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Neuropsychopharmacology : Official... Feb 2024Autism spectrum disorder (ASD) is a complicated, neurodevelopmental disorder characterized by social deficits and stereotyped behaviors. Accumulating evidence suggests...
Autism spectrum disorder (ASD) is a complicated, neurodevelopmental disorder characterized by social deficits and stereotyped behaviors. Accumulating evidence suggests that ferroptosis is involved in the development of ASD, but the underlying mechanism remains elusive. Puerarin has an anti-ferroptosis function. Here, we found that the administration of puerarin from P12 to P15 ameliorated the autism-associated behaviors in the VPA-exposed male mouse model of autism by inhibiting ferroptosis in neural stem cells of the hippocampus. We highlight the role of ferroptosis in the hippocampus neurogenesis and confirm that puerarin treatment inhibited iron overload, lipid peroxidation accumulation, and mitochondrial dysfunction, as well as enhanced the expression of ferroptosis inhibitory proteins, including Nrf2, GPX4, Slc7a11, and FTH1 in the hippocampus of VPA mouse model of autism. In addition, we confirmed that inhibition of xCT/Slc7a11-mediated ferroptosis occurring in the hippocampus is closely related to puerarin-exerted therapeutic effects. In conclusion, our study suggests that puerarin targets core symptoms and hippocampal neurogenesis reduction through ferroptosis inhibition, which might be a potential drug for autism intervention.
Topics: Male; Animals; Mice; Autism Spectrum Disorder; Valproic Acid; Ferroptosis; Autistic Disorder; Disease Models, Animal; Isoflavones
PubMed: 37491673
DOI: 10.1038/s41386-023-01659-4 -
Journal For Immunotherapy of Cancer Jul 2023The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy....
The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy. However, only limited efficacy is observed in acute myeloid leukaemia (AML). In the study, We detected CD123 and CLL-1 expression on leukaemia cells from Relapsed/Refractory AML (R/R AML) patients. Then, we constructed anti-CD123 CAR and CLL-1 CAR with different co-stimulation domains (CD28 or 4-1BB) and detected their anti-AML effects. To increase the efficacy of CAR-T cell therapy, we tested different strategies, including application of combined checkpoint inhibitors and histone deacetylase inhibitors (HDACi) and We found CD123 and CLL-1 were highly expressed on AML cells. The proportions of T cell subsets and NK cells involved in anti-tumour or anti-inflammation processes in AML patients significantly decreased when compared with healthy donors. Both CD123 CAR and CLL-1 CAR displayed specific anti-AML effects To improve the lysis effects of CAR-T cells, we combined CAR-T cell therapy with different agents. PD-1/PD-L1 antibodies only slightly improved the potency of CAR-T cell therapy (CD123 CAR-T 60.92% ± 2.9087% vs. 65.43% ± 2.1893%, 60.92% ± 2.9087% vs. 67.43% ± 3.4973%; 37.37% ± 3.908% vs. 41.89% ± 5.1568%, 37.37% ± 3.908% vs. 42.84% ± 4.2635%). However, one HDACi (valproic acid [VPA]) significantly improved CAR-T cell potency against AML cells (CLL-1 CAR-T 34.97% ± 0.3051% vs. 88.167% ± 1.5327%, p < 0.0001; CD123 CAR-T 26.87% ± 2.7010% vs. 82.56% ± 3.086%, p < 0.0001 in MV411; CLL-1 CAR-T 78.77% ± 1.2061% vs. 93.743% ± 1.2333%, p < 0.0001; CD123 CAR-T 64.10% ± 1.5130% vs. 94.427% ± 0.142%, p = 0.0001 in THP-1). Combination therapy prolonged the overall survival of mice when compared with single CD123 CAR-T cell therapy (median survival: 180 days vs. unfollowed). A possible mechanism is that activated CD8+T cells upregulate natural-killer group 2 member D (NKG2D), and VPA upregulates NKG2D ligand expression in AML cells, contributing to NKG2D-mediated cytotoxicity of CAR-T cells against tumour cells. In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.
Topics: Animals; Mice; Valproic Acid; Receptors, Chimeric Antigen; Leukemia, Lymphocytic, Chronic, B-Cell; NK Cell Lectin-Like Receptor Subfamily K; Cell Line, Tumor; Leukemia, Myeloid, Acute; T-Lymphocytes
PubMed: 37524506
DOI: 10.1136/jitc-2023-006857 -
Handbook of Clinical Neurology 2024Migraine headache is highly prevalent and the most common neurologic disorder, affecting one billion people worldwide. It is also the most disabling condition in people... (Review)
Review
Migraine headache is highly prevalent and the most common neurologic disorder, affecting one billion people worldwide. It is also the most disabling condition in people under 50, with a huge impact on working ability, family, and social life. Access to effective preventive medication is important and may be considered if the patient has 6 or more migraine days per month, ineffective abortive agents, or disability on 2 or more days per month. Propranolol, metoprolol, candesartan, topiramate, divalproex, lisinopril, amitriptyline, and venlafaxine have the strongest evidence to support for use. Flunarizine and pizotifen may also be effective. Selection of preventive treatments is based on individual characteristics, comorbid conditions, efficacy, contraindications, side effects, cost, compliance, and drug. An adequate trial of migraine prophylaxis is usually 2 months at the target dose, and it is always important to re-evaluate indication for prophylactic use after a period of time.
Topics: Humans; Administration, Oral; Amitriptyline; Migraine Disorders; Propranolol; Valproic Acid
PubMed: 38307673
DOI: 10.1016/B978-0-12-823357-3.00009-4 -
Toxicology and Applied Pharmacology Sep 2023The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion)....
The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion). Syncytialization of trophoblasts is important for maintaining placental functions. Epilepsy is one of the most common neurological conditions worldwide. Therefore, this study aimed to reveal the influence of antiepileptic drugs, including valproic acid (VPA), carbamazepine, lamotrigine, gabapentin, levetiracetam, topiramate, lacosamide, and clobazam, at clinically relevant concentrations on syncytialization using in vitro models of trophoblasts. To induce differentiation into syncytiotrophoblast-like cells, BeWo cells were treated with forskolin. Exposure to VPA was found to dose-dependently influence syncytialization-associated genes (ERVW-1, ERVFRD-1, GJA1, CGB, CSH, SLC1A5, and ABCC4) in differentiated BeWo cells. Herein, the biomarkers between differentiated BeWo cells and the human trophoblast stem model (TS) were compared. In particular, MFSD2A levels were low in BeWo cells but abundant in TS cells. VPA exposure affected the expression of ERVW-1, ERVFRD-1, GJA1, CSH, MFSD2A, and ABCC4 in differentiated cells (ST-TS). Furthermore, VPA exposure attenuated BeWo and TS cell fusion. Finally, the relationships between neonatal/placental parameters and the expression of syncytialization markers in human term placentas were analyzed. MFSD2A expression was positively correlated with neonatal body weight, head circumference, chest circumference, and placental weight. Our findings have important implications for better understanding the mechanisms of toxicity of antiepileptic drugs and predicting the risks to placental and fetal development.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Placenta; Trophoblasts; Valproic Acid; Anticonvulsants; Cell Line; ATP-Binding Cassette Transporters; Minor Histocompatibility Antigens; Amino Acid Transport System ASC
PubMed: 37385477
DOI: 10.1016/j.taap.2023.116611 -
International Journal of Molecular... Dec 2023Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials... (Review)
Review
Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.
Topics: Animals; Male; Female; Pregnancy; Humans; Valproic Acid; Cleft Lip; Cleft Palate; Fetus; Teratogenesis; Anticonvulsants; Teratogens; Epilepsy
PubMed: 38203562
DOI: 10.3390/ijms25010390 -
Drug Research Sep 2023Loads of new therapeutic regimes have been turned up to manage Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in elderly patients who are... (Review)
Review
Loads of new therapeutic regimes have been turned up to manage Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in elderly patients who are unfit for intensive chemotherapy. Despite accumulating research, the best MDS and AML management approach is indeterminate. Myelodysplastic syndrome implies a group of various hematopoietic stem cell disorders that may progress to acute myeloid leukemia. These disorders are more frequent in older adults. To the high rate of morbidity and abundant toxicities related to the therapeutic approaches, also, the treatment would be challenging. The clinical effectiveness of valproic acid, a histone deacetylase inhibitor, in MDS and AML patients is unknown, even though it has demonstrated positive activities to promote differentiation and apoptosis in cancer cells. We investigated the clinical research on the effects of valproic acid in conjunction with various drugs, including low-dose cytarabine, all-trans retinoic acid, DNA-hypomethylating agents, hydrazine, and theophylline. We conclude that VPA is a safe and effective treatment option for MDS and AML patients, particularly when used in conjunction with all-trans retinoic acid, DNA-hypomethylating drugs, and hydralazine. However, more randomized clinical studies are required to identify an ideal regimen.
Topics: Humans; Aged; Valproic Acid; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Tretinoin
PubMed: 37220791
DOI: 10.1055/a-2088-3718 -
Stem Cells (Dayton, Ohio) Aug 2023Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We...
Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator valproic acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells. VPA potentiated gene expression of key enterocyte markers ALPI, FABP2, and transporters such as SULT1B1. RNA-sequencing analysis further elucidated several function-related pathways involved in fatty acid metabolism, significantly upregulated by VPA when combined with VD3. Particularly, VPA treatment in tandem with VD3 significantly upregulated key regulators of enterohepatic circulation, such as FGF19, apical bile acid transporter SLCO1A2 and basolateral bile acid transporters SLC51A and SLC51B. To sum up, we could ascertain the genetic profile of our iPSC-ent cells to be specialized toward fatty acid absorption and metabolism instead of transporting other nutrients, such as amino acids, with the addition of VD3 and VPA in tandem. Together, these results suggest the possible application of VPA-treated iPSC-ent for modelling enterohepatic circulation.
Topics: Humans; Valproic Acid; Cholecalciferol; Induced Pluripotent Stem Cells; Enterocytes; Cells, Cultured
PubMed: 37228023
DOI: 10.1093/stmcls/sxad042 -
Medicina (Kaunas, Lithuania) Feb 2024Asterixis is a subtype of negative myoclonus characterized by brief, arrhythmic lapses of sustained posture due to involuntary pauses in muscle contraction. We performed... (Review)
Review
Asterixis is a subtype of negative myoclonus characterized by brief, arrhythmic lapses of sustained posture due to involuntary pauses in muscle contraction. We performed a narrative review to characterize further asterixis regarding nomenclature, historical aspects, etiology, pathophysiology, classification, diagnosis, and treatment. Asterixis has been classically used as a synonym for negative myoclonus across the literature and in previous articles. However, it is important to distinguish asterixis from other subtypes of negative myoclonus, for example, epileptic negative myoclonus, because management could change. Asterixis is not specific to any pathophysiological process, but it is more commonly reported in hepatic encephalopathy, renal and respiratory failure, cerebrovascular diseases, as well as associated with drugs that could potentially lead to hyperammonemia, such as valproic acid, carbamazepine, and phenytoin. Asterixis is usually asymptomatic and not spontaneously reported by patients. This highlights the importance of actively searching for this sign in the physical exam of encephalopathic patients because it could indicate an underlying toxic or metabolic cause. Asterixis is usually reversible upon treatment of the underlying cause.
Topics: Humans; Myoclonus; Tremor; Dyskinesias; Brain Diseases; Carbamazepine
PubMed: 38541088
DOI: 10.3390/medicina60030362 -
Infection and Drug Resistance 2023Cefoperazone/sulbactam is a β-lactam/β-lactamase inhibitor combination effective against intra-abdominal, urinary tract, and respiratory infections. Although some...
PURPOSE
Cefoperazone/sulbactam is a β-lactam/β-lactamase inhibitor combination effective against intra-abdominal, urinary tract, and respiratory infections. Although some studies have suggested that cefoperazone/sulbactam is associated with coagulation disorders, it remains debatable whether the combination of cefoperazone/sulbactam with tigecycline or valproic acid increases the risk of bleeding, as both drugs can lead to coagulation disorders. This study aimed to explore the risk factors of cefoperazone/sulbactam-induced coagulopathy.
PATIENTS AND METHODS
This was a single-center, retrospective, nested case-control study. The sample groups were derived from individuals registered at the Department of Neurosurgery, Shanxi Provincial People's Hospital. Propensity score matching (PSM) was used to adjust for demographic data. Conditional logistic regression was used to estimate the matched odds ratios representing the odds of cefoperazone/sulbactam-induced coagulopathy (CIC), and a receiver operating characteristic curve was used to determine the optimal cut-off conditions.
RESULTS
After PSM, 155 and 56 patients were included in the control and case groups, respectively. Multivariate analysis revealed that advanced age, treatment duration, and total dose were independent risk factors of cefoperazone/sulbactam-induced coagulation disorders. Concomitant use of vitamin K was an independent protective factor against CIC. The optimal cut-off for the length of treatment was 5 d, and the cut-off for the total dose was 48 g.
CONCLUSION
Tigecycline and valproic acid were not associated with CIC. Advanced age and long treatment duration are risk factors for CIC. Supplementation with vitamin K during cefoperazone/sulbactam treatment was associated with a reduced risk.
PubMed: 37766881
DOI: 10.2147/IDR.S429706 -
Phytomedicine : International Journal... Apr 2024Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has...
BACKGROUND
Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy.
PURPOSE
This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism.
METHODS/STUDY DESIGN
CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism.
RESULTS
The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma.
CONCLUSION
The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.
Topics: Humans; Valproic Acid; Reactive Oxygen Species; bcl-2-Associated X Protein; Apoptosis; Osteosarcoma; Cell Line, Tumor; Bone Neoplasms; Cell Proliferation; Early Growth Response Protein 1; Naphthoquinones
PubMed: 38417243
DOI: 10.1016/j.phymed.2024.155459