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PloS One 2023The demand for environmentally friendly foods with high nutritional value and low carbon emissions is increasing with the aging of the global population and the crisis...
Effects of Gryllus bimaculatus and Oxya chinensis sinuosa extracts on brain damage via blood-brain barrier control and apoptosis in mice with pentylenetetrazol-induced epilepsy.
The demand for environmentally friendly foods with high nutritional value and low carbon emissions is increasing with the aging of the global population and the crisis of food resources. Edible insects are becoming increasingly well-known as such foods. This study evaluated the effects and mechanisms of Gryllus bimaculatus (Cricket) (Gb) and Oxya chinensis sinuosa (Grasshopper) (Ocs) extracts on epilepsy. A pentylenetetrazol (PTZ)-induced seizure mouse model was used for the study, and Gb and Ocs extracts were administered for 29 days on alternate days at concentrations of 8 g/kg and 16 g/kg. The integrity of the blood-brain barrier (BBB) and brain edema was measured using the perfusion of Evans blue dye and brain water content. Gb and Ocs extracts prevented BBB permeabilization and cerebral edema through increasing the expression of tight junction-associated proteins in the endothelial cells and reducing water content in PTZ-treated mice. Additionally, Gb and Ocs extracts protected neurons from oxidative stress and apoptosis in different brain areas. These protective effects were demonstrated through the restoration of the expression of neuronal nuclear protein and postsynaptic density protein-95, thus increasing the levels of glutathione and superoxide dismutase, decreasing lipid peroxidation, and recovering apoptosis-associated proteins, such as Bax, cleaved PARP, and cleaved caspase-3, in epileptic mice. In addition, Gb and Ocs extracts rescued PTZ-induced hyperexcitable neurons to control mice level, as supported by the restored expression of gamma-aminobutyric acid (GABA) transporter 1, the metabotropic glutamate receptors-GRM2/3, and BDNF. This study suggested that Gb and Ocs extracts are novel medicinal candidates that can help ameliorate epilepsy by improving BBB health and preventing oxidative stress-mediated apoptosis.
Topics: Animals; Mice; Pentylenetetrazole; Blood-Brain Barrier; Gryllidae; Endothelial Cells; Epilepsy; Brain Injuries; Brain; Apoptosis; Brain Edema
PubMed: 37695764
DOI: 10.1371/journal.pone.0291191 -
Journal of Chemical Neuroanatomy Sep 2023Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent...
BACKGROUND AND OBJECTIVE
Epilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent research suggests that Kalirin plays a role in regulating neurological function. However, the pathogenesis of Kalirin in epileptic seizures remains unclear. This study aims to investigate the role and mechanism of Kalirin in epileptogenesis.
MATERIALS AND METHODS
An epileptic model was induced by intraperitoneal injection of pentylenetetrazole (PTZ). Endogenous Kalirin was inhibited using shRNA. The expression of Kalirin, Rac1, and Cdc42 in the hippocampal CA1 region was measured using Western blotting. Spine and synaptic structures were examined using Golgi staining and electron microscopy. Moreover, the necrotic neurons in CA1 were examined using HE staining.
RESULTS
The results indicated that the epileptic score increased in epileptic animals, while inhibition of Kalirin decreased the epileptic scores and increased the latent period of the first seizure attack. Inhibition of Kalirin attenuated the increases in Rac1 expression, dendritic spine density, and synaptic vesicle number in the CA1 region induced by PTZ. However, the increase in Cdc42 expression was not affected by the inhibition of Kalirin.
CONCLUSION
This study suggests that Kalirin is involved in the development of seizures by modulating the activity of Rac1, providing a novel anti-epileptic target.
Topics: Animals; CA1 Region, Hippocampal; Epilepsy; Neurons; Pentylenetetrazole; rac1 GTP-Binding Protein; Signal Transduction; Protein Serine-Threonine Kinases; Guanine Nucleotide Exchange Factors
PubMed: 37196826
DOI: 10.1016/j.jchemneu.2023.102289 -
Life Sciences Jan 2024The increasing resistance to anti-seizure medications (ASMs) and the ambiguous mechanisms of epilepsy highlight the pressing demand for the discovery of pioneering lead...
AIMS
The increasing resistance to anti-seizure medications (ASMs) and the ambiguous mechanisms of epilepsy highlight the pressing demand for the discovery of pioneering lead compounds. Berberine (BBR) has received significant attention in recent years within the field of chronic metabolic disorders. However, the reports on the treatment of epilepsy with BBR are not systematic and the mechanism remains unclear.
MAIN METHODS
In this study, the seizure behaviors of mice were recorded following subcutaneous injection of pentetrazol (PTZ). Non-targeted metabolomics was used to analyze the serum metabolites based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Meanwhile, multivariate statistical methods were used for metabolite identification and pathway analysis. Furthermore, network pharmacology, molecular docking, and quantitative real-time PCR assay were used for the target identification.
KEY FINDINGS
BBR had anti-seizure effects on PTZ-induced seizure mice after long-term treatment. Tryptophan metabolism and phenylalanine metabolism were involved in regulating the therapeutic effects of BBR.
SIGNIFICANCE
This study reveals the potential mechanism of BBR for epilepsy treatment based on non-targeted metabolomics and network pharmacology, which provides evidence for uncovering the pathogenesis of epilepsy, suggesting that BBR is a potential lead compound for anti-epileptic treatment.
Topics: Mice; Animals; Berberine; Network Pharmacology; Molecular Docking Simulation; Metabolomics; Pentylenetetrazole; Epilepsy; Seizures
PubMed: 38103728
DOI: 10.1016/j.lfs.2023.122347 -
Scientific Reports Feb 2024A series of novel azepine derivatives based on quinazolinone moiety was synthesized through the reaction of quinazolinone chalcones (2a-d) either with 2-amino aniline in...
A series of novel azepine derivatives based on quinazolinone moiety was synthesized through the reaction of quinazolinone chalcones (2a-d) either with 2-amino aniline in acidic medium to give diazepines (3a-d) or with 2-aminophenol to offer oxazepine (4a-d). The structure of the synthesized compounds was confirmed via melting points, elemental analyses, and different spectroscopic techniques. Moreover, these newly compounds mode of action was investigated in-silico using molecular docking against the outer membrane protein A (OMPA), exo-1,3-beta-glucanase for their antimicrobial activity, and against Smoothened (SMO), transcription factor glioma-associated homology (SUFU/GLI-1), the main proteins of Hedgehog signaling pathway to inspect their anticancer potential. Our results showed that, diazepine (3a) and oxazepine (4a) offered the highest binding energy against the target OMPA/ exo-1,3-beta-glucanase proteins and exhibited the potent antimicrobial activities against E. coli, P. aeruginosa, S. aureus, B. subtilis, C. Albicans and A. flavus. As well, diazepine (3a) and oxazepine (4a) achieved the best results among the other compounds, in their binding energy against the target SMO, SUFU/GLI-1 proteins. The in-vitro cytotoxic study was done for them on panel of cancer cell lines HCT-116, HepG2, and MCF-7 and normal cell line WI-38. Conclusively, it was revealed that molecular docking in-silico simulations and the in-vitro experiments were agreed. As a result, our findings elucidated that diazepine (3a) and oxazepine (4a), have the potential to be used as antimicrobial agents and as possible cancer treatment medications.
Topics: Structure-Activity Relationship; Molecular Docking Simulation; Hedgehog Proteins; Quinazolinones; Cell Proliferation; Escherichia coli; Staphylococcus aureus; Glucan 1,3-beta-Glucosidase; Oxazepines; Prospective Studies; Anti-Infective Agents; Antineoplastic Agents; Molecular Structure; Drug Screening Assays, Antitumor
PubMed: 38347004
DOI: 10.1038/s41598-024-53517-y -
Archives of Razi Institute Aug 2023Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological...
Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological diseases. In this regard, this study aimed to determine the effects of on pentylenetetrazol-induced epilepsy during the estrus cycle. For this purpose, 30 rats were randomly divided into five groups, namely control (saline), valproic acid (VPA, 75 mg/kg), (50 mg/kg), (100 mg/kg), and (150 mg/kg) with four subgroups (proestrus, estrus, metestrus, and diestrus). Subsequently, the initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), and seizure duration (SD) were determined. According to the results, ITMS and ITTS significantly increased in the VPA-treated group (<0.05). (100 and 150 mg/kg) administration significantly increased ITMS and ITTS (<0.05). Moreover, the ITMS and ITTS in -treated rats were significantly higher in luteal phases, compared to the follicular phase (<0.05). In addition, pretreatment with VPA significantly decreased SD, compared to the control group (<0.05). A significant decrease in SD was observed in the rats pretreated with (100 and 150 mg/kg) (<0.05). Seizure duration significantly decreased in animals that received in luteal phases, compared to the follicular phase (<0.05). These results suggested that have anticonvulsant effects that are more prominent during the luteal phase than the follicular phase.
Topics: Animals; Female; Rats; Anticonvulsants; Estrus; Ginsenosides; Pentylenetetrazole; Seizures; Valproic Acid
PubMed: 38226383
DOI: 10.32592/ARI.2023.78.4.1359 -
Organic Letters Jun 2023The 28-hetero-2,7-naphthiporphyrins reacted with triethylamine and diethylamine to form nonaromatic intracavity-extended macrocycles incorporating...
The 28-hetero-2,7-naphthiporphyrins reacted with triethylamine and diethylamine to form nonaromatic intracavity-extended macrocycles incorporating naphthodihydro-2-pyran, naphthotetrahydropyridine, and naphthopyrrolotetrahydro-1-azepine moieties. The new macrocycles were characterized in solution by means of NMR and UV-vis spectroscopy and in the solid state by XRD.
Topics: Magnetic Resonance Spectroscopy; Pyrans
PubMed: 37345966
DOI: 10.1021/acs.orglett.3c01715 -
Journal of the American Chemical Society Aug 2023In this study, we describe the direct insertion of an intramolecular nitrogen atom into an aromatic C-C bond. In this transformation, carbamoyl azides are activated by a...
In this study, we describe the direct insertion of an intramolecular nitrogen atom into an aromatic C-C bond. In this transformation, carbamoyl azides are activated by a Rh catalyst and subsequently directly inserted into the C-C bond of an arene ring to access fused azepine products. This transformation is challenging, owing to the existence of a competitive C-H amination pathway. The use of a paddlewheel dirhodium complex Rh(esp) effectively inhibited the undesired C-H insertion. Density functional theory calculations were performed to reveal the reaction mechanism and origin of the chemoselectivity of the Rh-catalyzed reactions. The novel fused azepine products are highly robust and allow for downstream diversification.
PubMed: 37535929
DOI: 10.1021/jacs.3c07640 -
BMC Chemistry Oct 2023As an essential marker of cancer treatment, PARP-1 inhibitors could effectively kill tumor cells through a mechanism known as synthetic lethality and are used to treat a...
As an essential marker of cancer treatment, PARP-1 inhibitors could effectively kill tumor cells through a mechanism known as synthetic lethality and are used to treat a variety of cancers. In order to explore novel PARP-1 inhibitors, a series of 22 novel erythrina derivatives were reported and preliminarily explored their mechanism of action. The antitumor activities against four human cancer cell lines including A549, OVCAR-3, HCT-116, and MCF-7 were evaluated, and the preliminary SARs were summarized. Among them, compound 11b exhibited better anti-proliferative effects against A549 cells (IC = 1.95 µM). The SI results showed that compound 11b had low toxicity. Moreover, compound 11b displayed excellent PARP-1 inhibitory activities with IC values of 19.24 nM. In addition, molecular docking studies provided the rational binding modes of compound 11b in complexes with PARP-1. The flow cytometry assays revealed that compound 11b could induce apoptosis of A549 cells (P < 0.001). Simultaneously, compound 11b could effectively reduce the formation of PAR (P < 0.001). The ADMET prediction results indicated compound 11b had similar properties to rucaparib. Collectively, compound 11b has potential research value for further investigation.
PubMed: 37891641
DOI: 10.1186/s13065-023-01060-8 -
Nucleic Acids Research Feb 2024Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes,...
Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (-)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1's tert-butyl moiety as a PXR anchor and explains binding by (-)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (-)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes.
Topics: Azepines; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 CYP3A; Nuclear Proteins; Pregnane X Receptor; Proto-Oncogene Proteins c-myc; Receptors, Cytoplasmic and Nuclear; Triazoles; Humans
PubMed: 38084912
DOI: 10.1093/nar/gkad1175 -
Organic Letters Sep 2023An unprecedented decomposition of unprotected alkynyl hydrazones is attempted that has provided allenoates, tetrasubstituted α,γ-dihaloallenoates, and functionalized...
An unprecedented decomposition of unprotected alkynyl hydrazones is attempted that has provided allenoates, tetrasubstituted α,γ-dihaloallenoates, and functionalized tricyclic azepines. A reaction of alkynyl hydrazones with -halosuccinimides captures the electrophile in 2-fold that delivers fully substituted dibromo- and diiodoallenoates in good yields. In addition, a DABCO-promoted Wolff-Kishner reduction of hydrazones, followed by isomerization, provides versatile allenoates under mild conditions. In contrast, a similar decomposition with ambiphilic DBU furnishes a completely different tricyclic azepine scaffold in excellent yield and diastereoselectivity.
PubMed: 37669229
DOI: 10.1021/acs.orglett.3c01994