RESUMEN

Many key aspects of retinal ganglion cell (RGC) neurodegeneration in glaucoma are associated with mitochondrial dysfunction. Understanding the mechanisms and relationships between structural and functional changes in mitochondria would be beneficial for developing mitochondria-targeted therapeutic strategies to protect RGCs from glaucomatous neurodegeneration. PURPOSE: This study determines the extent of mitochondrial dysfunction in patients with primary open-angle glaucoma (POAG) and evaluates the potential for stabilizing the glaucomatous process by improving mitochondrial functional activity and energy production by therapy with Mexidol and Mexidol FORTE 250. MATERIAL AND METHODS: The study included 80 patients with moderate POAG with compensated intraocular pressure and 20 healthy volunteers. The extent of mitochondrial dysfunction was assessed by measuring the activity levels of mitochondrial enzymes: succinate dehydrogenase (SDH) and α-glycerophosphate dehydrogenase (α-GPDH) in peripheral blood lymphocytes using cytochemical analysis and cytometric morphology and density analysis (cytomorphodensitometry). Patients in the main group received sequential therapy with Mexidol as follows: Mexidol solution for intravenous and intramuscular administration at 50 mg/ml, 300 mg daily intramuscularly for 14 days, followed by Mexidol FORTE 250 tablets, one tablet three times daily for 56 days. Stabilization of glaucomatous optic neuropathy during treatment was evaluated using a comprehensive set of perimetric, electrophysiological, and structural-topographical methods at 14, 56, and 90 days. RESULTS: Sequential therapy in the main group resulted in a significant increase in mitochondrial enzyme activity at 14 and 56 days compared to baseline, with a gradual regression by the end of the observation period (90 days). This was accompanied by an increase in the number of mitochondria and an increase in their optical density as measured by cytomorphodensitometry. The improvement in mitochondrial enzyme activity at 14 and 56 days was associated with positive changes in the structural and functional parameters of the retina, as evidenced by static perimetry, optical coherence tomography, and a series of electrophysiological tests. CONCLUSION: The obtained data can be used to optimize POAG therapy by reducing mitochondrial dysfunction and stabilizing glaucomatous optic neuropathy.

Asunto(s)

Glaucoma de Ángulo Abierto , Mitocondrias , Picolinas , Humanos , Masculino , Glaucoma de Ángulo Abierto/fisiopatología , Glaucoma de Ángulo Abierto/metabolismo , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Persona de Mediana Edad , Femenino , Mitocondrias/metabolismo , Picolinas/administración & dosificación , Presión Intraocular/fisiología , Presión Intraocular/efectos de los fármacos , Células Ganglionares de la Retina/patología , Resultado del Tratamiento , Antioxidantes/administración & dosificación , Succinato Deshidrogenasa/metabolismo , Anciano

RESUMEN

Dollar spot, a highly destructive turfgrasses disease worldwide, is caused by multiple species within the genus Clarireedia. Previous research indicated varying sensitivity to boscalid among Clarireedia populations not historically exposed to succinate dehydrogenase inhibitors (SDHIs). This study confirms that the differential sensitivity pattern is inherent among different Clarireedia spp., utilizing a combination of phylogenetic analyses, in vitro cross-resistance assays, and genetic transformation of target genes with different mutations. Furthermore, greenhouse inoculation experiments revealed that the differential boscalid sensitivity did not lead to pathogenicity issues or fitness penalties, thereby not resulting in control failure by boscalid. This research underscores the importance of continuous monitoring of fungicide sensitivity trends and highlights the complexity of chemical control of dollar spot due to the inherent variability in fungicide sensitivity among different Clarireedia spp.

Asunto(s)

Compuestos de Bifenilo , Fungicidas Industriales , Niacinamida , Enfermedades de las Plantas , Fungicidas Industriales/farmacología , Compuestos de Bifenilo/farmacología , Enfermedades de las Plantas/microbiología , Niacinamida/análogos & derivados , Niacinamida/farmacología , Poaceae/microbiología , Filogenia , Farmacorresistencia Fúngica/genética , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Basidiomycota/genética , Basidiomycota/efectos de los fármacos

RESUMEN

Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.

Asunto(s)

Respiración de la Célula , Ratones Noqueados , Contracción Muscular , Músculo Esquelético , Enfisema Pulmonar , Succinato Deshidrogenasa , Animales , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/patología , Enfisema Pulmonar/etiología , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/genética , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Complejo II de Transporte de Electrones/metabolismo , Complejo II de Transporte de Electrones/genética , Modelos Animales de Enfermedad , Ratones Transgénicos , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Consumo de Oxígeno

RESUMEN

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N-(2-(((5-chlorobenzo[d]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-yrazole-4-carboxamide, with EC50 values against four kinds of fungi tested below 10 µg/mL and against Cercospora arachidicola even below 2 µg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kühn, respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana. Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

Asunto(s)

Inhibidores Enzimáticos , Fungicidas Industriales , Pirazoles , Succinato Deshidrogenasa , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Rhizoctonia/efectos de los fármacos , Rhizoctonia/crecimiento & desarrollo , Simulación del Acoplamiento Molecular , Benzotiazoles/química , Benzotiazoles/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química , Ascomicetos/efectos de los fármacos , Ascomicetos/enzimología , Estructura Molecular

RESUMEN

Objective:To explore the gene expression characteristics of endothelial cells and fibroblasts in the microenvironment of SDHD-mutated carotid body tumors（SDHD-CBT）, to fine the functional enrichment of each subcluster, and to further explore the network of cell-cell interactions in the microenvironment of SDHD-CBT. Methods:The bioinformatics analysis was used to download and reanalyze the single-nuclear RNA sequencing data of SDHD-CBT, SDHB mutated thoracic and abdominal paraganglioma（SDHB-ATPGL）, SDHB-CBT, and normal adrenal medulla（NAM）, to clarify the information of cell populations of the samples. We focused on exploring the gene expression profiles of endothelial cells and fibroblasts subclusters, and performed functional enrichment analysis based on Gene Ontology（GO） resources. CellChat was used to compare the cell-cell interactions networks of different clinical samples and predict significant signaling pathways in SDHD-CBT. Results:A total of 7 cell populations were profiled. The main subtypes of endothelial cells in SDHD-CBT are arterial and venous endothelial cells, and the main subtypes of fibroblasts are myofibroblasts and pericytes. Compared to NAM, SDHB-CBT and SDHB-ATPGL, cell communication involving endothelial cells and fibroblasts in SDHD-CBT is more abundant, with significant enrichment in pathways such as FGF, PTN, WNT, PROS, PERIOSTIN, and TGFb. Conclusion:Endothelial cells and fibroblasts in SDHD-CBT are heterogeneous and involved in important cellular interactionprocesses, in which the discovery of FGF，PTN，WNT，PROS，PERIOSTIN and TGFb signals may play an important role in the regulation of microenvironment of SDHD-CBT.

Asunto(s)

Células Endoteliales , Fibroblastos , Microambiente Tumoral , Humanos , Células Endoteliales/metabolismo , Fibroblastos/metabolismo , Tumor del Cuerpo Carotídeo/metabolismo , Tumor del Cuerpo Carotídeo/genética , Tumor del Cuerpo Carotídeo/patología , Transducción de Señal , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/genética , Biología Computacional/métodos , Paraganglioma/genética , Paraganglioma/patología , Paraganglioma/metabolismo , Comunicación Celular , Mutación , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética

RESUMEN

Understanding the stereoselective bioactivity of chiral pesticides is crucial for accurately evaluating their effectiveness and optimizing their use. Isopyrazam, a widely used chiral SDHI fungicide, has been studied for its antifungal activity only at the racemic level. Therefore, to clarify the highly bioactive isomers, the stereoselective bioactivity of isopyrazam isomers against four typical phytopathogens was studied for the first time. The bioactivity ranking of the isomers was trans-1S,4R,9R-(+)-isopyrazam > cis-1R,4S,9R-(+)-isopyrazam > trans-1R,4S,9S-(-)-isopyrazam > cis-1S,4R,9S-(-)-isopyrazam. SDH activity was assessed by molecular docking simulation and actual detection to confirm the reasons for stereoselective bioactivity. The results suggest that the stereoselective bioactivity of isopyrazam is largely dependent on the differential binding ability of each isomer to the SDH ubiquitin-binding site, located within a cavity formed by the iron-sulfur subunit, the cytochrome b560 subunit, and the cytochrome b small subunit. Moreover, to reveal the molecular mechanism of isopyrazam stereoselectively affecting mycelial growth, the contents of succinic acid, fumaric acid, and ATP were measured. Furthermore, by measuring exospore polysaccharides and oxalic acid content, it was determined that 1S,4R,9R-(+)- and 1R,4S,9R-(+)-isopyrazam more strongly inhibited the ability of Sclerotinia sclerotiorum to infect plants. The findings provided essential data for the development of high-efficiency isopyrazam fungicides and offered a methodological reference for analyzing the enantioselective activity mechanism of SDHI fungicides.

Asunto(s)

Ascomicetos , Fungicidas Industriales , Simulación del Acoplamiento Molecular , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Estereoisomerismo , Ascomicetos/efectos de los fármacos , Ascomicetos/crecimiento & desarrollo , Ascomicetos/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/química , Piridinas/química , Piridinas/farmacología , Relación Estructura-Actividad , Enfermedades de las Plantas/microbiología , Norbornanos , Pirazoles

RESUMEN

Genetic testing is recommended for all patients with pheochromocytomas and paragangliomas (PPGL) to establish genotype-phenotype associations. We investigated germline mutations in 59 patients with PPGL at six Korean university hospitals using next-generation sequencing (NGS) targeting 38 PPGL-associated genes, including those recommended by the Korean PPGL Task Force. Germline mutations were identified in 13 patients (22%), and affected four genes: RET, NF1, VHL, and SDHD. Germline mutations were significantly associated with a family history of PPGL, smaller tumor size, and the presence of other types of tumors. Using 95 Korean PPGL cases with germline mutations identified through a literature review and 13 cases from our cohort, we characterized genotype-phenotype correlations. Mutation hotspots were identified in specific codons of RET (codons 631 and 634), VHL (157 and 167), and SDHB (131 and 253). NF1 mutations varied, indicating the absence of common hotspots. These findings highlight the efficacy of the recommended NGS panel for Korean patients with PPGL and the importance of genetic testing in establishing clinical management and personalized therapeutic strategies.

Asunto(s)

Neoplasias de las Glándulas Suprarrenales , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Paraganglioma , Feocromocitoma , Proteínas Proto-Oncogénicas c-ret , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Humanos , Feocromocitoma/genética , Feocromocitoma/patología , Paraganglioma/genética , Paraganglioma/patología , República de Corea , Adulto , Femenino , Masculino , Persona de Mediana Edad , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Proteínas Proto-Oncogénicas c-ret/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Pueblo Asiatico/genética , Succinato Deshidrogenasa/genética , Fenotipo , Estudios de Asociación Genética , Neurofibromina 1/genética , Adolescente , Adulto Joven , Pruebas Genéticas , Anciano

RESUMEN

This study aimed to evaluate the effects of Euryale ferox Seed Shell Polyphenol Extract (EFSSPE) on a foodborne pathogenic bacterium. EFSSPE showed antimicrobial activity toward Salmonella Typhimurium CICC 22956; the minimum inhibitory concentration of EFSSPE was 1.25 mg/mL, the inhibition curve also reflected the inhibitory effect of EFSSPE on the growth of S. Typhimurium. Detection of alkaline phosphatase outside the cell revealed that EFSSPE treatment damaged the cell wall integrity of S. Typhimurium. EFSSPE also altered the membrane integrity, thereby causing leaching of 260-nm-absorbing material (bacterial proteins and DNA). Moreover, the activities of succinate dehydrogenase and malate dehydrogenase were inhibited by EFSSPE. The hydrophobicity and clustering ability of cells were affected by EFSSPE. Scanning electron microscopy showed that EFSSPE treatment damaged the morphology of the tested bacteria. These results indicate that EFSSPE can destroy the cell wall integrity and alter the permeability of the cell membrane of S. Typhimurium.

Asunto(s)

Antibacterianos , Pruebas de Sensibilidad Microbiana , Extractos Vegetales , Polifenoles , Salmonella typhimurium , Semillas , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Extractos Vegetales/farmacología , Antibacterianos/farmacología , Semillas/química , Polifenoles/farmacología , Pared Celular/efectos de los fármacos , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidores , Microscopía Electrónica de Rastreo , Malato Deshidrogenasa/metabolismo , Proteínas Bacterianas/metabolismo , Membrana Celular/efectos de los fármacos , Interacciones Hidrofóbicas e Hidrofílicas

RESUMEN

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Asunto(s)

Ascomicetos , Benzamidas , Inhibidores Enzimáticos , Proteínas Fúngicas , Fungicidas Industriales , Simulación del Acoplamiento Molecular , Succinato Deshidrogenasa , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Relación Estructura-Actividad , Benzamidas/farmacología , Benzamidas/química , Ascomicetos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/química , Rhizoctonia/efectos de los fármacos , Botrytis/efectos de los fármacos , Botrytis/crecimiento & desarrollo , Pirazoles/química , Pirazoles/farmacología , Descubrimiento de Drogas , Estructura Molecular , Enfermedades de las Plantas/microbiología

RESUMEN

The emergence of waterlogged Oryza species ∼15Mya (million years ago) supplied an anoxic warm bed for methane-producing microorganisms, and methane emissions have hence accompanied the entire evolutionary history of the genus Oryza. However, to date no study has addressed how methane emission has been altered during Oryza evolution. In this paper we used a diverse collection of wild and cultivated Oryza species to study the relation between Oryza evolution and methane emissions. Phylogenetic analyses and methane detection identified a co-evolutionary pattern between Oryza and methane emissions, mediated by the diversity of the rhizospheric ecosystems arising from different oxygen levels. Fumarate was identified as an oxygen substitute used to retain the electron transport/energy production in the anoxic rice root, and the contribution of fumarate reductase to Oryza evolution and methane emissions has also been assessed. We confirmed the between-species patterns using genetic dissection of the traits in a cross between a low and high methane-emitting species. Our findings provide novel insights on the evolutionary processes of rice paddy methane emissions: the evolution of wild rice produces different Oryza species with divergent rhizospheric ecosystem attributing to the different oxygen levels and fumarate reductase activities, methane emissions are comprehensively assessed by the rhizospheric environment of diversity Oryza species and result in a co-evolution pattern.

Asunto(s)

Ecosistema , Metano , Oryza , Rizosfera , Oryza/genética , Metano/metabolismo , Filogenia , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/genética , Raíces de Plantas/metabolismo

RESUMEN

BACKGROUND: Previous studies have shown a lower hemodynamic response in patients with major depressive disorder (MDD) during cognitive tasks. However, the mechanism underlying impaired hemodynamic and neural responses to cognitive tasks in MDD patients remains unclear. Succinate dehydrogenase (SDH) is a key biomarker of mitochondrial energy generation, and it can affect the hemodynamic response via the neurovascular coupling effect. In the current study, cerebral hemodynamic responses were detected during verbal fluency tasks (VFTs) via functional near-infrared spectroscopy (fNIRS) and SDH protein levels were examined in serum from MDD patients to quickly identify whether these hemodynamic alterations were related to mitochondrial energy metabolism. METHODS: Fifty patients with first-episode drug-naïve MDD and 42 healthy controls (HCs) were recruited according to inclusion and exclusion criteria. The 17-item Hamilton Depression Rating Scale (17-HDRS), Hamilton Anxiety Rating Scale (HAMA) and Inventory of Depressive Symptomatology-Self Report (IDS-SR) were used to assess the clinical symptoms of the patients. All participants underwent fNIRS measurements to evaluate cerebral hemodynamic responses in the frontal and temporal cortex during VFTs; moreover, SDH protein levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Activation in the frontal-temporal brain region during the VFTs was lower in patients with MDD than in HCs. The SDH level in the serum of MDD patients was also significantly lower than that in HCs (p = 0.003), which significantly affected right lateral frontal (p = 0.025) and right temporal (p = 0.022) lobe activation. Both attenuated frontal-temporal activation during the VFTs (OR = 1.531) and lower SDH levels (OR = 1.038) were risk factors for MDD. CONCLUSIONS: MDD patients had lower cerebral hemodynamic responses to VFTs; this was associated with mitochondrial dysfunction, as indicated by SDH protein levels. Furthermore, attenuated hemodynamic responses in frontotemporal regions and lower SDH levels increased the risk for MDD. LIMITATIONS: The sample size is relatively small. SDH protein levels in peripheral blood may not necessarily reflect mitochondrial energy generation in the central nervous system.

Asunto(s)

Trastorno Depresivo Mayor , Lóbulo Frontal , Espectroscopía Infrarroja Corta , Succinato Deshidrogenasa , Lóbulo Temporal , Humanos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/sangre , Masculino , Femenino , Adulto , Lóbulo Temporal/fisiopatología , Succinato Deshidrogenasa/sangre , Succinato Deshidrogenasa/metabolismo , Lóbulo Frontal/fisiopatología , Cognición/fisiología , Hemodinámica/fisiología , Estudios de Casos y Controles , Adulto Joven , Persona de Mediana Edad

RESUMEN

Objective: To explore the correlation between clinical characteristics and pathological features in patients with pheochromocytoma/paraganglioma (PPGLs). Methods: A case series study. A retrospective analysis was conducted on patients with single and primary PPGLs after postoperative pathological diagnosis who were admitted to Peking Union Medical College Hospital between January 2019 and December 2022. The patients were divided into the Ki-67<3% group and the Ki-67≥3% group with Ki-67 proliferation index of 3% as the threshold. The relationship between clinical and pathological characteristics of PPGLs was analyzed. Results: A total of 399 PPGLs patients were included, with 177 males and 222 females, aged [M(Q1, Q3)] 45.0(35.5, 53.0) years. Among them, 226 (56.6%) cases originated from the adrenal gland, while 104 cases (26.1%) from the retroperitoneum. 20.9% (27/129) of the patients were found to harbor germline mutations of susceptibility genes, with SDHB mutations being the most common (10.1%, 13/129). The Ki-67 staining was performed on 302 cases, with a Ki-67 proliferation index [M(Q1, Q3)] of 2.0% (1.0%, 3.0%). There were 194 cases in Ki-67<3% group and 108 cases in Ki-67≥3% group. Compared with the patients in Ki-67<3% group, the age of onset in Ki-67≥3% group was younger (P=0.029). Compared with the patients with paragangliomas without SDHB or Cluster 1A-related gene mutations, positive 131I-meta-iodobenzylguanidine (131I-MIBG) imaging or negative O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry staining, those with SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging or positive MGMT immunohistochemistry staining had a higher Ki-67 index (all P<0.05). Compared with adrenal pheochromocytoma, retroperitoneal paragangliomas had a higher proportion of SDHB mutations and a higher proportion of normetanephrine (NMN) secretory types (all P<0.05). Compared with adrenal pheochromocytoma, the maximum diameter of head and neck paraganglioma tumors was smaller [3.0 (1.9, 3.8) cm vs 4.7 (3.4, 6.4) cm, P<0.001] and the proportion of Ki-67≥3% was higher (61.3% vs 33.8%, P=0.007). Conclusions: PPGLs patients with earlier onset age, SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging, or positive MGMT immunohistochemistry staining tend to have a higher Ki-67 index. Head and neck tumors, though smaller, exhibit a higher proliferation potential.

Asunto(s)

Neoplasias de las Glándulas Suprarrenales , Antígeno Ki-67 , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/patología , Feocromocitoma/genética , Masculino , Femenino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Paraganglioma/patología , Paraganglioma/genética , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/genética , Antígeno Ki-67/metabolismo , Mutación de Línea Germinal , Succinato Deshidrogenasa/genética

RESUMEN

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.

Asunto(s)

Neoplasias de las Glándulas Suprarrenales , Modelos Animales de Enfermedad , Paraganglioma , Feocromocitoma , Succinato Deshidrogenasa , Pez Cebra , Animales , Humanos , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/patología , Mutación , Paraganglioma/genética , Paraganglioma/patología , Paraganglioma/metabolismo , Fenotipo , Feocromocitoma/genética , Feocromocitoma/patología , Feocromocitoma/metabolismo , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Pez Cebra/genética

RESUMEN

Rice blast, caused by Magnaporthe oryzae, is a devastating fungal disease worldwide. Pydiflumetofen (Pyd) is a new succinate dehydrogenase inhibitor (SDHI) that exhibited anti-fungal activity against M. oryzae. However, control of rice blast by Pyd and risk of resistance to Pyd are not well studied in this pathogen. The baseline sensitivity of 109 M. oryzae strains to Pyd was determined using mycelial growth rate assay, with EC50 values ranging from 0.291 to 2.1313 µg/mL, and an average EC50 value of 1.1005 ± 0.3727 µg/mL. Totally 28 Pyd-resistant (PydR) mutants with 15 genotypes of point mutations in succinate dehydrogenase (SDH) complex were obtained, and the resistance level could be divided into three categories of very high resistance (VHR), high resistance (HR) and moderate resistance (MR) with the resistance factors (RFs) of >1000, 105.74-986.13 and 81.92-99.48, respectively. Molecular docking revealed that all 15 mutations decreased the binding-force score for the affinity between Pyd and target subunits, which further confirmed that these 15 genotypes of point mutations were responsible for the resistance to Pyd in M. oryzae. There was positive cross resistance between Pyd and other SDHIs, such as fluxapyroxad, penflufen or carboxin, while there was no cross-resistance between Pyd and carbendazim, prochloraz or azoxystrobin in M. oryzae, however, PydR mutants with SdhBP198Q, SdhCL66F or SdhCL66R genotype were still sensitive to the other 3 SDHIs, indicating lack of cross resistance. The results of fitness study revealed that the point mutations in MoSdhB/C/D genes might reduce the hyphae growth and sporulation, but could improve the pathogenicity in M. oryzae. Taken together, the risk of resistance to Pyd might be moderate to high, and it should be used as tank-mixtures with other classes of fungicides to delay resistance development when it is used for the control of rice blast in the field.

Asunto(s)

Sustitución de Aminoácidos , Farmacorresistencia Fúngica , Fungicidas Industriales , Succinato Deshidrogenasa , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Farmacorresistencia Fúngica/genética , Fungicidas Industriales/farmacología , Enfermedades de las Plantas/microbiología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Simulación del Acoplamiento Molecular , Magnaporthe/efectos de los fármacos , Magnaporthe/genética , Mutación Puntual , Oryza/microbiología , Ascomicetos

RESUMEN

Magnaporthe oryzae is a rice blast pathogen that seriously threatens rice yield. Benzovindiflupyr is a succinate dehydrogenase inhibitor (SDHI) fungicide that effectively controls many crop diseases. Benzovindiflupyr has a strong inhibitory effect on M. oryzae; however, control of rice blast by benzovindiflupyr and risk of resistance to benzovindiflupyr are not well studied in this pathogen. In this study, six benzovindiflupyr-resistant strains were obtained by domestication induced in the laboratory. The MoSdhBH245D mutation was the cause of M. oryzae resistance to benzovindiflupyr, which was verified through succinate dehydrogenase (SDH) activity assays, molecular docking, and site-specific mutations. Survival fitness analysis showed no significant difference between the benzovindiflupyr-resistant and parent strains. Positive cross-resistance to benzovindiflupyr and other SDHIs and negative cross-resistance to azoxystrobin were observed. Therefore, the risk of benzovindiflupyr resistance in M. oryzae might be medium to high. It should be combined with other classes of fungicides (tebuconazole and azoxystrobin) to slow the development of resistance.

Asunto(s)

Farmacorresistencia Fúngica , Fungicidas Industriales , Mutación , Succinato Deshidrogenasa , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Fungicidas Industriales/farmacología , Farmacorresistencia Fúngica/genética , Enfermedades de las Plantas/microbiología , Magnaporthe/efectos de los fármacos , Magnaporthe/genética , Simulación del Acoplamiento Molecular , Oryza/microbiología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Estrobilurinas/farmacología , Ascomicetos

RESUMEN

Vasogenic brain edema, a potentially life-threatening consequence following an acute ischemic stroke, is a major clinical problem. This research aims to explore the therapeutic benefits of nimodipine, a calcium channel blocker, in mitigating vasogenic cerebral edema and preserving blood-brain barrier (BBB) function in an ischemic stroke rat model. In this research, animals underwent the induction of ischemic stroke via a 60-min blockage of the middle cerebral artery and treated with a nonhypotensive dose of nimodipine (1 mg/kg/day) for a duration of five days. The wet/dry method was employed to identify cerebral edema, and the Evans blue dye extravasation technique was used to assess the permeability of the BBB. Furthermore, immunofluorescence staining was utilized to assess the protein expression levels of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). The study also examined mitochondrial function by evaluating mitochondrial swelling, succinate dehydrogenase (SDH) activity, the collapse of mitochondrial membrane potential (MMP), and the generation of reactive oxygen species (ROS). Post-stroke administration of nimodipine led to a significant decrease in cerebral edema and maintained the integrity of the BBB. The protective effects observed were associated with a reduction in cell apoptosis as well as decreased expression of MMP-9 and ICAM-1. Furthermore, nimodipine was observed to reduce mitochondrial swelling and ROS levels while simultaneously restoring MMP and SDH activity. These results suggest that nimodipine may reduce cerebral edema and BBB breakdown caused by ischemia/reperfusion. This effect is potentially mediated through the reduction of MMP-9 and ICAM-1 levels and the enhancement of mitochondrial function.

Asunto(s)

Barrera Hematoencefálica , Edema Encefálico , Bloqueadores de los Canales de Calcio , Accidente Cerebrovascular Isquémico , Metaloproteinasa 9 de la Matriz , Nimodipina , Animales , Nimodipina/farmacología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Masculino , Ratas , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas Sprague-Dawley , Molécula 1 de Adhesión Intercelular/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Dilatación Mitocondrial/efectos de los fármacos , Succinato Deshidrogenasa/metabolismo

RESUMEN

In this study, a series of novel hydrazide-containing flavonol derivatives was designed, synthesized, and evaluated for antifungal activity. In the in vitro antifungal assay, most of the target compounds exhibited potent antifungal activity against seven tested phytopathogenic fungi. In particular, compound C32 showed the best antifungal activity against Rhizoctonia solani (EC50 = 0.170 µg/mL), outperforming carbendazim (EC50 = 0.360 µg/mL) and boscalid (EC50 = 1.36 µg/mL). Compound C24 exhibited excellent antifungal activity against Valsa mali, Botrytis cinerea, and Alternaria alternata with EC50 values of 0.590, 0.870, and 1.71 µg/mL, respectively. The in vivo experiments revealed that compounds C32 and C24 were potential novel agricultural antifungals. 3D quantitative structure-activity relationship (3D-QSAR) models were used to analyze the structure-activity relationships of these compounds. The analysis results indicated that introducing appropriate electronegative groups at position 4 of a benzene ring could effectively improve the anti-R. solani activity. In the antifungal mechanism study, scanning electron microscopy and transmission electron microscopy analyses revealed that C32 disrupted the normal growth of hyphae by affecting the structural integrity of the cell membrane and cellular respiration. Furthermore, compound C32 exhibited potent succinate dehydrogenase (SDH) inhibitory activity (IC50 = 8.42 µM), surpassing that of the SDH fungicide boscalid (IC50 = 15.6 µM). The molecular dynamics simulations and docking experiments suggested that compound C32 can occupy the active site and form strong interactions with the key residues of SDH. Our findings have great potential for aiding future research on plant disease control in agriculture.

Asunto(s)

Alternaria , Botrytis , Flavonoles , Fungicidas Industriales , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Rhizoctonia , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Rhizoctonia/efectos de los fármacos , Rhizoctonia/crecimiento & desarrollo , Botrytis/efectos de los fármacos , Botrytis/crecimiento & desarrollo , Alternaria/efectos de los fármacos , Alternaria/crecimiento & desarrollo , Flavonoles/farmacología , Flavonoles/química , Enfermedades de las Plantas/microbiología , Estructura Molecular , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Ascomicetos/efectos de los fármacos , Ascomicetos/crecimiento & desarrollo , Ascomicetos/química , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química

RESUMEN

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

Asunto(s)

Ascomicetos , Diseño de Fármacos , Fungicidas Industriales , Fusarium , Simulación del Acoplamiento Molecular , Rhizoctonia , Silicio , Succinato Deshidrogenasa , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Silicio/química , Silicio/farmacología , Rhizoctonia/efectos de los fármacos , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Fusarium/efectos de los fármacos , Relación Estructura-Actividad , Ascomicetos/efectos de los fármacos , Botrytis/efectos de los fármacos , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Enfermedades de las Plantas/microbiología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Amidas/química , Amidas/farmacología , Amidas/síntesis química

RESUMEN

A series of new piperidine-4-carbohydrazide derivatives bearing a quinazolinyl moiety were prepared and evaluated for their fungicidal activities against agriculturally important fungi. Among these derivatives, the chemical structure of compound A45 was clearly verified by X-ray crystallographic analysis. The antifungal bioassays revealed that many compounds in this series possessed good to excellent inhibition effects toward the tested fungi. For example, compounds A13 and A41 had EC50 values of 0.83 and 0.88 µg/mL against Rhizoctonia solani in vitro, respectively, superior to those of positive controls Chlorothalonil and Boscalid (1.64 and 0.96 µg/mL, respectively). Additionally, the above two compounds also exhibited notable inhibitory activities against Verticillium dahliae (with EC50 values of 1.12 and 3.20 µg/mL, respectively), far better than the positive controls Carbendazim and Chlorothalonil (19.3 and 11.0 µg/mL, respectively). More importantly, compound A13 could potently inhibit the proliferation of R. solani in the potted rice plants, showing good in vivo curative and protective efficiencies of 76.9% and 76.6% at 200 µg/mL, respectively. Furthermore, compound A13 demonstrated an effective inhibition of succinate dehydrogenase (SDH) activity in vitro with an IC50 value of 6.07 µM. Finally, the molecular docking study revealed that this compound could be well embedded into the active pocket of SDH via multiple noncovalent interactions, involving residues like SER39, ARG43, and GLY46.

Asunto(s)

Diseño de Fármacos , Fungicidas Industriales , Hidrazinas , Simulación del Acoplamiento Molecular , Piperidinas , Rhizoctonia , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Hidrazinas/química , Hidrazinas/farmacología , Relación Estructura-Actividad , Rhizoctonia/efectos de los fármacos , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Estructura Molecular , Proteínas Fúngicas/química , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/química , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Pruebas de Sensibilidad Microbiana

RESUMEN

Bursaphelenchus xylophilus is a dangerous quarantine pest that causes extensive damage to pine ecosystems worldwide. Cyclobutrifluram, a succinate dehydrogenase inhibitor (SDHI), is a novel nematicide introduced by Syngenta in 2013. However, the nematocidal effect of cyclobutrifluram against plant-parasitic nematodes remains underexplored. Therefore, here, we aim to address this knowledge gap by evaluating the toxicity, effects, and mode of action of cyclobutrifluram on B. xylophilus. The result shows that cyclobutrifluram is the most effective agent, with an LC50 value of 0.1078 mg·L-1. At an LC20 dose, it significantly reduced the population size to 10.40 × 103 ± 737.56-approximately 1/23 that of the control group. This notable impact may stem from the agent's ability to diminish egg-laying and hatching rates, as well as to impede the nematodes' development. In addition, it has also performed well in the prevention of pine wilt disease, significantly reducing the incidence in greenhouses and in the field. SDH consists of a transmembrane assembly composed of four protein subunits (SDHA to SDHD). Four sdh genes were characterized and proved by RNAi to regulate the spawning capacity, locomotion ability, and body size of B. xylophilus. The mortality of nematodes treated with sdhc-dsRNA significantly decreased upon cyclobutrifluram application. Molecular docking further confirmed that SDHC, a cytochrome-binding protein, is the target. In conclusion, cyclobutrifluram has a good potential for trunk injection against B. xylophilus. This study provides valuable information for the screening and application of effective agents in controlling and preventing PWD in forests.

Asunto(s)

Antinematodos , Succinato Deshidrogenasa , Tylenchida , Animales , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinato Deshidrogenasa/metabolismo , Antinematodos/farmacología , Tylenchida/efectos de los fármacos , Tylenchida/genética , Tylenchida/fisiología , Pinus/parasitología , Simulación del Acoplamiento Molecular , Enfermedades de las Plantas/parasitología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo