RESUMO
Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.
Assuntos
Neoplasias , Linfócitos T , Humanos , Superantígenos/uso terapêutico , Antígenos de Neoplasias , Morte CelularRESUMO
Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%-20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10-30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.
RESUMO
Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (â¼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was â¼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.
Assuntos
Neoplasias , Linfócitos T , Camundongos , Animais , Neoplasias/metabolismo , Antígenos de NeoplasiasRESUMO
The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21â µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner inâ vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.
Assuntos
Antifúngicos/farmacologia , Cnidium/química , Cumarínicos/farmacologia , Frutas/química , Rhizoctonia/efeitos dos fármacos , Acetilcoenzima A/antagonistas & inibidores , Acetilcoenzima A/biossíntese , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Antifúngicos/química , Antifúngicos/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Ácidos Graxos/antagonistas & inibidores , Ácidos Graxos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rhizoctonia/crescimento & desenvolvimentoRESUMO
Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC50 value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi.
Assuntos
Trifosfato de Adenosina/metabolismo , Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Humulus/química , Peroxidação de Lipídeos/efeitos dos fármacos , Xantonas/farmacologia , Botrytis/crescimento & desenvolvimentoRESUMO
Despite the significant therapeutic advances in T-cell immunotherapy, many malignancies remain unresponsive, which might be because of the negative regulation of T cells by the tumor microenvironment (TME). T cells discriminate tumor cells and normal cells through T-cell receptors (TCRs); therefore, we generated a novel type of TCR-drug conjugates (TDCs) by referring antibody-drug conjugations (ADCs) to overcome the effects of the TME on T cells while preserving the specificity of TCR for tumor recognition. We selected HLA-A2/NY-ESO-1157-165 (peptide NY-ESO-1157-165 in complex with human leukocyte antigen serotype HLA-A*02:01) as the antigen and the antigen-specific TCR (1G4113) as the carrier. By sortase A-mediated ligation, we obtained three NY-TCR-vcMMAEs and further studied their properties, antitumor activity, and toxicity in vitro and in vivo. We found that all the NY-TCR-vcMMAEs had high endocytosis efficiency and specifically killed HLA-A2/NY-ESO-1157-165 positive tumor cells. In xenograft models, one of the TDCs, NY-TCR-2M, was effectively and specifically distributed into tumor tissues and inhibited tumor growth without inducing obvious toxicity. Our results demonstrated that TCRs can be carriers of toxic payloads and that the TDCs thus formed can specifically inhibit tumor growth, neglecting the immune microenvironment.
Assuntos
Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Proliferação de Células/efeitos dos fármacos , Imunoconjugados/farmacologia , Espaço Intracelular/efeitos dos fármacos , Proteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Humanos , Imunoconjugados/imunologia , Imunoconjugados/metabolismo , Imunoterapia , Espaço Intracelular/metabolismo , CamundongosRESUMO
Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 µg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 µg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 µg/mL and 3.48 µg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.
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Lignanas/farmacologia , Magnolia , Antifúngicos/farmacologia , Bioensaio , Compostos de BifeniloRESUMO
Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.
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Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas WT1/imunologia , Tumor de Wilms/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Antígenos HLA-A/imunologia , Humanos , Neoplasias Renais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Antígenos de Linfócitos T/imunologia , Tumor de Wilms/imunologiaRESUMO
OBJECTIVES: To investigate the effect of He-Ne laser therapy on wound healing after nail surgery. METHODS: Patients who needed nail surgery were divided into treatment group (n=20) and control group (n=20) randomly.The He-Ne laser was applied to the wound after nail surgery in treatment group. The wound healing time, the inflammation duration, the pain rating, and the nail plate full-grown time were compared with control group. RESULTS: No significant differences in baseline of two groups were observed. The wound healing time was (16.00±2.51) d in control group and (11.35±1.73 ) d in treatment group, the inflammation duration was (9.10±2.10) d in control group and (7.20±1.44) d in treatment group (P<0.05), both above differences were significant (P<0.05).The nail plate full-grown time was (21.00±2.13) weeks in treatment group, whereas (21.40±1.05) weeks in control group (P>0.05).The pain rating of the 2 groups was different from 25 h (after 3 times treatment)(P<0.05). Pain disappeared in 85.0% (17/20) patients of treatment group after 49 h (5 times treatment), and completely disappeared (20/20) after 54 h (6 times treatment), which were faster than those of control group at the same time points (pain disappeared only in 50.0% and 98.5% of patients respectively). CONCLUSIONS: He-Ne laser therapy can help wound healing after nail surgery.
Assuntos
Terapia a Laser , Terapia com Luz de Baixa Intensidade , Unhas/cirurgia , Cicatrização , Humanos , Dor , Manejo da DorRESUMO
Objective: To isolate the chemical constituents of ethyl acetate extract from Viola biflora. Methods: Isolation and purification were carried out on repeated silica gel column chromatography,PTLC,and Sephadex LH-20. The structures of these compounds were elucidated by physico-chemical properties and spectral analyses. Results: Twelve compounds were isolated from Viola biflora,which identified as aurantiamide acetate( 1),solalyratin B( 2),esculetin( 3),scopoletin( 4),lupeol( 5),132S-hydroxypheophytin a( 6),vomifoliol( 7),dibutyl phthalate( 8),(-)-dihydrovomifoliol( 9),grasshopper ketone( 10),crassifol( 11) and ß-sitosterol( 12). Conclusion: All the compounds are isolated from Viola biflora for the first time. Compounds 2,7,9 ~ 11 are isolated from Viola genus for the first time.
Assuntos
Escopoletina , Viola , Acetatos , Extratos Vegetais , SitosteroidesRESUMO
To investigate interference, and how to avoid it, by high-frequency electromagnetic fields (EMFs) of Global System for Mobile Communications (GSM) mobile phone with communication between cardiac rhythm management devices (CRMs) and programmers, a combined in vivo and in vitro testing was conducted. During in vivo testing, GSM mobile phones interfered with CRM-programmer communication in 33 of 65 subjects tested (50.8%). Losing ventricle sensing was representative in this study. In terms of clinical symptoms, only 4 subjects (0.6%) felt dizzy during testing. CRM-programmer communication recovered upon termination of mobile phone communication. During in vitro testing, electromagnetic interference by high-frequency (700-950 MHz) EMFs reproducibly occurred in duplicate testing in 18 of 20 CRMs (90%). During each interference, the pacing pulse signal on the programmer would suddenly disappear while the synchronous signal was normal on the amplifier-oscilloscope. Simulation analysis showed that interference by radiofrequency emitting devices with CRM-programmer communication may be attributed to factors including materials, excitation source distance, and implant depth. Results suggested that patients implanted with CRMs should not be restricted from using GSM mobile phones; however, CRMs should be kept away from high-frequency EMFs of GSM mobile phone during programming.
Assuntos
Telefone Celular , Campos Eletromagnéticos/efeitos adversos , Marca-Passo Artificial , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação , Simulação por Computador , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos TeóricosRESUMO
Chimeric antigen receptor T (CAR-T) cell therapy is a promising and precise targeted therapy for cancer that has demonstrated notable potential in clinical applications. However, severe adverse effects limit the clinical application of this therapy and are mainly caused by uncontrollable activation of CAR-T cells, including excessive immune response activation due to unregulated CAR-T cell action time, as well as toxicity resulting from improper spatial localization. Therefore, to enhance controllability and safety, a control module for CAR-T cells is proposed. Synthetic biology based on genetic engineering techniques is being used to construct artificial cells or organisms for specific purposes. This approach has been explored in recent years as a means of achieving controllability in CAR-T cell therapy. In this review, we summarize the recent advances in synthetic biology methods used to address the major adverse effects of CAR-T cell therapy in both the temporal and spatial dimensions.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/genética , Neoplasias/terapia , Terapia Baseada em Transplante de Células e TecidosRESUMO
OBJECTIVE: This study aimed to explore the clinical efficiency of an improved transosseous pullout suture technique for arthroscopic repair of a meniscus root tear. METHODS: From January 2017 to January 2021, 53 patients with posterior meniscus root tears combined with anterior cruciate ligament (ACL) and/or posterior cruciate ligament (PCL) tears were collected. Totally, in 29 patients (group A), the 2.0 mm modified pullout tunnel method was used to suture the posterior meniscus root, while 24 patients (group B) were treated with the traditional 4.5 mm pullout tunnel method. In group A, 20 patients had lateral meniscus posterior root (LMPR) combined with ACL tears, 5 patients had LMPR combined with ACL and PCL tears, and 4 patients had medial meniscus posterior root (MMPR) combined with ACL tears. In group B, 19 patients had LMPR combined with ACL tears, 3 patients had LMPR combined with ACL and PCL tears, and 2 patients had MMPR combined with ACL tears. The improvement of the Lysholm and VAS scores and the incidence of complications in group A and group B before the operation, 1 month and 3 months after the operation, and after the final follow-up were compared. RESULTS: Preoperative Lysholm score was 26.0±5.6 in group A and 26.7±5.8 in group B (P>0.05). One-month postoperative Lysholm score was 66.5±5.7 in group A and 54.3±2.4 in group B (P<0.001). Three-month postoperative Lysholm score was 81.1±7.2 in group A and 73.2±9.7 in group B (P<0.05). Lysholm scores after the final follow-up was 90.3±5.6 in group A and 90.0±5.0 in group B (P>0.05). Preoperative VAS score was 6.3±1.4 in group A and 6.3±1.2 in group B (P>0.05). One-month postoperative VAS score was 1.8±0.7 in group A and 2.4±0.9 in group B (P<0.05). Three-month postoperative VAS score was 0.7±0.6 in group A and 0.8±0.6 in group B (P>0.05). VAS score after the final follow-up was 0.2±0.4 in group A and 0.3±0.5 in group B (P>0.05). CONCLUSION: The improved transosseous pullout suture technique using a smaller 2.0 mm bone tunnel can virtually eliminate the risk of conflict with other bone tunnels and facilitate the management of bone tunnels in multiple ligament injuries, while also diminishing suture abrasion caused by the windshield wiper effect. The technique achieves good clinical efficacy.
Assuntos
Lesões do Ligamento Cruzado Anterior , Traumatismos do Joelho , Menisco , Lesões do Menisco Tibial , Humanos , Lesões do Ligamento Cruzado Anterior/cirurgia , Lesões do Menisco Tibial/cirurgia , Meniscos Tibiais/cirurgia , Traumatismos do Joelho/cirurgia , Menisco/cirurgia , Técnicas de SuturaRESUMO
BACKGROUND: Induction chemotherapy (IC) comprising docetaxel, cisplatin, and fluorouracil (TPF), combined with concurrent chemoradiotherapy (CCRT) effectively improves the survival rate of locally advanced nasopharyngeal carcinoma (LA-NPC). Selecting patients whose risk of tumor recurrence and metastasis is high and the appropriate chemotherapy intensity is a concern. We combined tumor-node-metastasis staging with the load of Epstein-Barr virus (EBV) after IC to select the individualized chemotherapy strength. METHODS: The clinical data and prognostic factors of patients with stage III-IV LA-NPC treated with TPF IC combined with CCRT were analyzed retrospectively. The conventional treatment group received the standard three cycles TPF IC combined with CCRT. For the new treatment group, the cycles of IC were determined according to whether the EBV-DNA disappeared completely after a certain course of IC, if so, subsequent IC was stopped and the chemoradiotherapy stage was entered. Propensity score matching (PSM) was performed at a ratio of 1:1 to balance baseline characteristics. Survival outcomes and adverse events between the conventional treatment group and the new method treatment group were compared. RESULTS: The study included 256 patients, among whom 192 were matched successfully into 96 pairs. The patients were followed up for a median of 51 months. The proportions of patients receiving three, two, and one cycle of IC after PSM in the routine and new treatment cohorts were 93.8%, 3.1%, 3.1% versus 21.9%, 49.0%, 24.0%, respectively. However, their 3-year distant metastasis-free survival, local recurrence-free survival, progression-free survival, and overall survival did not differ significantly. The incidence of grade 3-4 neutropenia toxicity in CCRT decreased significantly in patients receiving the new treatment method compared with that in the conventional treatment group (p = 0.026). CONCLUSION: Combining TNM stage and EBV-DNA load after IC to determine the courses of IC in patients with LA-NPC did not alter the curative effect but decreased toxicity.
Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Neutropenia , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Herpesvirus Humano 4/genética , Quimioterapia de Indução/efeitos adversos , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma/complicações , Neutropenia/etiologia , Quimiorradioterapia/métodos , DNA/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Epidemic diseases of crops caused by fungi deeply affected the course of human history and processed a major restriction on social and economic development. However, with the enormous misuse of existing antimicrobial drugs, an increasing number of fungi have developed serious resistance to them, making the diseases caused by pathogenic fungi even more challenging to control. Drug repurposing is an attractive alternative, it requires less time and investment in the drug development process than traditional R&D strategies. In this work, we screened 600 existing commercially available drugs, some of which had previously unknown activity against pathogenic fungi. From the primary screen at a fixed concentration of 100 µg/mL, 120, 162, 167, 85, 102, and 82 drugs were found to be effective against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Phytophthora capsici, Fusarium graminearum and Fusarium oxysporum, respectively. They were divided into nine groups lead compounds, including quinoline alkaloids, benzimidazoles/carbamate esters, azoles, isothiazoles, pyrimidines, pyridines, piperidines/piperazines, ionic liquids and miscellaneous group, and simple structure-activity relationship analysis was carried out. Comparison with fungicides to identify the most promising drugs or lead structures for the development of new antifungal agents in agriculture.
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Anti-Infecciosos , Fungicidas Industriais , Fusarium , Humanos , Fungicidas Industriais/química , Reposicionamento de Medicamentos , Antifúngicos/farmacologia , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologiaRESUMO
Phytopathogenic bacteria are a major cause of crop mortality and yield reduction, especially in field cultivation. The lack of effective chemistry agri-bactericides is responsible for challenging field prevention and treatment, prompting the development of long-lasting solutions to prevent, reduce, or manage some of the most devastating plant diseases facing modern agriculture today and in the future. Therefore, there is an urgent need to find lead drugs preventing and treating phytopathogenic bacterial infection. Drug repurposing, a strategy used to identify novel uses for existing approved drugs outside of their original indication, takes less time and investment than Traditional R&D Strategies in the process of drug development. Based on this method, we conduct a screen of 700 chemically diverse and potentially safe drugs against Xanthomonas oryzae PV. oryzae ACCC 11602 (Xoo), Xanthomonas axonopodis PV. citri (Xac), and Pectobacterium atrosepticum ACCC 19901 (Pa). Furthermore, the structure-activity relationship and structural similarity analysis of active drugs classify potent agri-bactericides into 8 lead series: salicylanilides, cationic nitrogen-containing drugs, azole antifungals, N-containing group, hydroxyquinolines, piperazine, kinase inhibitor and miscellaneous groups. MIC values were evaluated as antibacterial activities in this study. Identifying highly active lead compounds from the screening of approved drugs and comparison with the currently applied plant pathogenic bactericide to validate the bactericidal activity of the best candidates and assess if selected molecules or scaffolds lead to develop new antibacterial agents in the future. In conclusion, this study provides a possibility for the development of potent and highly selective agri-bactericides leads.
Assuntos
Infecções Bacterianas , Oryza , Xanthomonas , Testes de Sensibilidade Microbiana , Reposicionamento de Medicamentos , Antibacterianos/farmacologia , Antibacterianos/química , Doenças das Plantas/microbiologia , Oryza/microbiologiaRESUMO
Aspergillus flavus, a widespread saprotrophic filamentous fungus, could colonize agricultural crops with aflatoxin contamination, which endangers food security and the agricultural economy. A safe, effective and environmentally friendly fungicide is urgently needed. Pterostilbene, a natural phytoalexin originated from Pterocarpus indicus Willd., Vaccinium spp. and Vitis vinifera L., has been reported to possess excellent antimicrobial activity. More importantly, it is quite safe and healthy. In our screening tests of plant polyphenols for the inhibition of A. flavus, we found that pterostilbene evidently inhibited mycelial growth of Aspergillus flavus (EC50 = 15.94 µg/mL) and the inhibitory effect was better than that of natamycin (EC50 = 22.01 µg/mL), which is a natural product widely used in food preservation. Therefore, we provided insights into the efficacy of pterostilbene suppression on A. flavus growth, aflatoxin B1 biosynthesis and its potential mechanisms against A. flavus in the present study. Here, pterostilbene at concentrations of 250 and 500 µg/mL could effectively inhibit the infection of A. flavus on peanuts. And the biosynthesis of the secondary metabolite aflatoxin B1 was also inhibited. The antifungal effects of pterostilbene are exerted by inducing a large amount of intracellular reactive oxygen species production to bring the cells into a state of oxidative stress, damaging cellular biomolecules such as DNA, proteins and lipids and destroying the integrity of the cell membrane. Taken together, our study strongly supported the fact that pterostilbene could be considered a safe and effective antifungal agent against A. flavus infection.
Assuntos
Aflatoxinas , Aspergillus flavus , Aspergillus flavus/metabolismo , Aflatoxina B1 , Antifúngicos/farmacologia , Antifúngicos/metabolismoRESUMO
BACKGROUND: Chemical fungicides are the mainstay of plant disease control in agricultural production, but there are a very limited number of drugs that can effectively control plant diseases. Two series of secondary amine derivatives were synthesized using the diamine skeleton combined with saturated aromatic and aliphatic aldehydes, and their antibacterial and antifungal activities against plant pathogens were determined. In addition, the antimicrobial mechanism of the highly active compound A26 was preliminarily examined against Xanthomonas oryzae (Xoo). RESULTS: Compound A26 exhibited the highest antibacterial potency among all the target compounds, with MIC values of 3.12, 3.12 and 12.5 µg mL-1 against Xoo, Xanthomonas axonopodis pv. Citri and Pseudomonas sollamacearum, respectively. In addition, compound A26 had powerful curative and protective effects against Xoo at 200 µg mL-1 , and was better than the control agent Xinjunan. Preliminary mechanistic studies showed that compound A26 reduced the bacterial pathogenicity by targeting cell membranes and inhibiting the secretion of extracellular polysaccharides. Meanwhile, the toxicity of compound A26 to Human Embryonic Kidney 293 cells and Human Liver-7702 was similar to that of Xinjunan, and it had moderate toxicity according to the World Health Organization classification standard of oral exogenous toxicity, with an LD50 of 245.47 mg kg-1 . CONCLUSION: Secondary amines have efficient and broad-spectrum antibacterial activity against plant pathogenic bacteria and are expected to be a new class of candidate compounds for antibacterial drugs. © 2023 Society of Chemical Industry.
Assuntos
Oryza , Xanthomonas , Humanos , Testes de Sensibilidade Microbiana , Oxidiazóis/química , Antibacterianos/farmacologia , Antibacterianos/química , Poliaminas/farmacologia , Doenças das PlantasRESUMO
The inhibitory effect of tavaborole on the invasion of Botrytis cinerea in grapes and tomatoes, as well as the potential mechanism involved, was discovered in this study. Our findings showed that tavaborole inhibited Botrytis cinerea spore germination and mycelial expansion in vitro and that the control efficiency in vivo on fruit decay was dose-dependent, which was effective in reducing disease severity and maintaining the organoleptic quality of the fruit, such as reducing weight loss and retaining fruit hardness and titratable acid contents during storage. Furthermore, the precise mechanism of action was investigated further. Propidium iodide staining revealed that Botrytis cinerea treated with tavaborole lost membrane integrity. For further validation, cytoplasmic malondialdehyde accumulation and leakage of cytoplasmic constituents were determined. Notably, the inhibitory effect was also dependent on inhibiting the activities of aminoacyl-tRNA synthetases involved in the aminoacyl-tRNA biosynthesis pathway in Botrytis cinerea. The above findings concluded that tavaborole was effective against Botrytis cinerea infection in postharvest fruit, and a related mechanism was also discussed, which may provide references for the drug repurposing of tavaborole as a postharvest fungicide.