-
Current Pharmaceutical Design 2024Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its...
BACKGROUND
Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear.
OBJECTIVE
This study aims to reveal the anti-SMA mechanisms of securinine.
METHODS
Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein Interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine.
RESULTS
Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway.
CONCLUSION
Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.
Topics: Network Pharmacology; Muscular Atrophy, Spinal; Humans; Plants, Medicinal; Molecular Docking Simulation; Azepines; Lactones; Molecular Structure; Heterocyclic Compounds, Bridged-Ring; Piperidines
PubMed: 38561613
DOI: 10.2174/0113816128288504240321041408 -
Neurochemistry International Jun 2024Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations...
Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.
Topics: Animals; Male; Mice; Anticonvulsants; Brain; Deferasirox; Epilepsy; Homeostasis; Iron; Iron Chelating Agents; Kindling, Neurologic; Pentylenetetrazole; Rats, Sprague-Dawley; Membrane Proteins
PubMed: 38561151
DOI: 10.1016/j.neuint.2024.105725 -
Molecules (Basel, Switzerland) Mar 2024The fruits of Swartz, a wild relative of eggplant, are consumed as a wild vegetable in tropical regions of Africa, Asia, and South America. In traditional Chinese...
The fruits of Swartz, a wild relative of eggplant, are consumed as a wild vegetable in tropical regions of Africa, Asia, and South America. In traditional Chinese medicine, it is believed to have anti-inflammatory and sedative effects. In the Philippines, water decoction is used to treat hyperactivity disorder. Twenty-two steroidal saponins were isolated and purified from the fruits grown in Yunnan, China, including six new compounds: torvosides U-Z (-). During drying and cooking, the saponins may undergo transformation, resulting in small amounts of sapogenins. These transformations can include dehydration of hydroxyl groups at position C22, formation of double bonds at position 20, 22 or 22, 23, and even formation of peroxide products. Saponin compounds torvoside X (), torvoside Y (), torvoside A (), and (25)-3-oxo-5-spirostan-6-yl---d-xylopyranoside (), which are glycosylated at C-6, showed certain anti-epileptic activity in a pentylenetetrazole-induced zebrafish seizure model. No antiproliferative activity was detected when tested on the cancer cell line HepG2, and no hepatotoxic effect was noted on normal liver cell line LO2.
Topics: Animals; Solanum; Solanum melongena; Fruit; Zebrafish; Pentylenetetrazole; China; Saponins; Anticonvulsants; Seizures
PubMed: 38542951
DOI: 10.3390/molecules29061316 -
International Journal of Molecular... Mar 2024Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally...
Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM's anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography-mass spectrometry (LC-MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.
Topics: Animals; Topiramate; Zebrafish; Pentylenetetrazole; Caffeine; Chromatography, Liquid; Fructose; Tandem Mass Spectrometry; Seizures; Anticonvulsants; Epilepsy
PubMed: 38542281
DOI: 10.3390/ijms25063309 -
Biomedicine & Pharmacotherapy =... May 2024Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and...
Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney-an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.
Topics: Animals; Azepines; Reperfusion Injury; Triazoles; Renal Insufficiency, Chronic; Mice; Disease Progression; Mice, Inbred C57BL; Kidney; Male; Liposomes; Transcription Factors; Acute Kidney Injury; Disease Models, Animal; Nanoparticles; Cell Cycle Proteins; Bromodomain Containing Proteins; Nuclear Proteins
PubMed: 38537579
DOI: 10.1016/j.biopha.2024.116492 -
Molecular Pharmaceutics May 2024Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor...
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(β-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both and , the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.
Topics: Triple Negative Breast Neoplasms; Tumor Microenvironment; Animals; Female; Mice; Humans; Celecoxib; Cell Line, Tumor; Chondroitin Sulfates; Nanoparticles; Melitten; Apoptosis; Nanoparticle Drug Delivery System; Xenograft Model Antitumor Assays; Mice, Inbred BALB C; Cyclooxygenase 2 Inhibitors; Polymers; Mice, Nude; Drug Delivery Systems; Azepines; Triazoles
PubMed: 38536949
DOI: 10.1021/acs.molpharmaceut.3c00242 -
The Journal of Organic Chemistry Apr 2024Formal total syntheses of stemonamine and cephalotaxine bearing the core cyclopenta[1,2-]pyrrolo[1,2-]azepine ring skeleton were achieved. The general synthetic strategy...
Reductive Oxy-Nazarov Cyclization toward Expedient Construction of a Cyclopenta[1,2-]pyrrolo[1,2-]azepine Ring System: Formal Total Syntheses of Stemonamine and Cephalotaxine.
Formal total syntheses of stemonamine and cephalotaxine bearing the core cyclopenta[1,2-]pyrrolo[1,2-]azepine ring skeleton were achieved. The general synthetic strategy in the synthesis features the reductive oxy-Nazarov cyclization as key step, leading to the versatile construction of N-substituted spiro quaternary stereogenic centers from readily available starting materials.
PubMed: 38536410
DOI: 10.1021/acs.joc.4c00035 -
Journal of Opioid Management 2024Tianeptine, an antidepressant and full µ-opioid receptor agonist, has increased in popularity and has been used as an over-the-counter supplement over the past decade....
Tianeptine, an antidepressant and full µ-opioid receptor agonist, has increased in popularity and has been used as an over-the-counter supplement over the past decade. Due to its well-documented euphoric effects, there exists elevated risk for potential abuse. Buprenorphine-naloxone has been successfully utilized to treat opioid use disorder (OUD) in patients concurrently using tianeptine, limiting withdrawal symptoms and abstinence. However, there is limited evidence on the management of tianeptine use disorder, specifically methadone or naltrexone. The current opioid epidemic, the emerging use of tianeptine, and the lack of physician awareness have emphasized the need for further research on the role of tianeptine in medication-assisted treatment for OUD. This case report aims to demonstrate how medication-assisted therapy can be successfully utilized in a patient with opioid and severe other (tianeptine) drug use disorder.
Topics: Humans; Methadone; Analgesics, Opioid; Buprenorphine; Opiate Alkaloids; Opiate Substitution Treatment; Opioid-Related Disorders; Naltrexone; Thiazepines
PubMed: 38533719
DOI: 10.5055/jom.0851 -
Organic Letters Apr 2024A novel class of alkyne-tethered amides facilitates an unprecedented photoinduced palladium-catalyzed radical relay formal [5 + 2] reaction. This innovative strategy...
A novel class of alkyne-tethered amides facilitates an unprecedented photoinduced palladium-catalyzed radical relay formal [5 + 2] reaction. This innovative strategy allows for the rapid construction of diverse fused benzoazepine structures, yielding structurally novel and compelling compounds. With a broad substrate scope and excellent functional group tolerance, the methodology synthesizes biologically active compounds. Notably, the resulting tricyclic benzo[]azepines offer diversification opportunities through simple transformations. DFT calculations elucidate a seven-membered ring closure mechanism involving the alkenyl radical and Pd(I) rebound alongside a concerted metalation-deprotonation (CMD) process.
PubMed: 38530133
DOI: 10.1021/acs.orglett.4c00979 -
Pharmacology, Biochemistry, and Behavior Jun 2024One of the mechanisms of epileptgenesis is impairment of inhibitory neural circuits. Several studies have compared neural changes among subtypes of gamma-aminobutyric...
INTRODUCTION
One of the mechanisms of epileptgenesis is impairment of inhibitory neural circuits. Several studies have compared neural changes among subtypes of gamma-aminobutyric acid-related (GABAergic) neurons after acquired epileptic seizure. However, it is unclear that GABAergic neural modifications that occur during acquisition process of epileptic seizure.
METHODS
Male rats were injected with pentylenetetrazole (PTZ kindling: n = 30) or saline (control: n = 15) every other day to observe the development of epileptic seizure stages. Two time points were identified: the point at which seizures were most difficult to induce, and the point at which seizures were most easy to induce. The expression of GABAergic neuron-related proteins in the hippocampus was immunohistochemically compared among GABAergic subtypes at each of these time points.
RESULTS
Bimodal changes in seizure stages were observed in response to PTZ kindling. The increase of seizure stage was transiently suppressed after 8 or 10 injections, and then progressed again by the 16th injection. Based on these results, we defined 10 injections as a short-term injection period during which seizures are less likely to occur, and 20 injections as a long-term injection period during which continuous seizures are likely to occur. The immunohistochemical analysis showed that hippocampal glutamic acid decarboxylase 65 (GAD65) expression was increased after short-term kindling but unchanged after long-term kindling. Increased GAD65 expression was limited to somatostatin-positive (SOM) cells among several GABAergic subtypes. By contrast, GAD, GABA, GABAR α1, GABAR1, and VGAT cells showed no change following short- or long-term PTZ kindling.
CONCLUSION
PTZ kindling induces bimodal changes in the epileptic seizure stage. Seizure stage is transiently suppressed after short-term PTZ injection with GAD65 upregulation in SOM cells. The seizure stage is progressed again after long-term PTZ injection with GAD65 reduction to baseline level.
Topics: Animals; Pentylenetetrazole; Male; Glutamate Decarboxylase; Kindling, Neurologic; Rats; Hippocampus; Interneurons; Somatostatin; Rats, Sprague-Dawley; Seizures
PubMed: 38527654
DOI: 10.1016/j.pbb.2024.173755