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The intricate interplay between resident cells and the extracellular matrix (ECM) profoundly influences cancer progression. In triple-negative breast cancer (TNBC), ECM architecture evolves due to the enrichment of lysyl oxidase, fibronectin, and collagen, promoting distant metastasis. Here we uncover a pivotal transcription regulatory mechanism involving the epigenetic regulator UBR7 and histone methyltransferase EZH2 in regulating transforming growth factor (TGF)-ß/Smad signaling, affecting the expression of ECM genes. UBR7 loss leads to a dramatic reduction in facultative heterochromatin mark H3K27me3, activating ECM genes. UBR7 plays a crucial role in matrix deposition in adherent cancer cells and spheroids, altering collagen content and lysyl oxidase activity, directly affecting matrix stiffness and invasiveness. These findings are further validated in vivo in mice models and TNBC patients, where reduced UBR7 levels are accompanied by increased ECM component expression and activity, leading to fibrosis-mediated matrix stiffness. Thus, UBR7 is a master regulator of matrix stiffening, influencing the metastatic potential of TNBC.
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Proteína Potenciadora do Homólogo 2 de Zeste , Matriz Extracelular , Transdução de Sinais , Fator de Crescimento Transformador beta , Neoplasias de Mama Triplo Negativas , Ubiquitina-Proteína Ligases , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
A newly discovered E3 ubiquitin ligase, UBR7, plays a crucial role in histone H2BK120 monoubiquitination. Here, we report a novel function of UBR7 in promoting hepatitis B virus (HBV) pathogenesis, which further leads to HBV-induced hepatocellular carcinoma (HCC). Transcriptomics analysis from HCC patients revealed the deregulation of UBR7 in cancer. Remarkably, targeting UBR7, particularly its catalytic function, led to a significant decrease in viral copy numbers. We also identified the speckled family protein Sp110 as an important substrate of UBR7. Notably, Sp110 has been previously shown to be a resident of promyelocytic leukemia nuclear bodies (PML-NBs), where it remains SUMOylated, and during HBV infection, it undergoes deSUMOylation and exits the PML body. We observed that UBR7 ubiquitinates Sp110 at critical residues within its SAND domain. Sp110 ubiquitination downregulates genes in the type I interferon response pathway. Comparative analysis of RNA-Seq from the UBR7/Sp110 knockdown data set confirmed that the IFN-ß signaling pathway gets deregulated in HCC cells in the presence of HBV. Single-cell RNA-Seq analysis of patient samples further confirmed the inverse correlation between the expression of Sp110/UBR7 and the inflammation score. Notably, silencing of UBR7 induces IRF7 phosphorylation, thereby augmenting interferon (IFN)-ß and the downstream interferon-stimulated genes (ISGs). Further, wild-type but not the ubiquitination-defective mutant of Sp110 could be recruited to the type I interferon response pathway genes. Our study establishes a new function of UBR7 in non-histone protein ubiquitination, promoting viral persistence, and has important implications for the development of therapeutic strategies targeting HBV-induced HCC.
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The present investigation entails the first report on entrapment of Carum carvi essential oil (CCEO) into chitosan polymer matrix for protection of stored herbal raw materials against fungal inhabitation and aflatoxin B1 (AFB1) production. Physico-chemical characterization of nanoencapsulated CCEO was performed through Fourier transform infrared spectroscopy, dynamic light scattering, X-ray diffractometry, and scanning electron microscopy. The nanoencapsulated CCEO displayed improved antifungal and AFB1 suppressing potentiality along with controlled delivery over unencapsulated CCEO. The encapsulated CCEO nanoemulsion obstructed the ergosterol production and escalated the efflux of cellular ions, thereby suggesting plasma membrane as prime target of antifungal action in Aspergillus flavus cells. The impairment in methyglyoxal production and modeling based carvone interaction with Afl-R protein validated the antiaflatoxigenic mechanism of action. In addition, CCEO displayed augmentation in antioxidant potentiality after encapsulation into chitosan nanomatrix. Moreover, the in-situ study demonstrated the effective protection of Withania somnifera root samples (model herbal raw material) against fungal infestation and AFB1 contamination along with prevention of lipid peroxidation. The acceptable organoleptic qualities of W. somnifera root samples and favorable safety profile in mice (animal model) strengthen the application of nanoencapsulated CCEO emulsion as nano-fungitoxicant for preservation of herbal raw materials against fungi and AFB1 mediated biodeterioration.
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Aflatoxina B1 , Antifúngicos , Aspergillus flavus , Carum , Quitosana , Emulsões , Óleos Voláteis , Quitosana/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Emulsões/química , Carum/química , Aspergillus flavus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Animais , Camundongos , Contaminação de Alimentos/prevenção & controle , Antioxidantes/farmacologia , Antioxidantes/químicaRESUMO
Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8) is a crucial epigenetic regulator that plays a multifaceted role in governing a spectrum of vital cellular processes, encompassing proliferation, apoptosis, migration, tumor suppression, and differentiation. It has emerged as a key player in neuronal differentiation by orchestrating the expression of neuronal lineage-committed genes. The present study uncovers the role of ZMYND8 in regulating the Sonic Hedgehog (SHH) signaling axis, which is crucial for neuronal differentiation. Genetic deletion of ZMYND8 leads to a significant reduction in SHH pathway genes, GLI1, and PTCH1 expression during all-trans-retinoic acid (ATRA)-induced differentiation. ZMYND8 and RNA pol II S5P are found to co-occupy the GLI1 and PTCH1 gene promoters, positively impacting their gene transcription upon ATRA treatment. Interestingly, ZMYND8 is found to counteract the inhibitory effects of Cyclopamine that block the upstream SHH pathway protein SMO, resulting in enhanced neurite formation in neuroblastoma cells following their treatment with ATRA. These results indicate that ZMYND8 is an epigenetic regulator of the SHH signaling pathway and has tremendous therapeutic potential in ATRA-mediated differentiation of neuroblastoma.
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Diferenciação Celular , Proteínas Hedgehog , Neuroblastoma , Transdução de Sinais , Tretinoína , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Humanos , Diferenciação Celular/efeitos dos fármacos , Tretinoína/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/genética , Linhagem Celular Tumoral , Receptor Patched-1/metabolismo , Receptor Patched-1/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Animais , Proteínas Supressoras de TumorRESUMO
T cells, a key component of cancer immunotherapy, undergo a variety of histone modifications and DNA methylation changes since their bone marrow progenitor stages before developing into CD8+ and CD4+ T cells. These T cell types can be categorized into distinct subtypes based on their functionality and properties, such as cytotoxic T cells (Tc), helper T cells (Th), and regulatory T cells (Treg) as subtypes for CD8+ and CD4+ T cells. Among these, the CD4+ CD25+ Tregs potentially contribute to cancer development and progression by lowering T effector (Teff) cell activity under the influence of the tumor microenvironment (TME). This contributes to the development of therapeutic resistance in patients with cancer. Subsequently, these individuals become resistant to monoclonal antibody therapy as well as clinically established immunotherapies. In this review, we delineate the different epigenetic mechanisms in cancer immune response and its involvement in therapeutic resistance. Furthermore, the possibility of epi-immunotherapeutic methods based on histone deacetylase inhibitors and histone methyltransferase inhibitors are under investigation. In this review we highlight EZH2 as the principal driver of cancer cell immunoediting and an immune escape regulator. We have addressed in detail how understanding T cell epigenetic regulation might bring unique inventive strategies to overcome drug resistance and increase the efficacy of cancer immunotherapy.
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Epigênese Genética , Neoplasias , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Linfócitos T Reguladores , Metilação de DNA , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: The genus Costus is the largest genus in the family Costaceae and encompasses about 150 known species. Among these, Costus pictus D. Don (Synonym: Costus mexicanus) is a traditional medicinal herb used to treat diabetes and other ailments. Currently, available treatment options in modern medicine have several adverse effects. Herbal medicines are gaining importance as they are cost-effective and display improved therapeutic effects with fewer side effects. Scientists have been seeking therapeutic compounds in plants, and various in vitro and in vivo studies report Costus pictus D. Don as a potential source in treating various diseases. Phytochemicals with various pharmacological properties of Costus pictus D. Don, viz. anti-cancer, anti-oxidant, diuretic, analgesic, and anti-microbial have been worked out and reported in the literature. OBJECTIVE: The aim of the review is to categorize and summarize the available information on phytochemicals and pharmacological properties of Costus pictus D. Don and suggest outlooks for future research. METHODS: This review combined scientific data regarding the use of Costus pictus D. Don plant for the management of diabetes and other ailments. A systematic search was performed on Costus pictus plant with anti-diabetic, anti-cancer, anti-microbial, anti-oxidant, and other pharmacological properties using several search engines such as Google Scholar, PubMed, Science Direct, Sci-Finder, other online journals and books for detailed analysis. RESULTS: Research data compilation and critical review of the information would be beneficial for further exploration of its pharmacological and phytochemical aspects and, consequently, new drug development. Bioactivity-guided fractionation, isolation, and purification of new chemical entities from the plant as well as pharmacological evaluation of the same will lead to the search for safe and effective novel drugs for better healthcare. CONCLUSION: This review critically summarizes the reports on natural compounds, and different extract of Costus pictus D. Don with their potent anti-diabetic activity along with other pharmacological activity. Since this review has been presented in a very interactive manner showing the geographical region of availability, parts of plant used, mechanism of action and phytoconstituents in different extracts of Costus pictus responsible for particular action, it will be of great importance to the interested readers to focus on the development of the new drug leads for the treatment of diseases.
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Costus , Hipoglicemiantes , Compostos Fitoquímicos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Humanos , Costus/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Animais , Diabetes Mellitus/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/química , Plantas Medicinais/químicaRESUMO
Microbial communities within seeds play a vital role in transmitting themselves to the next generation of plants. These microorganisms significantly impact seed vigor and early seedling growth, for successful crop establishment. Previous studies reported on seed-associated microbial communities and their influence on processes like dormancy release, germination, and disease protection. Modern sequencing and conventional methods reveal microbial community structures and environmental impacts, these information helps in microbial selection and manipulation. These studies form the foundation for using seed microbiomes to enhance crop resilience and productivity. While existing research has primarily focused on characterizing microbiota in dried mature seeds, a significant gap exists in understanding how these microbial communities assemble during seed development. The review also discusses applying seed-associated microorganisms to improve crops in the context of climate change. However, limited knowledge is available about the microbial assembly pattern on seeds, and their impact on plant growth. The review provides insight into microbial composition, functions, and significance for plant health, particularly regarding growth promotion and pest control.
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Microbiota , Sementes , Germinação , Plântula , Produtos Agrícolas , Microbiota/genéticaRESUMO
Contamination of drinking water due to fluoride (F-) is a major concern worldwide. Although fluoride is an essential trace element required for humans, it has severe human health implications if levels exceed 1.5 mg. L-1 in groundwater. Several treatment technologies have been adopted to remove fluoride and reduce the exposure risk. The present article highlights the source, geochemistry, spatial distribution, and health implications of high fluoride in groundwater. Also, it discusses the underlying mechanisms and controlling factors of fluoride contamination. The problem of fluoride-contaminated water is more severe in India's arid and semiarid regions than in other Asian countries. Treatment technologies like adsorption, ion exchange, precipitation, electrolysis, electrocoagulation, nanofiltration, coagulation-precipitation, and bioremediation have been summarized along with case studies to look for suitable technology for fluoride exposure reduction. Although present technologies are efficient enough to remove fluoride, they have specific limitations regarding cost, labour intensity, and regeneration requirements.
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Água Potável , Água Subterrânea , Poluentes Químicos da Água , Humanos , Fluoretos/análise , Monitoramento Ambiental , Poluentes Químicos da Água/análise , Água Potável/análiseRESUMO
Ayurveda is considered to be one of the most ancient forms of medicine still practiced. The Ayurvedic preparation Raudra Rasa and its derivatives have been widely employed against cancer since the 12th century, but the effect of these traditional formulations on platelet function and signaling has not previously been examined. Here we demonstrate that Raudra Rasa and its derivatives significantly reduce thrombin-induced integrin activation and granule secretion in platelets, as observed by reduced PAC-1 binding and P-selectin externalization, respectively. These formulations also inhibited thrombin-stimulated phosphatidylserine exposure, mitochondrial reactive oxygen species generation, and mitochondrial transmembrane potential in platelets. Consistent with the above, Raudra Rasa significantly reduced thrombin-induced tyrosine phosphorylation of the platelet proteins, as well as phosphorylation of the enzymes AKT and GSK-3ß. In summary, Raudra Rasa inhibits agonist-mediated platelet activation without affecting cell viability, suggesting it may have therapeutic potential as an anti-platelet/anti-thrombotic agent.
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Agregação Plaquetária , Trombina , Sobrevivência Celular , Glicogênio Sintase Quinase 3 beta , Ativação Plaquetária , Trombina/antagonistas & inibidores , Trombina/metabolismo , Trombina/farmacologiaRESUMO
The considerable loss of crop productivity each year due to plant disease or pathogen invasion during pre- or post-harvest storage conditions is one of the most severe challenges to achieving the goals of food security for the rising global population. Although chemical pesticides severally affect the food quality and health of consumers, a large population relies on them for plant disease management. But currently, endophytes have been considered one of the most suitable biocontrol agents due to better colonization and acclimatization potential. However, a very limited number of endophytes have been used commercially as biocontrol agents. Isolation of endophytes and their screening to represent potential characteristics as biocontrol agents are considered challenging by different procedures. Through a web search using the keywords "endophytes as biocontrol agents" or "biocontrol mechanism of endophytes," we have succinctly summarised the isolation strategies and different in vitro and in vivo biocontrol screening methods of endophytic biocontrol agents in the present review. In this paper, biocontrol mechanisms of endophytes and their potential application in plant disease management have also been discussed. Furthermore, the registration and regulatory mechanism of the endophytic biocontrol agents are also covered.
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Background Endotracheal intubation in the intensive care unit (ICU) is often a risky procedure due to the emergency situation, unstable condition of the patient, and technical problems such as inadequate positioning. Several new techniques, such as video laryngoscopy, have been developed recently to improve the success rate of first-pass intubations and reduce complications. We conducted this study to compare a non-channeled reusable video laryngoscope BPL VL-02 (manufactured by BPL Medical Technologies, Bangalore, India) with a conventional laryngoscope for intubation of adult patients in the ICU. Methodology A total of 72 ICU patients were randomly allocated to be intubated with either conventional direct laryngoscopy via Macintosh blade (group A) or video laryngoscopy with BPL VL-02 (group B). All patients were intubated by the primary investigator and the assistant noted the following parameters: the total number of intubation attempts, total duration of intubation, assistance or alternative technique required, Cormack Lehane grading, and any complications. Results There was no significant difference in the Cormack Lehane grading, number of attempts, or complications between the two groups. On comparing the assistance required during intubation in patients, it was observed that four (11.11%) patients in group A and seven (19.44%) patients in group B needed backward, upward, and rightward pressure on the larynx assistance during intubation. In five (13.89%) patients in group B, Stylet was required during intubation. The difference was statistically significant (p = 0.0308). The video laryngoscopy group (group B) had a longer mean duration of intubation (64.36 ± 6.28 seconds) compared to group A (45.72 ± 11.45 seconds), and the difference was statistically significant (p < 0.0001). Conclusions Non-channeled video laryngoscope (BPL VL-02) is not a suitable alternative to conventional direct laryngoscopy with a Macintosh blade in terms of successful first-pass intubation, total duration of intubation, and assistance required.
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AIMS: Psoriasis is an immune-mediated skin disease characterized by keratinocytes hyperproliferation, abnormal differentiation and inflammation. Therefore, this study aimed to investigate in-vitro and in-vivo anti-inflammatory and anti-proliferative activity to evaluate anti-psoriatic potential of apigenin. MAIN METHODS: For in-vivo study, 5 % imiquimod cream was used to induce psoriasis-like skin inflammation in BALB/c mice to mimic human psoriatic conditions. PASI score, CosCam score, histopathology, immunohistochemistry, qRT-PCR, and ELISA were done to evaluate the anti-psoriatic potential of topically applied apigenin. For in-vitro studies, LPS-induced inflammation in RAW 264.7 was done, and qRT-PCR, ELISA, and immunofluorescence were conducted to evaluate the anti-inflammatory activity of apigenin. Migration and cell doubling assay in HaCaT cells were performed to assess the anti-proliferative effect of apigenin. Acute dermal toxicity profile of apigenin has also been done as per OECD guidelines. KEY FINDINGS: Results showed that apigenin significantly reduce the PASI and CosCam scores, ameliorate the deteriorating histopathology, and effectively downregulated the expression of CCR6, IL-17A, and NF-κB. Apigenin effectively downregulated the expression and secretion of pro-inflammatory cytokines through IL-23/IL-17/IL-22 axis. Apigenin suppressed nuclear translocation of NF-κB in LPS-induced RAW 264.7 cells. Cell migration and cell doubling assay in HaCaT cells showing the anti-proliferative potential of apigenin and it was found safe in acute dermal toxicity study. SIGNIFICANCE: Apigenin was found effective against psoriasis in both in-vitro and in-vivo models suggesting apigenin as a potential candidate for the development of anti-psoriatic agent.
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Dermatite , Psoríase , Animais , Camundongos , Humanos , Apigenina/farmacologia , Apigenina/uso terapêutico , Células HaCaT/metabolismo , Células HaCaT/patologia , NF-kappa B/metabolismo , Camundongos Endogâmicos BALB C , Lipopolissacarídeos/farmacologia , Células RAW 264.7 , Psoríase/induzido quimicamente , Queratinócitos/metabolismo , Anti-Inflamatórios/uso terapêutico , Dermatite/tratamento farmacológico , Dermatite/patologia , Inflamação/patologia , Modelos Animais de DoençasRESUMO
Necroptosis is a form of programmed cell death executed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL). Platelets are circulating cells that play central roles in haemostasis and pathological thrombosis. In this study we demonstrate seminal contribution of MLKL in transformation of agonist-stimulated platelets to active haemostatic units progressing eventually to necrotic death on a temporal scale, thus attributing a yet unrecognized fundamental role to MLKL in platelet biology. Physiological agonists like thrombin instigated phosphorylation and subsequent oligomerization of MLKL in platelets in a RIPK3-independent but phosphoinositide 3-kinase (PI3K)/AKT-dependent manner. Inhibition of MLKL significantly curbed agonist-induced haemostatic responses in platelets that included platelet aggregation, integrin activation, granule secretion, procoagulant surface generation, rise in intracellular calcium, shedding of extracellular vesicles, platelet-leukocyte interactions and thrombus formation under arterial shear. MLKL inhibition, too, prompted impairment in mitochondrial oxidative phosphorylation and aerobic glycolysis in stimulated platelets, accompanied with disruption in mitochondrial transmembrane potential, augmented proton leak and drop in both mitochondrial calcium as well as ROS. These findings underscore the key role of MLKL in sustaining OXPHOS and aerobic glycolysis that underlie energy-intensive platelet activation responses. Prolonged exposure to thrombin provoked oligomerization and translocation of MLKL to plasma membranes forming focal clusters that led to progressive membrane permeabilization and decline in platelet viability, which was prevented by inhibitors of PI3K/MLKL. In summary, MLKL plays vital role in transitioning of stimulated platelets from relatively quiescent cells to functionally/metabolically active prothrombotic units and their ensuing progression to necroptotic death.
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Plaquetas , Proteínas Quinases , Proteínas Quinases/metabolismo , Plaquetas/metabolismo , Necroptose , Cálcio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Trombina/farmacologia , Trombina/metabolismo , Morte Celular , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
LaTe3 is a non-centrosymmetric material with time reversal symmetry, where the charge density wave is hosted by the Te bilayers. Here, we show that LaTe3 hosts a Kramers nodal line-a twofold degenerate nodal line connecting time reversal-invariant momenta. We use angle-resolved photoemission spectroscopy, density functional theory with an experimentally reported modulated structure, effective band structures calculated by band unfolding, and symmetry arguments to reveal the Kramers nodal line. Furthermore, calculations confirm that the nodal line imposes gapless crossings between the bilayer-split charge density wave-induced shadow bands and the main bands. In excellent agreement with the calculations, spectroscopic data confirm the presence of the Kramers nodal line and show that the crossings traverse the Fermi level. Furthermore, spinless nodal lines-completely gapped out by spin-orbit coupling-are formed by the linear crossings of the shadow and main bands with a high Fermi velocity.
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The structural motif of an indole-fused azabicyclo[3.3.1]nonane is common in many biologically significant indole-based natural products. Because of its structural complexity, this N-bridged scaffold has become an enticing target for organic chemists. Many efficient strategies have been developed to access this ring system synthetically, but a radical approach remains unexplored. Herein, we report a radical-based strategy to construct an indole-fused azabicyclo[3.3.1]nonane structural framework. Although our initial attempt to use a Cp2TiCl-mediated radical cyclization method was found to be unsuccessful, an alternative approach using a SmI2-mediated radical cyclization protocol was effective for enabling the desired ring closure, leading to the target indole-fused azabicyclo[3.3.1]nonane ring system. The modular approach developed here can be extended with appropriate functionalities on this indole-fused N-bridged ring system to synthesize many alkaloids.
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Globally, substantial research into endophytic microbes is being conducted to increase agricultural and environmental sustainability. Endophytic microbes such as bacteria, actinomycetes, and fungi inhabit ubiquitously within the tissues of all plant species without causing any harm or disease. Endophytes form symbiotic relationships with diverse plant species and can regulate numerous host functions, including resistance to abiotic and biotic stresses, growth and development, and stimulating immune systems. Moreover, plant endophytes play a dominant role in nutrient cycling, biodegradation, and bioremediation, and are widely used in many industries. Endophytes have a stronger predisposition for enhancing mineral and metal solubility by cells through the secretion of organic acids with low molecular weight and metal-specific ligands (such as siderophores) that alter soil pH and boost binding activity. Finally, endophytes synthesize various bioactive compounds with high competence that are promising candidates for new drugs, antibiotics, and medicines. Bioprospecting of endophytic novel secondary metabolites has given momentum to sustainable agriculture for combating environmental stresses. Biotechnological interventions with the aid of endophytes played a pivotal role in crop improvement to mitigate biotic and abiotic stress conditions like drought, salinity, xenobiotic compounds, and heavy metals. Identification of putative genes from endophytes conferring resistance and tolerance to crop diseases, apart from those involved in the accumulation and degradation of contaminants, could open new avenues in agricultural research and development. Furthermore, a detailed molecular and biochemical understanding of endophyte entry and colonization strategy in the host would better help in manipulating crop productivity under changing climatic conditions. Therefore, the present review highlights current research trends based on the SCOPUS database, potential biotechnological interventions of endophytic microorganisms in combating environmental stresses influencing crop productivity, future opportunities of endophytes in improving plant stress tolerance, and their contribution to sustainable remediation of hazardous environmental contaminants.
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Endófitos , Simbiose , Endófitos/fisiologia , Fungos/fisiologia , Estresse Fisiológico , Plantas/microbiologia , AgriculturaRESUMO
In this study, a novel chitosan nanoemulsion coating embedded with Valeriana officinalis essential oil (Ne-VOEO) was synthesized in order to improve the postharvest quality of Citrus sinensis fruits against infesting fungi, and aflatoxin B1 (AFB1) mediated nutritional deterioration. The developed nanoemulsion was characterized through SEM, FTIR, XRD, and DLS analyses. The nanoemulsion showed controlled delivery of VOEO responsible for effective inhibition of Aspergillus flavus, A. niger, A. versicolor, Penicillium italicum, and Fusarium oxysporum growth at 6.5, 5.0, 4.0, 5.5, and 3.5 µL/mL, respectively and AFB1 production at 5.0 µL/mL. The biochemical and molecular mechanism of aflatoxigenic A. flavus inhibition, and AFB1 diminution was associated with impairment in ergosterol biosynthesis, methylglyoxal production, and stereo-spatial binding of valerianol in the cavity of Ver-1 protein. During in vivo investigation, Ne-VOEO coating potentially restrained the weight loss, and respiratory rate of C. sinensis fruits with delayed degradation of soluble solids, titrable acidity, pH, and phenolic contents along with maintenance of SOD, CAT, APX activities (p < 0.05) and sensory attributes under specific storage conditions. Based on overall findings, Ne-VOEO nanoemulsion could be recommended as green, and smart antifungal coating agent in prolonging the shelf-life of stored fruits with enhanced AFB1 mitigation.
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Quitosana , Citrus sinensis , Citrus , Filmes Comestíveis , Óleos Voláteis , Valeriana , Aflatoxina B1/metabolismo , Óleos Voláteis/química , Quitosana/química , Citrus sinensis/metabolismo , Valeriana/metabolismo , Frutas/química , Citrus/metabolismo , Melhoria de Qualidade , Fungos/metabolismo , Aspergillus flavus , Antifúngicos/farmacologiaRESUMO
Total synthesis of cis and trans diastereomers of prenylated davanoids like davanone, nordavanone, and davana acid ethyl ester was achieved in an enantioselective strategy. Various other davanoids could also be synthesized using standard procedures from the Weinreb amides derived from davana acids. Enantioselectivity in our synthesis was achieved employing a Crimmins' non-Evans syn aldol reaction that fixed the stereochemistry of the C3-hydroxyl group, while the C2-methyl group was epimerized in a late stage of the synthesis. A Lewis acid-mediated cycloetherification reaction was used to establish the tetrahydrofuran core of these molecules. Interestingly, a slight alteration of the Crimmins' non-Evans syn aldol protocol led to the complete conversion of the aldol adduct to the core tetrahydrofuran ring of davanoids, thus essentially dovetailing two important steps in the synthesis. The resulting one-pot tandem aldol-cycloetherification strategy enabled the enantioselective synthesis of trans davana acid ethyl esters and 2-epi-davanone/nordavanone in just three steps in excellent overall yields. The modularity of the approach will enable the synthesis of various other isomers in stereochemically pure forms for further biological profiling of this important class of molecules.
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A highly efficient pot, atom, and step economical method for the construction of pharmacologically potent structurally functionalized 1,4-dihydropyridines, quaternary centered C-3 functionalized spiro[indoline-3,4'-pyridines], and C-11 functionalized spiro[indeno[1,2-b]quinoxaline-11,4'-pyridines] via rose bengal photoredox catalysis under blue LED irradiation in an aqueous medium at room temperature has been developed. The products were isolated in excellent yields within a short reaction time for a variety of functional groups under transition metal- and ligand-free energy-efficient conditions in a green solvent system with high reaction mass efficiency and process mass intensity, which are the key advantages of the current work.
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Platelet mitochondria possess remarkable plasticity for oxidation of energy substrates, where metabolic dependency on glucose or fatty acids is higher than glutamine. Since platelets metabolize nearly the entire pool of glucose to lactate rather than fluxing through mitochondrial tricarboxylic acid cycle, we posit that majority of mitochondrial ATP, which is essential for platelet granule secretion and thrombus formation, is sourced from oxidation of fatty acids. We performed a comprehensive analysis of bioenergetics and function of stimulated platelets in the presence of etomoxir, trimetazidine and oxfenicine, three pharmacologically distinct inhibitors of ß-oxidation. Each of them significantly impaired oxidative phosphorylation in unstimulated as well as thrombin-stimulated platelets leading to a small but consistent drop in ATP level in activated cells due to a lack of compensation from glycolytic ATP. Trimetazidine and oxfenicine attenuated platelet aggregation, P-selectin externalization and integrin αIIb ß3 activation. Both etomoxir and trimetazidine impeded agonist-induced dense granule release and platelet thrombus formation on collagen under arterial shear. The effect of inhibitors on platelet aggregation and dense granule release was dose- and incubation time- dependent with significant inhibition at higher doses and prolonged incubation times. Neither of the inhibitors could protect mice from collagen-epinephrine-induced pulmonary embolism or prolong mouse tail bleeding times. However, mice pre-administered with etomoxir, trimetazidine and oxfenicine were protected from ferric chloride-induced mesenteric thrombosis. In conclusion, ß-oxidation of fatty acids sustains ATP level in stimulated platelets and is therefore essential for energy-intensive agonist-induced platelet responses. Thus, fatty acid oxidation may constitute an attractive therapeutic target for novel antiplatelet agents.