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1.
Mol Plant ; 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38946140

RESUMO

Over the past few decades, significant improvements in maize yield have been largely attributed to increased plant density of upright hybrid varieties rather than increased yield per plant. However, dense planting triggers shade avoidance responses (SAR) that optimize light absorption but impair plant vigor and performance, limiting yield improvement through increasing plant density. In this study, we demonstrated that high-density induced leaf angle narrowing and stem/stalk elongation are largely dependent on phytochrome B (phyB1/B2), the primary photoreceptor responsible for perceiving red (R) and far-red (FR) light in maize. Maize phyB physically interacts with the LIGULELESS1 (LG1), a classical key regulator of leaf angle, to coordinately regulate plant architecture and density tolerance. The abundance of LG1 is significantly increased by phyB under high R:FR light (low density) but rapidly decreases under low R:FR light (high density), correlating with variations in leaf angle and plant height under various densities. Additionally, we identified the homeobox transcription factor HB53 as a target co-repressed by both phyB and LG1 but rapidly induced by canopy shade, indicating its central role in response to varying densities. Notably, HB53 regulates plant architecture by controlling the elongation and division of ligular adaxial and abaxial cells. These findings uncover the phyB-LG1-HB53 regulatory module as a key molecular mechanism governing plant architecture and density tolerance, providing potential genetic targets for breeding maize hybrid varieties optimized for high-density planting.

2.
Chem Sci ; 15(27): 10499-10507, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38994430

RESUMO

Chirality plays an indispensable role in various biological processes, and interactions between chiral enantiomers and biomolecular targets provide new perspectives in precision drug development. While ferroptosis has received increasing attention as a novel pathway to reverse drug resistance, work on the design of precise ferroptosis-targeting molecules through chiral programming was limited. In this work, we designed and synthesized a pair of chirality-dependent ferroptosis-inducing Ir(iii)-phenylquinazolinone complexes (Δ-IrPPQ and Λ-IrPPQ) by inhibiting ferroptosis suppressor protein-1 (FSP1), while the pair of IrPPQ complexes induced extremely different ferroptosis effects as well as distinct photodynamic therapy (PDT) responses toward pancreatic cancer cells. Interestingly, this chirality-dependent biological mechanism through proteomic analysis and molecular simulation revealed that the specific binding and inhibition of metallothionein-1 (MT1) by Λ-IrPPQ sensitized cancer cells to ferroptosis, inducing a burst of reactive oxygen species, lipid peroxidation, glutathione depletion, and inactivation of FSP1. While in comparison, Δ-IrPPQ induced mild ferroptotic cell death. Through simple chiral resolution, the obtained Λ-IrPPQ achieved precise regulation of ferroptosis in pancreatic cancer cells. This work provides new insights into the design of chiral ferroptosis-inducing metallodrugs for future pancreatic cancer therapy.

3.
Front Plant Sci ; 15: 1406592, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006964

RESUMO

Artemisia argyi, a perennial herb of the genus Artemisia in the family Asteraceae, holds significant importance in Chinese traditional medicine, referred to as "Aicao". Here, we report a high-quality reference genome of Artemisia argyi L. cv. beiai, with a genome size up to 4.15 Gb and a contig N50 of 508.96 Kb, produced with third-generation Nanopore sequencing technology. We predicted 147,248 protein-coding genes, with approximately 68.86% of the assembled sequences comprising repetitive elements, primarily long terminal repeat retrotransposons(LTRs). Comparative genomics analysis shows that A. argyi has the highest number of specific gene families with 5121, and much more families with four or more members than the other 6 plant species, which is consistent with its more expanded gene families and fewer contracted gene families. Furthermore, through transcriptome sequencing of A. argyi in response to exogenous MeJA treatment, we have elucidated acquired regulatory insights into MeJA's impact on the phenylpropanoid, flavonoid, and terpenoid biosynthesis pathways of A. argyi. The whole-genome information obtained in this study serves as a valuable resource for delving deeper into the cultivation and molecular breeding of A. argyi. Moreover, it holds promise for enhancing genome assemblies across other members of the Asteraceae family. The identification of key genes establishes a solid groundwork for developing new varieties of Artemisia with elevated concentrations of active compounds.

4.
Discov Med ; 36(185): 1268-1279, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38926113

RESUMO

BACKGROUND: Tuberculosis (TB) stands as the second most prevalent infectious agent-related cause of death worldwide in 2022, trailing only COVID-19. With 1.13 million reported deaths, this figure is more than half of the mortality associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), which accounted for 0.63 million deaths. Diagnosing Mycobacterium tuberculosis (MTB) infection remains a formidable challenge due to the inability to isolate and detect MTB in sputum and within the human body. The absence of universally reliable diagnostic criteria for MTB infection globally poses a significant obstacle to preventing the progression of tuberculosis from the MTB infection stage. METHODS: In this study, our objective was to formulate a diagnostic biomarker cluster capable of discerning the progression of MTB infection and disease. This was achieved through a comprehensive joint multiomics analysis, encompassing transcriptome, proteome, and metabolome, conducted on lung tissue samples obtained from both normal control mice and those infected with MTB. RESULTS: A total of 1690 differentially expressed genes and 94 differentially expressed proteins were systematically screened. From this pool, 10 core genes were singled out. Additionally, eight long non-coding ribonucleic acids and eight metabolites linked to these core genes were identified to establish a cohesive cluster of biomarkers. This multiomics-based biomarker cluster demonstrated its capability to differentiate uninfected samples from MTB-infected samples effectively in both principle component analysis and the construction of a random forest model. CONCLUSION: The outcomes of our study strongly suggest that the multiomics-based biomarker cluster holds significant potential for enhancing the diagnosis of MTB infection.


Assuntos
Biomarcadores , Modelos Animais de Doenças , Mycobacterium tuberculosis , Tuberculose Pulmonar , Animais , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/metabolismo , Camundongos , Biomarcadores/metabolismo , Mycobacterium tuberculosis/genética , Transcriptoma , Humanos , Pulmão/microbiologia , Pulmão/patologia , Pulmão/metabolismo , Feminino , Metaboloma , Proteômica/métodos , Proteoma/metabolismo , Multiômica
5.
Plants (Basel) ; 13(6)2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38592849

RESUMO

Brassinosteroids (BRs) are involved in the regulation of biotic and abiotic stresses in plants. The molecular mechanisms of BRs that alleviate the drought stress in quinoa have rarely been reported. Here, quinoa seedlings were treated with 24-epibrassinolide (EBR) and we transiently transferred CqBIN2 to the quinoa seedlings' leaves using VIGS technology to analyze the molecular mechanism of the BR mitigation drought stress. The results showed that EBR treatment significantly increased the root growth parameters, the antioxidant enzyme activities, and the osmolyte content, resulting in a decrease in the H2O2, O2∙-, and malondialdehyde content in quinoa. A transcriptome analysis identified 8124, 2761, and 5448 differentially expressed genes (DEGs) among CK and Drought, CK and EBR + Drought, and Drought and EBR + Drought groups. WGCNA divided these DEGs into 19 modules in which these characterized genes collectively contributed significantly to drought stress. In addition, the EBR application also up-regulated the transcript levels of CqBIN2 and proline biosynthesis genes. Silenced CqBIN2 by VIGS could reduce the drought tolerance, survival rate, and proline content in quinoa seedlings. These findings not only revealed that exogenous BRs enhance drought tolerance, but also provided insight into the novel functions of CqBIN2 involved in regulating drought tolerance in plants.

6.
Redox Biol ; 72: 103115, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38554522

RESUMO

BACKGROUND: Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. METHODS: Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. RESULTS: An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. CONCLUSION: The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.


Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Displasia Broncopulmonar , Hiperóxia , Succinatos , Succinatos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Ratos , Humanos , Hiperóxia/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Ciclo do Ácido Cítrico/efeitos dos fármacos , Feminino , Mitofagia/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Recém-Nascido
7.
Angew Chem Int Ed Engl ; 63(15): e202400829, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38349715

RESUMO

Due to multidrug resistance and the high risk of recurrence, effective and less toxic alternative pancreatic cancer treatments are urgently needed. Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis. In this study, an innovative nanoplatform (AsIr@PDA) was developed by electrostatic adsorption of a cationic iridium complex (IrFN) onto two-dimensional (2D) arsenene nanosheets. This nanoplatform exhibits superior ferroptosis-inducing effects with high drug loading capacity and, importantly, excellent anti-cancer immune activation function, leading to efficient elimination of pancreatic tumors with no observable side effects. Interestingly, AsIr@PDA significantly prevents the recurrence of pancreatic cancer in vivo when compared with a cisplatin-loaded nanoplatform. This designed nanoplatform demonstrated superior therapeutic efficacy by synergistic ferroptosis-induced chemotherapy with immunotherapy via an all-in-one strategy, providing new insights for future pancreatic cancer therapy.


Assuntos
Ferroptose , Neoplasias Pancreáticas , Humanos , Irídio , Neoplasias Pancreáticas/tratamento farmacológico , Imunoterapia , Adsorção , Linhagem Celular Tumoral
8.
Early Hum Dev ; 190: 105950, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301336

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of premature birth, exerts considerable impact on the respiratory health of infants. This study aimed to identify the role of plasma metabolites in predicting respiratory outcomes in BPD-afflicted infants. METHODS: This was a case-control study including 15 BPD premature infants and 15 gestational age and birth weight matched no-BPD preterm infants. Plasma samples, obtained at 36 weeks postmenstrual age (PMA), were subjected to a comprehensive analysis of over 300 metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The respiratory outcomes of the infants were collected with the first 2 years of corrected postnatal age. RESULTS: The analysis revealed a significant upregulation of urea and downregulation of nine metabolites in BPD infants, including oxalacetic acid, cis-aconitic acid, itaconic acid, betaine, L-asparagine, L-alanine, picolinic acid, inositol, and purine (p < 0.05). These metabolites primarily pertained to the citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. Furthermore, seven metabolites demonstrated substantial predictive capacity for respiratory readmissions within the first two years of corrected postnatal age, achieving an area under curve (AUC) exceeding or equal to 0.8. These included chenodeoxycholic acid, dehydrolithocholic acid, glucaric acid, D-glucuronic acid, gamma-glutamylvaline, mevalonic acid, and 3-ureidopropionic acid. CONCLUSIONS: This study identified ten distinct plasma metabolites at 36 weeks PMA that differentiate BPD infants from their non-BPD counterparts, implicating three major metabolic pathways. Additionally, seven metabolites showed strong predictive value for heightened risk of respiratory readmission within two years, underscoring their potential utility in clinical prognostication and management strategies for BPD.


Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Lactente , Feminino , Gravidez , Recém-Nascido , Humanos , Displasia Broncopulmonar/etiologia , Estudos de Casos e Controles , Cromatografia Líquida , Espectrometria de Massas em Tandem , Idade Gestacional
9.
J Neurochem ; 168(2): 142-160, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38169121

RESUMO

White matter injury (WMI) is one of the most serious complications associated with preterm births. Damage to oligodendrocytes, which are the key cells involved in WMI pathogenesis, can directly lead to myelin abnormalities. L-ascorbyl-2-phosphate (AS-2P) is a stable form of vitamin C. This study aimed to explore the protective effects of AS-2P against chronic hypoxia-induced WMI, and elucidate the underlying mechanisms. An in vivo chronic hypoxia model and in vitro oxygen-glucose deprivation (OGD) model were established to explore the effects of AS-2P on WMI using immunofluorescence, immunohistochemistry, western blotting, real-time quantitative polymerase chain reaction, Morris water maze test, novel object recognition test, beaming-walking test, electron microscopy, and flow cytometry. The results showed that AS-2P resulted in the increased expression of MBP, Olig2, PDGFRα and CC1, improved thickness and density of the myelin sheath, and reduced TNF-α expression and microglial cell infiltration to alleviate inflammation in the brain after chronic hypoxia. Moreover, AS-2P improved the memory, learning and motor abilities of the mice with WMI. These protective effects of AS-2P may involve the upregulation of protein arginine methyltransferase 5 (PRMT5) and downregulation of P53 and NF-κB. In conclusion, our study demonstrated that AS-2P attenuated chronic hypoxia-induced WMI in vivo and OGD-induced oligodendrocyte injury in vitro possibly by regulating the PRMT5/P53/NF-κB pathway, suggesting that AS-2P may be a potential therapeutic option for WMI.


Assuntos
Lesões Encefálicas , Substância Branca , Animais , Camundongos , NF-kappa B/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais Recém-Nascidos , Substância Branca/patologia , Hipóxia/metabolismo , Lesões Encefálicas/patologia , Ácido Ascórbico/metabolismo , Oxigênio/metabolismo
10.
J Med Virol ; 95(10): e29140, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37800627

RESUMO

The epidemic of Mpox virus (MPXV) from May 2022 was once declared as a Public Health Emergency of International Concern by the World Health Organization. Vaccines play an important role in prevention of infectious diseases, and mRNA vaccine technology was proved to be a safe and effective platform with successful application in defense of coronavirus disease 2019. In this study, based on A29L, M1R, A35R, and B6R of MPXV, we developed two MPXV mRNA vaccine candidates, designated as MPXfus and MPXmix. The MPXfus was one-component, in which these four antigen proteins were linked in tandem by flexible linker and encoded by an individual mRNA as a fusion protein. The MPXmix was multicomponent containing four mRNA, and each mRNA encoded one antigen protein respectively. Mice were immunized with equal quality of MPXfus or MPXmix, delivered by lipid nanoparticles for evaluation and comparison of the immune responses induced by these two MPXV vaccine candidates. Results of immune response analyses indicated that both MPXfus and MPXmix could elicit high-level of antigen-specific antibodies and robust cellular immune response in mice. Moreover, results of virus neutralization assays suggested that sera from MPXfus- or MPXmix-immunized mice possessed high neutralizing activities against vaccinia virus. In addition, titers of antigen-specific antibody, levels of cellular immune response, and activities of neutralizing antibody against vaccinia virus induced by MPXfus and MPXmix presented no significant difference. In summary, this study provides valuable insights for further clinical development of one-component and multicomponent mRNA vaccine candidates for the prevention of MPXV and other orthomyxoviruses.


Assuntos
Mpox , Animais , Camundongos , Anticorpos Neutralizantes , Vaccinia virus/genética , Imunidade Celular , RNA Mensageiro/genética , Anticorpos Antivirais
11.
FASEB J ; 37(12): e23278, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37902573

RESUMO

Obesity is a major health concern that lacks effective intervention strategies. Traumatic acid (TA) is a potent wound-healing agent in plants, considered an antioxidant food ingredient. This study demonstrated that TA treatment significantly reduced lipid accumulation in human adipocytes and prevented high-fat diet induced obesity in zebrafish. Transcriptome sequencing revealed TA-activated fatty acid (FA) degradation and FA metabolism signaling pathways. Moreover, western blotting and quantitative polymerase chain reaction showed that TA inhibited the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Overexpression of ACSL4 resulted in the reversal of TA beneficiary effects, indicating that the attenuated lipid accumulation of TA was regulated by ACSL4 expression. Limited proteolysis-mass spectrometry and microscale thermophoresis were then used to confirm hexokinase 2 (HK2) as a direct molecular target of TA. Thus, we demonstrated the molecular basis of TA in regulating lipid accumulation and gave the first evidence that TA may function through the HK2-ACSL4 axis.


Assuntos
Dieta Hiperlipídica , Peixe-Zebra , Humanos , Animais , Dieta Hiperlipídica/efeitos adversos , Adipócitos , Obesidade/etiologia , Lipídeos
13.
Vaccines (Basel) ; 11(9)2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37766097

RESUMO

With no specific antiviral drugs and preventive vaccines against Mpox virus (MPXV), the epidemic has led to the declaration of a Public Health Emergency of International Concern. As a developmental direction for new vaccines, studies of subunit vaccines based upon MPXV antigen proteins are lacking. In this study, A29L, M1R, A35R, and B6R of MPXV were expressed and purified from a prokaryotic system. The four MPXV antigen proteins in combination were mixed with aluminum hydroxide or CpG7909 as adjuvant, and subsequently used to inoculate mice. The results of enzyme-linked immunosorbent assay (ELISA), flow cytometry analyses, and enzyme-linked immunospot (ELISPOT) assays indicated that A29L, M1R, A35R, and B6R elicited high-level antigen-specific antibodies and CD4+ T cells-based cellular immune response in mice. Moreover, the results of virus neutralization assays suggested that sera from the mice immunized with four proteins elicited high neutralizing activities against the vaccinia virus. Notably, the results of ELISA, ELISPOT, and virus neutralization assays also showed that the CpG7909 adjuvant was more effective in inducing an immune response compared with the aluminum adjuvant. In summary, this study offers valuable insights for further studies of subunit vaccine candidates for the prevention of MPXV and other orthomyxoviruses.

14.
Front Microbiol ; 14: 1203355, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37547674

RESUMO

Monkeypox (mpox) is a zoonotic infectious disease caused by the mpox virus. Mpox symptoms are similar to smallpox with less severity and lower mortality. As yet mpox virus is not characterized by as high transmissibility as some severe acute respiratory syndrome 2 (SARS-CoV-2) variants, still, it is spreading, especially among men who have sex with men (MSM). Thus, taking preventive measures, such as vaccination, is highly recommended. While the smallpox vaccine has demonstrated considerable efficacy against the mpox virus due to the antigenic similarities, the development of a universal anti-mpox vaccine remains a necessary pursuit. Recently, nucleic acid vaccines have garnered special attention owing to their numerous advantages compared to traditional vaccines. Importantly, DNA vaccines have certain advantages over mRNA vaccines. In this study, a potentially universal DNA vaccine candidate against mpox based on conserved epitopes was designed and its efficacy was evaluated via an immunoinformatics approach. The vaccine candidate demonstrated potent humoral and cellular immune responses in silico, indicating the potential efficacy in vivo and the need for further research.

15.
Early Hum Dev ; 184: 105833, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37523802

RESUMO

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disorder occurring in newborns, with a mortality rate ranging from 20 % to 30 %. The existing therapeutic approaches for NEC are limited in their effectiveness. Various factors contribute to the development of NEC, including disruption of barrier function, dysregulation of the intestinal immune system, and abnormal colonization of the intestinal microbiota. Researchers have shown considerable interest in exploring the therapeutic potential of the constituents present in human breast milk (HBM) for treating NEC. HBM contains numerous bioactive components, such as exosomes, growth factors, and oligosaccharides. However, the precise mechanisms by which HBM exerts its protective effects against NEC remain incompletely understood. In this study, our objective was to comprehensively review the bioactive substances present in HBM, aiming to facilitate the development of novel therapeutic strategies for NEC.


Assuntos
Enterocolite Necrosante , Microbioma Gastrointestinal , Doenças do Recém-Nascido , Feminino , Recém-Nascido , Humanos , Leite Humano , Doenças do Recém-Nascido/metabolismo
16.
Eur J Med Res ; 28(1): 198, 2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37370148

RESUMO

BACKGROUND: Urinary pan-cancer system is a general term for tumors of the urinary system including renal cell carcinoma (RCC), prostate cancer (PRAD), and bladder cancer (BLCA). Their location, physiological functions, and metabolism are closely related, making the occurrence and outcome of these tumors highly similar. Cuproptosis is a new type of cell death that is different from apoptosis and plays an essential role in tumors. Therefore, it is necessary to study the molecular mechanism of cuproptosis-related lncRNAs to urinary system pan-cancer for the prognosis, clinical diagnosis, and treatment of urinary tumors. METHOD: In our study, we identified 35 co-expression cuproptosis-related lncRNAs (CRLs) from the urinary pan-cancer system. 28 CRLs were identified as prognostic-related CRLs by univariate Cox regression analysis. Then 12 CRLs were obtained using lasso regression and multivariate cox analysis to construct a prognostic model. We divided patients into high- and low-risk groups based on the median risk scores. Next, Kaplan-Meier analysis, principal component analysis (PCA), functional rich annotations, and nomogram were used to compare the differences between the high- and low-risk groups. Finally, the prediction of tumor immune dysfunction and rejection, gene mutation, and drug sensitivity were discussed. CONCLUSION: Finally, the candidate molecules of the urinary system pan-cancer were identified. This CRLs risk model may be promising for clinical prediction of prognosis and immunotherapy response in urinary system pan-cancer patients.


Assuntos
Neoplasias Renais , RNA Longo não Codificante , Masculino , Humanos , RNA Longo não Codificante/genética , Prognóstico , Imunoterapia , Nomogramas , Apoptose
17.
Biochem Biophys Res Commun ; 668: 55-61, 2023 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-37244035

RESUMO

Despite advancements in medical research, androgenetic alopecia (AGA) remains a humankind problem that still needs to be overcome. To date, clinical practice lacks an ideal treatment for AGA. The Wnt/ß-catenin signaling pathway is evidenced to play a key role in hair regrowth, hence, modulating this signaling pathway for AGA therapy appears to be rational. One of the major inhibitors of the canonical Wnt/ß-catenin signaling pathway is dickkopf-related protein 1 (DKK1). In this report, we have selected a small interfering RNA (siRNA) targeting DKK1 in vitro via qPCR and then tested its efficacy in vivo on the depilated dorsal skin of the mice. The changes in hair growth in different groups were observed over time. Moreover, the visual observation of the hair growth and hematoxylin and eosin (HE) staining showed that DKK1-targeting siRNA reveals non-inferior results compared with the mice treated with the Food and Drug Administration (FDA)-approved, commercially available minoxidil (5%) topical solution that was used as a positive control. Both- positive control and DKK1-targeting siRNA groups demonstrated significantly superior results compared with the control group that received negative control siRNA. Consequently, siRNAs targeting DKK1 may promote hair growth regulation in the AGA population via potentially activating the Wnt/ß-catenin signaling pathway.


Assuntos
Cabelo , Proteínas Wnt , Camundongos , Animais , RNA Interferente Pequeno/genética , Cabelo/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Alopecia/genética , Alopecia/terapia , Alopecia/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/genética , beta Catenina/metabolismo
18.
NPJ Vaccines ; 8(1): 76, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37231060

RESUMO

Pseudomonas aeruginosa (PA) is a leading cause of hospital-acquired and ventilator-associated pneumonia. The multidrug-resistance (MDR) rate of PA is increasing making the management of PA a global challenge. Messenger RNA (mRNA) vaccines represent the most promising alternative to conventional vaccines and are widely studied for viral infection and cancer immunotherapy while rarely studied for bacterial infections. In this study, two mRNA vaccines encoding PcrV- the key component of the type III secretion system in Pseudomonas and the fusion protein OprF-I comprising outer membrane proteins OprF and OprI were constructed. The mice were immunized with either one of these mRNA vaccines or with the combination of both. Additionally, mice were vaccinated with PcrV, OprF, or the combination of these two proteins. Immunization with either mRNA-PcrV or mRNA-OprF-I elicited a Th1/Th2 mixed or slighted Th1-biased immune response, conferred broad protection, and reduced bacterial burden and inflammation in burn and systemic infection models. mRNA-PcrV induced significantly stronger antigen-specific humoral and cellular immune responses and higher survival rate compared with the OprF-I after challenging with all the PA strains tested. The combined mRNA vaccine demonstrated the best survival rate. Moreover, the mRNA vaccines showed the superiority over protein vaccines. These results suggest that mRNA-PcrV as well as the mixture of mRNA-PcrV and mRNA-OprF-I are promising vaccine candidates for the prevention of PA infection.

19.
Transl Pediatr ; 12(1): 46-55, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36798938

RESUMO

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in preterm infants and lacks effective treatment. We aim to reveal the relationship between amniotic fluid (AF) peptides and lung development by analyzing the differences in the composition of AF peptides at different gestational periods, thus providing a new means of prevention and treatment for BPD. Methods: Based on the stages of lung development, we collected AF by amniocentesis in two different gestational periods, using the 25th week of pregnancy as the cut-off. We conducted a peptide omics analysis of these AF samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Additionally, we verified the regulatory effects of hyperoxia and the peptide COL5A2 on BPD-related cells [(mouse lung epithelial (MLE-12) cells] by 5-Ethynyl-2'-deoxyuridine (EdU) staining, JC-1 staining, flow cytometry, and reactive oxygen species (ROS) assay. Results: There were 131 differentially expressed peptides, including 85 up-regulated and 46 down-regulated [fold change (FC) ≥1.2 or ≤1/1.2, P<0.05], in the ≥25 weeks' gestation group compared to the <25 weeks' gestation group. Further bioinformatics analysis revealed that the precursor proteins of the differentially expressed peptides between these two groups were involved in the regulation of the developmental process, anatomical structure development, and other biological processes, suggesting that these differential peptides may play a key role in lung development. We found peptide COL5A2 with the sequence GPPGEPGPPG and verified the regulatory effects of COL5A2 on the proliferation, apoptosis, cell viability, and ROS levels of MLE-12 cells by cell assays. Conclusions: In this study, peptidomic studies using AF from different gestational periods revealed that peptides in AF may be involved in lung development. They could be used in the future to assist in the postnatal development of preterm infants and provide new therapeutic prospects for BPD.

20.
Chem Commun (Camb) ; 59(13): 1797-1800, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36722411

RESUMO

The spike protein of SARS-CoV-2 has been widely used as an effective vaccine immunogen, although some limitations still remain. Herein, O-GalNAc glycosylated RBD (Tn-RBD) was synthesized as an antigen via in vitro glycosylation reactions. The inhibition ability against hACE2 binding of antibodies induced with Tn-RBD was 30-40% increased compared to that induced with RBD. This result implies that Tn-glycosylation might play important roles in the immunogenicity of the RBD protein, which should be considered in the design of novel vaccines to fight against COVID-19.


Assuntos
COVID-19 , Vacinas Virais , Humanos , Glicoproteína da Espícula de Coronavírus/química , SARS-CoV-2 , Anticorpos Antivirais , Glicosilação
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