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Cells Jul 2023Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast...
Breast cancer treatment can be improved with biomarkers for early detection and individualized therapy. A set of 86 microRNAs (miRNAs) were identified to separate breast cancer tumors from normal breast tissues ( = 52) with an overall accuracy of 90.4%. Six miRNAs had concordant expression in both tumors and breast cancer patient blood samples compared with the normal control samples. Twelve miRNAs showed concordant expression in tumors vs. normal breast tissues and patient survival ( = 1093), with seven as potential tumor suppressors and five as potential oncomiRs. From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. Combined with in-vitro proliferation assays using CRISPR-Cas9/RNAi and patient survival analysis, MEK inhibitors PD19830 and BRD-K12244279, pilocarpine, and tremorine were discovered as potential new drug options for treating breast cancer. Multi-omics biomarkers of response to the discovered drugs were identified using human breast cancer cell lines. This study presented an artificial intelligence pipeline of miRNA-based discovery of biomarkers, therapeutic targets, and repositioning drugs that can be applied to many cancer types.
Topics: Humans; Animals; Female; MicroRNAs; Breast Neoplasms; Drug Repositioning; Artificial Intelligence; Biomarkers; Mammary Neoplasms, Animal
PubMed: 37508580
DOI: 10.3390/cells12141917 -
IScience Sep 2023A single episode of pilocarpine-induced can trigger the development of spontaneous recurrent seizures in a rodent model for epilepsy. The initial seizure-induced events...
A single episode of pilocarpine-induced can trigger the development of spontaneous recurrent seizures in a rodent model for epilepsy. The initial seizure-induced events in neuronal nuclei that lead to long-term changes in gene expression and cellular responses likely contribute toward epileptogenesis. Using a transgenic mouse model to specifically isolate excitatory neuronal nuclei, we profiled the seizure-induced nuclear proteome via tandem mass tag mass spectrometry and observed robust enrichment of nuclear proteins associated with the SUMOylation pathway. In parallel with nuclear proteome, we characterized nuclear gene expression by RNA sequencing which provided insights into seizure-driven transcriptional regulation and dynamics. Strikingly, we saw widespread downregulation of zinc-finger transcription factors, specifically proteins that harbor Krüppel-associated box (KRAB) domains. Our results provide a detailed snapshot of nuclear events induced by seizure activity and demonstrate a robust method for cell-type-specific nuclear profiling that can be applied to other cell types and models.
PubMed: 37694138
DOI: 10.1016/j.isci.2023.107707 -
CNS Neuroscience & Therapeutics Sep 2023Deep brain stimulation (DBS) of the anterior nucleus of the thalamus, is an effective therapy for patients with drug-resistant epilepsy, yet, its mechanism of action...
AIMS
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus, is an effective therapy for patients with drug-resistant epilepsy, yet, its mechanism of action remains elusive. Adenosine kinase (ADK), a key negative regulator of adenosine, is a potential modulator of epileptogenesis. DBS has been shown to increase adenosine levels, which may suppress seizures via A1 receptors (A Rs). We investigated whether DBS could halt disease progression and the potential involvement of adenosine mechanisms.
METHODS
Control group, SE (status epilepticus) group, SE-DBS group, and SE-sham-DBS group were included in this study. One week after a pilocarpine-induced status epilepticus, rats in the SE-DBS group were treated with DBS for 4 weeks. The rats were monitored by video-EEG. ADK and A Rs were tested with histochemistry and western blot, respectively.
RESULTS
Compared with the SE group and SE-sham-DBS group, DBS could reduce the frequency of spontaneous recurrent seizures (SRS) and the number of interictal epileptic discharges. The DPCPX, an A R antagonist, reversed the effect of DBS on interictal epileptic discharges. In addition, DBS inhibited the overexpression of ADK and the downregulation of A Rs.
CONCLUSION
The findings indicate that DBS can reduce SRS in epileptic rats via inhibition of ADK and activation of A Rs. A Rs might be a potential target of DBS for the treatment of epilepsy.
Topics: Animals; Rats; Receptor, Adenosine A1; Adenosine Kinase; Epilepsy; Seizures; Status Epilepticus; Pilocarpine; Male; Rats, Sprague-Dawley; Disease Progression
PubMed: 37017409
DOI: 10.1111/cns.14199 -
Neuropeptides Oct 2023The unrelenting progression of neurodegenerative diseases has a negative impact on affected individuals, their families, and society. Recurrent epileptic seizures are...
The unrelenting progression of neurodegenerative diseases has a negative impact on affected individuals, their families, and society. Recurrent epileptic seizures are the hallmark of epilepsy, and treating it effectively remains difficult. Clarify and understanding effects of the antiepileptic drugs (AEDs) in epilepsy by comparing the therapeutic effects between rats receiving valproic acid (VPA) and Bee venom (BV) was aimed throughout the present study. Four male Wistar rat groups were included: control, epileptic group receiving pilocarpine (PILO), epileptic group treated with VPA and BV respectively. Cognitive functions were assessed by evaluating latency time in hot plate, despair swim test, grooming, rearing and ambulation frequency in the open field. BV has ameliorative effect on electrolytes balancing, assured by decreasing lipid peroxidation, nitric oxide and increasing catalase, superoxide dismutase and glutathione peroxidase activities. BV enhanced restoration of liver functions indicated by alanine transaminase (ALT) and aspartate transaminase (AST), total proteins, and albumin; hormonal parameters total and free testosterone, follicle stimulating hormone (FSH) and Luteinizing hormone (LH) were preserved by BV with great recovery of hippocampus, liver and testicular histopathology and ultrastructure comparing with the epileptic rats. The present findings suggested that BV and its active components offer fresh options for controlling epilepsy and prospective methods via minimize or manage the severe consequences.
Topics: Rats; Male; Animals; Testis; Rats, Wistar; Bee Venoms; Oxidative Stress; Epilepsy; Antioxidants; Liver; Seizures; Lipid Peroxidation; Hippocampus
PubMed: 37562116
DOI: 10.1016/j.npep.2023.102368 -
Acta Pharmacologica Sinica Mar 2024Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop...
Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABA receptors (GABARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC values at around 5 μM, and application of SchB (10 μM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 μM) eliminated both PTZ-induced inhibition on GABA-induced current (I) and strychnine (STR)-induced inhibition on glycine-induced current (I). Moreover, SchB (10 μM) efficiently rescued the impaired GABARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABARs-α1(S297Q)β2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of I and I. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABARs and GlyRs, supporting its potential as alternative therapies for epilepsy.
Topics: Mice; Animals; Humans; Receptors, Glycine; Pilocarpine; Strychnine; Seizures; Receptors, GABA-A; Epilepsy; Glycine; Hypnotics and Sedatives; gamma-Aminobutyric Acid; Polycyclic Compounds; Lignans; Cyclooctanes
PubMed: 38017298
DOI: 10.1038/s41401-023-01195-3 -
Biomedical Chromatography : BMC Apr 2024Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of... (Review)
Review
Temporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of such a metabolic profile using animal models of epilepsy could help identify new metabolites and pathways involved in the mechanisms of epileptogenesis process. In this study, we evaluated the metabolic profile during the epileptogenesis periods. Using a pilocarpine model of epilepsy, we analyzed the global metabolic profile of hippocampal extracts by untargeted metabolomics based on ultra-performance liquid chromatography-high-resolution mass spectrometry, at three time points (3 h, 1 week, and 2 weeks) after status epilepticus (SE) induction. We demonstrated that epileptogenesis periods presented different hippocampal metabolic profiles, including alterations of metabolic pathways of amino acids and lipid metabolism. Six putative metabolites (tryptophan, N-acetylornithine, N-acetyl-L-aspartate, glutamine, adenosine, and cholesterol) showed significant different levels during epileptogenesis compared to their respective controls. These putative metabolites could be associated with the imbalance of neurotransmitters, mitochondrial dysfunction, and cell loss observed during both epileptogenesis and epilepsy. With these findings, we provided an overview of hippocampal metabolic profiles during different stages of epileptogenesis that could help investigate pathways and respective metabolites as predictive tools in epilepsy.
Topics: Animals; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Metabolome; Pilocarpine
PubMed: 38154955
DOI: 10.1002/bmc.5820 -
Glia Jun 2024Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3...
Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti-inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine-induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE-induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF-κB) activity, and the production of interleukin-1β (IL1β) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF-κB signaling and the production of IL1β. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF-κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.
Topics: Animals; Humans; Mice; Astrocytes; Epilepsy; Hippocampus; NF-kappa B; Signal Transduction; Sirtuin 3; Status Epilepticus
PubMed: 38406970
DOI: 10.1002/glia.24520 -
International Journal of Molecular... Oct 2023Low phosphorus (LP) stress leads to a significant reduction in wheat yield, primarily in the reduction of biomass, the number of tillers and spike grains, the delay in...
Low phosphorus (LP) stress leads to a significant reduction in wheat yield, primarily in the reduction of biomass, the number of tillers and spike grains, the delay in heading and flowering, and the inhibition of starch synthesis and grouting. However, the differences in regulatory pathway responses to low phosphorus stress among different wheat genotypes are still largely unknown. In this study, metabolome and transcriptome analyses of G28 (LP-tolerant) and L143 (LP-sensitive) wheat varieties after 72 h of normal phosphorus (CK) and LP stress were performed. A total of 181 and 163 differentially accumulated metabolites (DAMs) were detected for G28CK vs. G28LP and L143CK vs. L143LP, respectively. Notably, the expression of pilocarpine (C07474) in G28CK vs. G28LP was significantly downregulated 4.77-fold, while the expression of neochlorogenic acid (C17147) in L143CK vs. L143LP was significantly upregulated 2.34-fold. A total of 4023 differentially expressed genes (DEGs) were acquired between G28 and L143, of which 1120 DEGs were considered as the core DEGs of LP tolerance of wheat after LP treatment. The integration of metabolomics and transcriptomic data further revealed that the LP tolerance of wheat was closely related to 15 metabolites and 18 key genes in the sugar and amino acid metabolism pathway. The oxidative phosphorylation pathway was enriched to four ATPases, two cytochrome c reductase genes, and fumaric acid under LP treatment. Moreover, , TFs (, ), and genes were related to the Pi starvation stress of wheat roots. Therefore, the differences in LP tolerance of different wheat varieties were related to energy metabolism, amino acid metabolism, phytohormones, and PHT proteins, and precisely regulated by the levels of various molecular pathways to adapt to Pi starvation stress. Taken together, this study may help to reveal the complex regulatory process of wheat adaptation to Pi starvation and provide new genetic clues for further study on improving plant Pi utilization efficiency.
Topics: Transcriptome; Seedlings; Triticum; Plant Proteins; Gene Expression Profiling; Metabolome; Phosphorus; Amino Acids; Gene Expression Regulation, Plant
PubMed: 37834288
DOI: 10.3390/ijms241914840 -
Rheumatology International Jul 2024Primary Sjögren's Syndrome (pSS) is a systemic chronic autoimmune disorder that contributes to dry mouth (xerostomia) and eyes (xerophthalmia). It mainly affects...
BACKGROUND
Primary Sjögren's Syndrome (pSS) is a systemic chronic autoimmune disorder that contributes to dry mouth (xerostomia) and eyes (xerophthalmia). It mainly affects females between 40 and 60 years old. So far, there is no treatment to cure SS; however, there is a list of medications that can ameliorate the symptoms. In addition, there has been no single test until now to detect pSS, but clinical and immunological investigations are applied as diagnostic tools. Therefore, this study aimed to explore the characteristics of pSS in Saudi patients based on the onset of the disease through laboratory findings and pharmaceutical management.
METHODOLOGY
This retrospective study examined diagnosed patients with pSS between 2018 and 2023 from the National Guard Hospital, Saudi Arabia. Data of pSS patients was categorized into two groups: early (under 40 years old) and late-onset (40 years old and above). Data on demographic information, mortality rate, and blood tests such as complete blood count (CBC), creatinine, erythrocyte sedimentation rate (ESR), and vitamin levels, in addition to prescribed medications, were collected from the patient's medical record. Chi-square and t-tests were mainly used, and statistical significance was determined at a P-value less than 0.05.
RESULTS
A total of 453 patients were included in the study, where the early-onset group comprised 136 and the late-onset group comprised 317 patients. The mean age of the early and late onset was 34.2 and 60.4, respectively. ESR was significantly higher in the early (46.3 mm/hr) and late-onset (49.8 mm/hr). The most common medication used by all pSS patients was hydroxychloroquine. However, artificial tears were mainly observed in the late-onset group. Other medications, such as pilocarpine, methotrexate, and azathioprine, were prescribed to pSS patients to a lesser extent.
CONCLUSION
This study suggests that the onset of pSS could occur even before the age of 40 among Saudi citizens. Notably, elevated ESR levels appeared to be a feature of pSS, which was consistent with other previous findings. The variability of some medications between early-onset and late-onset pSS may indicate disease progression. However, further investigations are required to confirm this observation.
Topics: Humans; Sjogren's Syndrome; Female; Adult; Retrospective Studies; Middle Aged; Male; Age of Onset; Saudi Arabia; Blood Sedimentation; Aged; Antirheumatic Agents
PubMed: 38839658
DOI: 10.1007/s00296-024-05626-0 -
Molecular Biotechnology Oct 2023To analyze the role of Nrf2-ARE signaling pathway in the regulation of the acute phase of pilocarpine-induced epilepsy in juvenile rats by Tatarinow Sweetflag Extract...
To analyze the role of Nrf2-ARE signaling pathway in the regulation of the acute phase of pilocarpine-induced epilepsy in juvenile rats by Tatarinow Sweetflag Extract (TSE). One hundred and twenty SPF-grade Wistar male rats were were divided into five groups by random number table method, namely, normal group, model group, low-dose TSE group, high-dose TSE group, low-dose TSE + Nrf2 inhibitor Brusatol group (low-dose TSE + BRU group), and high-dose TSE + Nrf2 inhibitor Brusatol group (high-dose TSE + BRU group), with 20 rats in each group. The success rate of modelling in the model group, low-dose TSE group, high-dose TSE group, low-dose TSE + BRU group, high-dose TSE + BRU group were 60.00% (12/20), 65.00% (13/20), 65.00% (13/20), 70.00% (14/20), and 70.00% (14/20), respectively, showing no significant difference (P > 0.05). The latency and incidence of class IV and V, discharge amplitude as well as frequency of rats in the low- and high-dose TSE groups were lower than those in the model group (P < 0.05); the lipid peroxide and malondialdehyde concentrations in hippocampal tissues in the low- and high-dose TSE groups were lower than those in the model group (P < 0.05); The Nrf2, NQO-1 and HO- 1 protein and mRNA expression levels were increased in the low- and high-dose TSE groups compared with the model group (P < 0.05). The therapeutic effect of TSE in rats with acute epilepsy was satisfactory, and its mechanism of action may be related to activation of Nrf2-ARE signaling pathway to reduce the degree of oxidative stress.
PubMed: 37878228
DOI: 10.1007/s12033-023-00911-y