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Neurologia May 2024In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica...
INTRODUCTION
In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice.
METHODS
HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests.
RESULTS
All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures.
CONCLUSIONS
It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.
Topics: Animals; Mice; Anticonvulsants; Pentylenetetrazole; Paeonia; Flumazenil; Seizures
PubMed: 38616060
DOI: 10.1016/j.nrleng.2021.08.004 -
International Journal of Molecular... Mar 2024This study presents the synthesis of four series of novel hybrid chalcones ()- and ()- and six series of 1,3,5-triazine-based pyrimido[4,5-][1,4]diazepines (-)- and the...
Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7-pyrimido[4,5-][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.
This study presents the synthesis of four series of novel hybrid chalcones ()- and ()- and six series of 1,3,5-triazine-based pyrimido[4,5-][1,4]diazepines (-)- and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones ,, ,, ,-, - and the pyrimido[4,5-][1,4]diazepines ,, , ,,-, ,,- exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI values between 0.01 and 100 μM and LC values in the range of 4.09 μM to >100 μM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against , (ATCC 43300), and were exhibited by the pyrimido[4,5-][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone and triazinyloxy-chalcone were the most active compounds against and and , respectively (MICs = 62.5 μg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.
Topics: Chalcones; Antifungal Agents; Staphylococcus aureus; Anti-Bacterial Agents; Azepines; Fluorouracil; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Triazines; Isocyanates
PubMed: 38612435
DOI: 10.3390/ijms25073623 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2024To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism...
OBJECTIVE
To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect.
METHODS
Male C57BL/6J mouse models of depression was established by oral administration of corticosterone drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining.
RESULTS
The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1β, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1β, IL-10, TNF-α, and IFN-γ in the hippocampus ( < 0.05).
CONCLUSION
Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.
Topics: Male; Mice; Animals; Pentylenetetrazole; Interleukin-10; Microglia; Tumor Necrosis Factor-alpha; Depression; Corticosterone; Mice, Inbred C57BL; Seizures; Epilepsy; Hippocampus; Inflammation; Interleukin-1beta; Disease Models, Animal; Oleanolic Acid; Saponins
PubMed: 38597443
DOI: 10.12122/j.issn.1673-4254.2024.03.13 -
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 -
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 -
Biochemical Pharmacology May 2024Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance,...
Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/β-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, β-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/β-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.
Topics: Humans; Animals; Mice; Wnt Signaling Pathway; MAP Kinase Signaling System; Cell Proliferation; Antineoplastic Agents; Urinary Bladder Neoplasms; Cell Line, Tumor; beta Catenin; Cell Movement; Apoptosis; Azepines; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines
PubMed: 38484850
DOI: 10.1016/j.bcp.2024.116125 -
Water Research May 2024Municipal wastewater treatment plants (WWTPs) play a crucial role in the collection and redistribution of plastic particles from both households and industries,...
Municipal wastewater treatment plants (WWTPs) play a crucial role in the collection and redistribution of plastic particles from both households and industries, contributing to their presence in the environment. Previous studies investigating the levels of plastics in WWTPs, and their removal rates have primarily focused on polymer type, size, shape, colour, and particle count, while comprehensive understanding of the mass concentration of plastic particles, particularly those <1 µm (nanoplastics), remains unclear and lacking. In this study, pyrolysis gas chromatography-mass spectrometry was used to simultaneously determine the mass concentration of nine selected polymers (i.e., polyethylene (PE), polypropylene (PP), polystyrene (PS), poly(ethylene terephthalate) (PET), nylon 6, nylon 66, polyvinylchloride (PVC), poly(methyl methacrylate) (PMMA) and polycarbonate (PC)) below 1 µm in size across the treatment processes or stages of three WWTPs in Australia. All the targeted nanoplastics were detected at concentrations between 0.04 and 7.3 µg/L. Nylon 66 (0.2-7.3 µg/L), PE (0.1-6.6 µg/L), PP (0.1-4.5 µg/L), Nylon 6 (0.1-3.6 µg/L) and PET (0.1-2.2 µg/L), were the predominant polymers in the samples. The mass concentration of the total nanoplastics decreased from 27.7, 18 and 9.1 µg/L in the influent to 1, 1.4 and 0.8 µg/L in the effluent, with approximate removal rates of 96 %, 92 % and 91 % in plants A, B and C, respectively. Based on annual wastewater effluent discharge, it is estimated that approximately 24, 2 and 0.7 kg of nanoplastics are released into the environment per year for WWTPs A, B and C, respectively. This study investigated the mass concentrations and removal rates of nanoplastics with a size range of 0.01-1 µm in wastewater, providing important insight into the pollution levels and distribution patterns of nanoplastics in Australian WWTPs.
Topics: Wastewater; Microplastics; Nylons; Pyrolysis; Gas Chromatography-Mass Spectrometry; Australia; Plastics; Polypropylenes; Polymethyl Methacrylate; Polyethylenes; Water Purification; Water Pollutants, Chemical; Environmental Monitoring; Caprolactam; Polymers
PubMed: 38461599
DOI: 10.1016/j.watres.2024.121397 -
Biomedicine & Pharmacotherapy =... Apr 2024Lilii Bulbus (Lilium lancifolium Thunberg) has a proneurogenic effect on the hippocampus. However, its effects on epilepsy and associated pathological features remain...
Lilii Bulbus (Lilium lancifolium Thunberg) has a proneurogenic effect on the hippocampus. However, its effects on epilepsy and associated pathological features remain unknown. In this study, we investigated the antiseizure effects of a water extract of Lilii Bulbus (WELB) in mouse model of pentylenetetrazol (PTZ)-induced seizure. Mice were injected with PTZ once every 48 h until full kindling was achieved. WELB (100 and 500 mg/kg) was orally administered once daily before PTZ administration and during the kindling process. We found that WELB treatment protected against PTZ-induced low seizure thresholds and high seizure severity. Further, WELB-treated mice showed attenuated PTZ kindling-induced anxiety and memory impairment. Immunostaining and immunoblots showed that hyperactivation and ectopic migration of dentate granule cells (DGCs) were significantly reduced by WELB treatment in PTZ kindling-induced seizure mice. Staining for mossy fiber sprouting (MFS) using Timm staining and ZnT3 showed that WELB treatment significantly decreased PTZ kindling-induced MFS. Furthermore, the increased or decreased expression of proteins related to ectopic DGCs (Reelin and Dab-1), MFS (Netrin-1, Sema3A, and Sema3F), and their downstream effectors (ERK, AKT, and CREB) in the hippocampus of PTZ kindling mice was significantly restored by WELB treatment. Overall, our findings suggest that WELB is a potential antiseizure drug that acts by reducing ectopic DGCs and MFS and modulating epileptogenesis-related signaling in the hippocampus.
Topics: Animals; Mice; Kindling, Neurologic; Netrin-1; Pentylenetetrazole; Seizures; Semaphorins
PubMed: 38460369
DOI: 10.1016/j.biopha.2024.116385