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Redox Biology Jul 2023Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays...
Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.
Topics: Rats; Animals; AMP-Activated Protein Kinases; Ferroptosis; Forkhead Box Protein O3; Mitochondria; Signal Transduction; DNA, Mitochondrial; Glucose
PubMed: 37267686
DOI: 10.1016/j.redox.2023.102760 -
Science Advances Oct 2023Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed...
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Topics: Humans; Glioblastoma; Trifluoperazine; Brain Neoplasms; Temozolomide; Chemoradiotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37878712
DOI: 10.1126/sciadv.adf1332 -
Frontiers in Oncology 2023The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One... (Review)
Review
The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One promising avenue lies in the repurposing of existing drugs. This review explores the impact of phenothiazines, primarily used as antipsychotic agents, on key mechanisms driving tumor growth and metastasis. The cationic and amphiphilic nature of phenothiazines allows interaction with the lipid bilayer of cellular membranes, resulting in alterations in lipid composition, modulation of calcium channels, fluidity, thinning, and integrity of the plasma membrane. This is especially significant in the setting of increased metabolic activity, a higher proliferative rate, and the invasiveness of cancer cells, which often rely on plasma membrane repair. Therefore, properties of phenothiazines such as compromising plasma membrane integrity and repair, disturbing calcium regulation, inducing cytosolic K-RAS accumulation, and sphingomyelin accumulation in the plasma membrane might counteract multidrug resistance by sensitizing cancer cells to membrane damage and chemotherapy. This review outlines a comprehensive overview of the mechanisms driving the anticancer activities of phenothiazines derivates such as trifluoperazine, prochlorperazine, chlorpromazine, promethazine, thioridazine, and fluphenazine. The repurposing potential of phenothiazines paves the way for novel approaches to improve future cancer treatment.
PubMed: 38074670
DOI: 10.3389/fonc.2023.1320621 -
EMBO Molecular Medicine Jan 2024Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to...
Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.
Topics: Animals; Mice; Encephalitis Virus, Japanese; Methotrimeprazine; Neuroinflammatory Diseases; Encephalitis, Japanese; Antiviral Agents; Autophagy; Anti-Inflammatory Agents
PubMed: 38177535
DOI: 10.1038/s44321-023-00014-w -
Antiviral Research Feb 2024JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their...
JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their kidneys, while severe immunosuppression can result in JCPyV spread to the brain, causing the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Due to a lack of approved therapies to treat JCPyV and PML, the disease results in rapid deterioration, and is often fatal. In order to identify potential antiviral treatments for JCPyV, a high-throughput, large-scale drug screen was performed using the National Institutes of Health Clinical Collection (NCC). Drugs from the NCC were tested for inhibitory effects on JCPyV infection, and drugs from various classes that reduced JCPyV infection were identified, including receptor agonists and antagonists, calcium signaling modulators, and enzyme inhibitors. Given the role of calcium signaling in viral infection including Merkel cell polyomavirus and simian virus 40 polyomavirus (SV40), calcium signaling inhibitors were further explored for the capacity to impact JCPyV infection. Calcium and calmodulin inhibitors trifluoperazine (TFP), W-7, tetrandrine, and nifedipine reduced JCPyV infection, and TFP specifically reduced viral internalization. Additionally, TFP and W-7 reduced infection by BK polyomavirus, SV40, and SARS-CoV-2. These results highlight specific inhibitors, some FDA-approved, for the possible treatment and prevention of JCPyV and several other viruses, and further illuminate the calcium and calmodulin pathway as a potential target for antiviral drug development.
Topics: Humans; Calcium; Calmodulin; Neurodegenerative Diseases; Leukoencephalopathy, Progressive Multifocal; Polyomavirus Infections; JC Virus; Simian virus 40; Antiviral Agents; Sulfonamides
PubMed: 38246207
DOI: 10.1016/j.antiviral.2024.105817 -
RSC Advances Aug 2023Trifluoperazine (TFLP) is an important psychiatric medication that balances the dopamine (DA) level in the brain for patients suffering from neurological disorder...
Trifluoperazine (TFLP) is an important psychiatric medication that balances the dopamine (DA) level in the brain for patients suffering from neurological disorder diseases. An efficient electrochemical sensor is developed for detecting TFLP in real human serum samples. The sensor is fabricated by casting the GC surface with two consecutive thin layers, namely a graphene oxide-carbon nanotubes mixture (GRO-CNT), and iron-nickel nanoparticles (Fe-Ni). The diffusion-controlled oxidation process of TFLP at the composite surface includes one electron transfer process. Under optimized conditions, the sensor in human serum shows excellent catalytic effect for simultaneous determination of TFLP and dopamine (DA) in the same concentration range (0.5 μM to 18 μM) with low detection limits of 0.13 μM and 0.32 μM respectively. The combined effect of a large conductive surface area and the excellent catalytic activity of the nanocomposite improves the sensor's performance. The sensor exhibits a stable current response over four weeks, excellent reproducibility, and insignificant interference from common species present in human serum samples. The reliability test of using the sensor in serum samples shows good recovery of TFLP.
PubMed: 37622009
DOI: 10.1039/d3ra04334g -
Neurotherapeutics : the Journal of the... Mar 2024The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the upregulation of astrocytic...
Inhibition of aquaporin-4 and its subcellular localization attenuates below-level central neuropathic pain by regulating astrocyte activation in a rat spinal cord injury model.
The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the upregulation of astrocytic aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly upregulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocyte activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of the AQP4 channel and perivascular localization in the SDH. Targeted inhibition of AQP4 subcellular localization with trifluoperazine effectively diminished astrocyte activation in vitro and further ablated astrocyte activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerge as a promising agent to prevent chronic CNP after SCI.
Topics: Animals; Rats; Aquaporin 4; Astrocytes; Neuralgia; Niacinamide; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Dorsal Horn; Spinal Cord Injuries; Thiadiazoles
PubMed: 38237380
DOI: 10.1016/j.neurot.2023.e00306 -
IScience Mar 2024Blood-brain barrier (BBB) disruption following ischemic stroke (IS) can induce significant aftereffects. Elevated calmodulin (CaM) expression following stroke causes...
Blood-brain barrier (BBB) disruption following ischemic stroke (IS) can induce significant aftereffects. Elevated calmodulin (CaM) expression following stroke causes calcium overload-a key contributor to BBB collapse. Trifluoperazine (TFP), a CaM inhibitor, reduces CaM overexpression following IS. However, it remains unclear whether TFP participates in BBB repair after IS. We administered TFP to mice subjected to middle cerebral artery occlusion (MCAO) and bEnd.3 cells subjected to oxygen-glucose deprivation (OGD). TFP treatment in MCAO mice reduced cerebral CaM expression and infarct size and decreased BBB permeability. OGD-treated bEnd.3 cells showed significantly increased CaM protein levels and reduced tight junction (TJ) protein levels; these changes were reversed by TFP treatment. Our results found that TFP administration in mice inhibited actin contraction following cerebral ischemia-reperfusion by suppressing the MLCK/p-MLC pathway, thereby attenuating cell retraction, improving TJ protein integrity, and reducing BBB permeability. Consequently, this treatment may promote neurological function recovery after IS.
PubMed: 38439960
DOI: 10.1016/j.isci.2024.109156 -
Cureus Feb 2024This study aimed to evaluate the trends in the sociodemographic, clinical, and prescription characteristics of patients with psychotic illnesses seen in the outpatient...
A Naturalistic, Non-interventional Investigation of the Clinical and Sociodemographic Characteristics and Prescription Patterns in Patients With Psychotic Disorders at a Tertiary Care Facility in South Asia.
OBJECTIVES
This study aimed to evaluate the trends in the sociodemographic, clinical, and prescription characteristics of patients with psychotic illnesses seen in the outpatient psychiatry department of a tertiary care facility.
METHODS
Between March 2021 and April 2022, a cross-sectional, prospective, observational, naturalistic, non-interventional study was conducted. A total of two hundred prescriptions were analyzed. To assess the rationality of prescriptions, World Health Organization (WHO) indicators were also computed.
RESULTS
With a range of 18 to 75 years, the cohort's mean age was 40.26 years, and its average disease duration was 10.75 years. Sixty-seven patients (68.5%) were diagnosed with schizophrenia. Of the 200 prescriptions that were analyzed, 13 antipsychotic prescriptions were written 343 times. Olanzapine was prescribed as an antipsychotic the most frequently (132, 66%), followed by clozapine (75, 37.5%). Haloperidol (41, 20.5%), trifluoperazine (3, 1.5%), loxapine (1, 0.5%), and flupenthixol depot (1, 0.5%) were the most commonly prescribed typical antipsychotics. 91% (181/200) of patients received prescriptions for other drugs in addition to antipsychotics. Trihexyphenidyl (45%), escitalopram (30%), clonazepam (26.5%), sodium valproate (10%), propranolol (10.5%), and modafinil (9.5%) were the most frequently prescribed concurrent medicines. Forty-eight percent (95/200) of prescriptions demonstrated polypharmacy. Among patients, the frequency of antipsychotic prescriptions was 1 in 44% (88/200), 2 in 36.50% (73/200), 3 in 17% (34/200), 4 in 0.5% (1/200), and 5 again in 0.5% (1/200). Conclusions: On average, the cohort of the current study was young. The commonest diagnosis was mainly schizophrenia. Atypical antipsychotics accounted for the majority of antipsychotic prescriptions in the current study. In this study, a high prevalence of polypharmacy was noted.
PubMed: 38445139
DOI: 10.7759/cureus.53541