fields.
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Peptídeos Catiônicos Antimicrobianos , Ácidos Graxos , PropionatosRESUMO
Two new compounds K3TaP2O9 and Na3TaP2O9 were obtained by spontaneous crystallization with KH2PO4 and K2HPO4 or NaH2PO4 and Na2HPO4 as fluxes, respectively. K3TaP2O9 belongs to the P21/m space group of the monoclinic system, with cell parameters of a = 9.8912(7) Å, b = 7.1861(5) Å, c = 13.6457(9) Å, ß = 94.047(2)°, and Z = 4. In contrast, Na3TaP2O9 pertains to the P212121 space group of the orthorhombic system, with cell parameters of a = 7.1241(7) Å, b = 9.3071(10) Å, c = 12.3752(13) Å, and Z = 4. Both of the structures feature the existence of the zigzag (TaP2O9)∞ chains with the -(O4Ta)-O-(TaO4)- connection. Also, two compounds have high transparency of about 90% in the 400-2500 nm range. Theoretical calculations and powder second-harmonic generation test show that the compound Na3TaP2O9 has a large band gap of 5.5 eV, a moderate powder second-harmonic generation response of 0.6 × KDP, and a large birefringence of 0.11.
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BACKGROUND: Sarcopenia has been identified as a risk factor for cognitive impairment, and motoric cognitive risk syndrome (MCR) is a recently defined pre-dementia syndrome. It is not known whether they are related. We aimed to investigate the association and potential pathways between sarcopenia and MCR in the community elderly by establishing a moderated mediation model. METHODS: 846 community residents aged ≥ 60 years were recruited from May 2021 to September 2021 and had a comprehensive geriatric evaluation. The diagnosis of sarcopenia followed the criteria issued by the Asian Working Group for Sarcopenia in 2019. MCR was defined as subjective cognitive decline and slow gait. Apathy symptoms and physical activity were assessed by the Apathy Evaluation Scale (AES) and the International Physical Activity Questionnaire (IPAQ). Logistic regression and moderated mediation analyses were conducted to explore the association between the four. RESULTS: 60 (7.1%) had MCR among 846 participants. After full adjustment, sarcopenia (odds ratio [OR] = 3.81, 95% confidence interval [CI] = 1.69-8.60, P = 0.001), AES score (OR = 1.09, 95% CI = 1.04-1.14, P < 0.001), and IPAQ level (OR = 0.43, 95% CI = 0.28-0.66, P < 0.001) were associated with MCR. Apathy partially mediated the relationship between sarcopenia and MCR. Physical activity played a moderation role in the indirect pathway of the mediation model. The increase in physical activity can alleviate the indirect effect of sarcopenia on MCR. CONCLUSION: We established a moderated mediation model to uncover the underlying association mechanism of sarcopenia and MCR preliminarily. These findings suggest that attention should be paid to the management of apathy and physical activity in the context of sarcopenia to prevent early dementia actively. Further validation is needed in future longitudinal studies.
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Disfunção Cognitiva , Sarcopenia , Idoso , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Marcha , Avaliação Geriátrica , Humanos , Fatores de Risco , Sarcopenia/diagnóstico , Sarcopenia/epidemiologiaRESUMO
BACKGROUND: This cross-sectional study aimed to investigate the association between serum free fatty acids and high-density lipoprotein-cholesterol ratio (FHR) and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. METHODS: A total of 760 NAFLD subjects and 379 healthy controls who took their annual health checkups were enrolled during 2019. Fasting blood samples were obtained from the population. NAFLD was diagnosed based on hepatic ultrasound examination. RESULTS: Serum FHR (*100) in NAFLD subjects was significantly higher than that in controls. We found that the serum FHR in NAFLD participants was positively correlated with BMI, DBP, WBC, HGB, ALT, AST, GGT, TG, FPG, UA, and hsCRP. Univariate and multivariate logistic regression analysis showed that FHR was independently associated with the presence of NAFLD. The area under curve (AUC) of the receiver operating characteristic (ROC) curve of FHR for NAFLD was 0.781 with the 95% confidence interval from 0.753 to 0.810. The optimal cutoff point of FHR for predicting NAFLD was 41.14 with 78.8% sensitivity and 77.3%, respectively. CONCLUSIONS: FHR was significantly associated with NAFLD and may serve as an effective indicator in NAFLD patients.
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Hepatopatia Gordurosa não Alcoólica , HDL-Colesterol , Estudos Transversais , Ácidos Graxos não Esterificados , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND: Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy. METHODS: The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated. RESULTS: miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3'UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m6A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer. CONCLUSIONS: Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.
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Adenosina/análogos & derivados , Neoplasias Encefálicas/secundário , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Modelos Biológicos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Interferência de RNA , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The blood-brain barrier (BBB)/blood-tumor barrier (BTB) impedes brain entry of most brain-targeted drugs, whether they are water-soluble or hydrophobic. Endothelial WNT signaling and neoplastic pericytes maintain BTB low permeability by regulating tight junctions. Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases. At the optimal NTZ/IBR mass ratio (1:2), BTB opening reached the optimum effect at 48-72 h without any sign of intracranial edema and cognitive impairment. The combination of NI@I-NPs and chemotherapeutic drugs (doxorubicin and etoposide) extended the median survival of mice with breast cancer brain metastases. Targeting BTB endothelial WNT signaling and tumor pericytes via NI@I-NPs could open the BTB to improve chemotherapeutic efficiency against brain metastases.
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Barreira Hematoencefálica , Neoplasias Encefálicas , Nanopartículas , Pericitos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Pericitos/metabolismo , Pericitos/efeitos dos fármacos , Feminino , Humanos , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Linhagem Celular Tumoral , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Camundongos Endogâmicos BALB C , Via de Sinalização Wnt/efeitos dos fármacos , Camundongos , Sistemas de Liberação de Medicamentos , Adenina/análogos & derivadosRESUMO
Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the bloodâtumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, e.g., Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
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Much effort has been devoted to synthesizing nonlinear optical crystals with efficient second harmonic responses. Herein, a tantalum phosphate crystal Na11Ta8P7O43 with a moderate second harmonic response was obtained using self-fluxes of NaH2PO4 and Na2HPO4. Na11Ta8P7O43 belongs to the Cc space group of monoclinic systems with cell parameters of a = 8.5710(2) Å, b = 15.1144(4) Å, c = 28.7712(7) Å, ß = 92.304(2)°, Z = 4. Its structural features were unique (Ta8O33) bi-capped triangular prisms uniformly oriented with a PO4 connection in the ab plane, which were further joined through additional PO4 groups in the c direction, resulting in moderate nonlinear effects. In addition, this crystal has the characteristics of phase-matchable second harmonic generation, a shorter cutoff edge than the known materials LiTaO3 and KTiOPO4, and high transmittance from the visible to the near infrared band, and may serve as a potential nonlinear optical crystal.
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Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as N6-methyladenosine (m6A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating VEGFA, a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A modification of the 5'UTR (untranslated region) of VEGFA positively regulates its translation. Specifically, methylation of a 5'UTR internal ribosome entry site (IRES) recruited the YTHDC2/eIF4GI complex to trigger cap-independent translation initiation. Intriguingly, the m6A methylation site A856 of the 5'UTR was located within the conserved upstream open reading frame (uORF) of VEGFA IRES-A, which overcomes uORF-mediated translation suppression while facilitating G-quadruplex-induced translation of VEGFA. Targeted specific demethylation of VEGFA m6A significantly decreased expression of VEGFA and reduced lung cancer cell-driven angiogenesis. In vivo and clinical data confirmed the positive effects of m6A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m6A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m6A modification of IRES in the 5'UTR of mRNA on translation regulation. SIGNIFICANCE: Methylation of the 5'UTR IRES of VEGFA mRNA increases cap-independent translation via recruitment of the YTHDC2/eIF4GI complex, which stimulates angiogenesis to promote lung tumor growth.
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Neoplasias Pulmonares , Humanos , Regiões 5' não Traduzidas/genética , RNA Mensageiro/genética , Sequência de Bases , Neoplasias Pulmonares/genética , Biossíntese de Proteínas , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Nanoscale and non-self-replicating outer membrane vesicles (OMVs) are naturally secreted by some bacteria with their structures and compositions similar to that of the outer membrane of parental bacteria. With some specific bacterial physiological characteristics, e.g., immunomodulations and intercellular communications, OMVs have been intensively studied and extensively used and engineered as vaccines, immunotherapeutic drugs, anti-bacterial agents, and drug delivery carriers. In this review, we describe the extraction, characterization, and functionalization of OMVs with emphasis on the latest progress and prospects in biomedical applications.
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Membrana Externa Bacteriana , Vesículas Extracelulares , Antibacterianos/farmacologia , Bactérias , Sistemas de Liberação de MedicamentosRESUMO
Bacillomycin D is a cyclic lipopeptide produced by Bacillus amyloliquefaciens fmbJ. At present, no relevant report has described the combinatorial biosynthesis of bacillomycin D. Due to the strong biosynthetic potential of the communication-mediating (COM) domains, its crosstalk between NRPS subunits has been studied to some extent, but the interaction of COM domain between modules is rarely reported. Therefore, in this study, we conducted the combinatorial biosynthesis of bacillomycin D through the deletion of the COM donor and acceptor domains between the modules and elucidated the interaction between the NRPS modules. The results showed that the deletion of the donor domain between modules 2 and 3 did not affect catalysis by upstream modules, but prevented downstream modules from catalysing the extension of the lipopeptide product, ultimately resulting in mutant complexes that could form linear dipeptides with the sequence ß-NH2FA-Asn-Tyr. However, the engineered hybrid bacillomycin D NRPSs lacking the donor domains between modules 3 and 4 and modules 6 and 7 could form multiple assembly lines that produced bacillomycin D and its analogs (linear tripeptides, cyclic hexapeptides and linear hexapeptides). In addition, all the acceptor domain deletion strains failed to produce bacillomycin D, only truncated peptides produced by module interruption (except for the acceptor domain deletion strains between modules 3 and 4, which also produced cyclic hexapeptides). In conclusion, deletion of the inter-module donor domains led to a more flexible hybrid biosynthetic system for the production of diverse peptide products; compared with the inter-subunit donor domain deletion strains that could only produce truncated peptides, the former had a greater biosynthetic capacity. Meanwhile, the acceptor domains between modules were an important part of module-module interactions and efficient communication within bacillomycin D synthetase.
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Treadmill exercise has been recognized as an effectively therapeutic strategy for Parkinson's disease (PD). However, its exact molecular mechanism of promoting PD remain unclear. Recently, the NLRP3 inflammasome is considered to play a critical role in the pathogenesis of PD. In this study, we investigated whether NLRP3 inflammasome was involved in treadmill exercise-induced neuroprotection and anti-inflammation effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. 8-week-old male mice (C57BL/6 strain) were divided into four groups: Control, MPTP, MPTP + EX and EX. MPTP was intraperitoneally injected into mice to establish chronic PD model. The open-field test and pole test were used to assess motor function. The results showed that treadmill exercise significantly alleviated motor dysfunction and dopaminergic neuron degeneration induced by MPTP. In addition, we also found that treadmill exercise suppressed MPTP-triggered microglia activation and the co-localization of NLRP3+/Iba-1+ cells in the substantia nigra. These effects were associated with suppression NLRP3 inflammasome via down-regulation of TLR4/MyD88/NF-κB pathway. Overall, our study demonstrated that treadmill exercise could effectively alleviates neuronal damage via inhibition of NLRP3 inflammasome and microglial activation in MPTP-induced PD mouse model.
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Inflamassomos/genética , Intoxicação por MPTP/patologia , Intoxicação por MPTP/terapia , Microglia/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neurônios/patologia , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/terapia , Condicionamento Físico Animal/fisiologia , Animais , Terapia por Exercício , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Substância Negra/patologia , Receptor 4 Toll-Like/efeitos dos fármacosRESUMO
S-palmitoylation is one of the most common post-translational modifications in nature; however, its importance has been overlooked for decades. Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), is an autoimmune disease characterized by chronic inflammation involving the entire gastrointestinal tract. Bowel damage and subsequent disabilities caused by CD are a growing global health issue. Well-acknowledged risk factors for CD include genetic susceptibility, environmental factors, such as a westernized lifestyle, and altered gut microbiota. However, the pathophysiological mechanisms of this disorder are not yet comprehensively understood. With the rapidly increasing global prevalence of CD and the evident role of S-palmitoylation in CD, as recently reported, there is a need to investigate the relationship between CD and S-palmitoylation. In this review, we summarize the concept, detection, and function of S-palmitoylation as well as its potential effects on CD, and provide novel insights into the pathogenesis and treatment of CD.
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Doença de Crohn , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Humanos , LipoilaçãoRESUMO
The autonomic nervous system has been studied for its involvement in the control of macrophages; however, the mechanisms underlying the interaction between the adrenergic receptors and alternatively activated macrophages (M2) remain obscure. Using FVB wild-type and beta 2 adrenergic receptors knockout, we found that ß2-AR deficiency alleviates hepatobiliary damage in mice infected with C. sinensis. Moreover, ß2-AR-deficient mice decrease the activation and infiltration of M2 macrophages and decrease the production of type 2 cytokines, which are associated with a significant decrease in liver fibrosis in infected mice. Our in vitro results on bone marrow-derived macrophages revealed that macrophages from Adrb2-/- mice significantly decrease M2 markers and the phosphorylation of ERK/mTORC1 induced by IL-4 compared to that observed in M2 macrophages from Adrb2+/+ . This study provides a better understanding of the mechanisms by which the ß2-AR enhances type 2 immune response through the ERK/mTORC1 signaling pathway in macrophages and their role in liver fibrosis.
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Clonorquíase/complicações , Cirrose Hepática Biliar/imunologia , Cirrose Hepática/imunologia , Ativação de Macrófagos , Neuroimunomodulação/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Ductos Biliares/parasitologia , Ductos Biliares/patologia , Células Cultivadas , Clonorquíase/imunologia , Clonorquíase/fisiopatologia , Citocinas/sangue , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Cirrose Hepática Biliar/etiologia , Cirrose Hepática Biliar/parasitologia , Cirrose Hepática Biliar/patologia , Sistema de Sinalização das MAP Quinases , Macrófagos/classificação , Macrófagos/imunologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Camundongos Knockout , Receptores Adrenérgicos beta 2/deficiência , Organismos Livres de Patógenos EspecíficosRESUMO
N6-methyladenosine (m6A) is the most abundant modification on eukaryotic mRNA, which regulates all steps of the mRNA life cycle. An increasing number of studies have shown that m6A methylation plays essential roles in tumor development. However, the relationship between m6A and the progression of cancers remains to be explored. Here, we reported that transforming growth factor-ß (TGFß1)-induced epithelial-mesenchymal transition (EMT) was inhibited in methyltransferase-like 3 (METTL3) knockdown (Mettl3Mut/-) cells. The expression of TGFß1 was up-regulated, while self-stimulated expression of TGFß1 was suppressed in Mettl3Mut/- cells. We further revealed that m6A promoted TGFB1 mRNA decay, but impaired TGFB1 translation progress. Besides this, the autocrine of TGFß1 was disrupted in Mettl3Mut/- cells via interrupting TGFß1 dimer formation. Lastly, we found that Snail, which was down-regulated in Mettl3Mut/- cells, was a key factor responding to TGFß1-induced EMT. Together, our research demonstrated that m6A performed multi-functional roles in TGFß1 expression and EMT modulation, suggesting the critical roles of m6A in cancer progression regulation.