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Scientific Reports Jul 2024This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion...
This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.
Topics: Ferroptosis; Animals; PPAR alpha; Myocardial Reperfusion Injury; 14-3-3 Proteins; Mice; Male; Reactive Oxygen Species; Up-Regulation; Mitochondria; Cell Line; Myocytes, Cardiac; Mice, Inbred C57BL; Rats; Disease Models, Animal
PubMed: 38956068
DOI: 10.1038/s41598-024-64638-9 -
Nature Communications Jul 2024Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially...
Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.
Topics: Dopamine; Animals; Humans; Optogenetics; Mice; Male; Corpus Striatum; Receptors, Dopamine; Mice, Inbred C57BL; Allosteric Regulation; Photometry; HEK293 Cells
PubMed: 38956067
DOI: 10.1038/s41467-024-49442-3 -
Scientific Reports Jul 2024Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists...
Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP), respectively. Ferroptosis was identified by assessing the levels of Fe, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.
Topics: Ferroptosis; Animals; Flavonoids; Rats; Disease Models, Animal; Male; Reactive Oxygen Species; Dopaminergic Neurons; Humans; Parkinson Disease; Cell Line, Tumor; Iron; alpha-Synuclein; Rats, Sprague-Dawley; Glutathione; Lipid Peroxidation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-E2-Related Factor 2
PubMed: 38956066
DOI: 10.1038/s41598-024-62910-6 -
Nature Communications Jul 2024C-H bond activation enables the facile synthesis of new chemicals. While C-H activation in short-chain alkanes has been widely investigated, it remains largely...
C-H bond activation enables the facile synthesis of new chemicals. While C-H activation in short-chain alkanes has been widely investigated, it remains largely unexplored for long-chain organic molecules. Here, we report light-driven C-H activation in complex organic materials mediated by 2D transition metal dichalcogenides (TMDCs) and the resultant solid-state synthesis of luminescent carbon dots in a spatially-resolved fashion. We unravel the efficient H adsorption and a lowered energy barrier of C-C coupling mediated by 2D TMDCs to promote C-H activation and carbon dots synthesis. Our results shed light on 2D materials for C-H activation in organic compounds for applications in organic chemistry, environmental remediation, and photonic materials.
PubMed: 38956055
DOI: 10.1038/s41467-024-49783-z -
Translational Psychiatry Jul 2024Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a...
Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a crucial role in cocaine addiction, involving decision-making, impulse control, memory, and emotional regulation. The PFC interacts with the brain's reward system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc). The PFC also projects to the lateral habenula (LHb), a brain region critical for encoding negative reward and regulating the reward system. In the current study, we examined the role of PFC-LHb projections in regulating cocaine reward-related behaviors. We found that optogenetic stimulation of the PFC-LHb circuit during cocaine conditioning abolished cocaine preference without causing aversion. In addition, increased c-fos expression in LHb neurons was observed in animals that received optic stimulation during cocaine conditioning, supporting the circuit's involvement in cocaine preference regulation. Molecular analysis in animals that received optic stimulation revealed that cocaine-induced alterations in the expression of GluA1 subunit of AMPA receptor was normalized to saline levels in a region-specific manner. Moreover, GluA1 serine phosphorylation on S845 and S831 were differentially altered in LHb and VTA but not in the PFC. Together these findings highlight the critical role of the PFC-LHb circuit in controlling cocaine reward-related behaviors and shed light on the underlying mechanisms. Understanding this circuit's function may provide valuable insights into addiction and contribute to developing targeted treatments for substance use disorders.
Topics: Animals; Prefrontal Cortex; Cocaine; Male; Reward; Habenula; Neurons; Receptors, AMPA; Optogenetics; Cocaine-Related Disorders; Neural Pathways; Rats; Proto-Oncogene Proteins c-fos; Phosphorylation; Ventral Tegmental Area; Behavior, Animal
PubMed: 38956048
DOI: 10.1038/s41398-024-02988-8 -
Nature Communications Jul 2024Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being...
Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills nematodes including diverse species of plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Cyprocide fails to kill organisms beyond nematodes, suggesting that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.
Topics: Animals; Cytochrome P-450 Enzyme System; Nematoda; Antinematodal Agents; Sulfides
PubMed: 38956039
DOI: 10.1038/s41467-024-49738-4 -
Cell Death & Disease Jul 2024The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute...
The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute injury. The therapeutic protein, a membrane-GPI anchored protein called Cripto, was immobilized in an injectable hydrogel delivery vehicle for local administration and sustained release. The hydrogel was made of poly(ethylene glycol)-fibrinogen (PEG-Fibrinogen, PF), in the form of injectable microspheres. The PF microspheres exhibited a spherical morphology with an average diameter of approximately 100 micrometers, and the Cripto protein was uniformly entrapped within them. The release rate of Cripto from the PF microspheres was controlled by tuning the crosslinking density of the hydrogel, which was varied by changing the concentration of poly(ethylene glycol) diacrylate (PEG-DA) crosslinker. In vitro experiments confirmed a sustained-release profile of Cripto from the PF microspheres for up to 27 days. The released Cripto was biologically active and promoted the in vitro proliferation of mouse myoblasts. The therapeutic effect of PF-mediated delivery of Cripto in vivo was tested in a cardiotoxin (CTX)-induced muscle injury model in mice. The Cripto caused an increase in the in vivo expression of the myogenic markers Pax7, the differentiation makers eMHC and Desmin, higher numbers of centro-nucleated myofibers and greater areas of regenerated muscle tissue. Collectively, these results establish the PF microspheres as a potential delivery system for the localized, sustained release of therapeutic proteins toward the accelerated repair of damaged muscle tissue following acute injuries.
Topics: Animals; Muscle, Skeletal; Mice; Polyethylene Glycols; Delayed-Action Preparations; Microspheres; Fibrinogen; Hydrogels; Regeneration; Myoblasts; Humans; Cell Proliferation; PAX7 Transcription Factor; Male; Mice, Inbred C57BL; Muscular Diseases
PubMed: 38956034
DOI: 10.1038/s41419-024-06645-2 -
Cell Death & Disease Jul 2024Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people's health. Current therapies include bone marrow transplantation and...
Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people's health. Current therapies include bone marrow transplantation and several hypomethylating agents. However, many elderly patients cannot benefit from bone marrow transplantation and many patients develop drug resistance to hypomethylating agents, making it urgent to explore novel therapy. RSL3 can effectively induce ferroptosis in various tumors and combination of RSL3 and hypomethylating agents is promising to treat many tumors. However, its effect in MDS was unknown. In this study, we found that RSL3 inhibited MDS cell proliferation through inducing ROS-dependent apoptosis. RSL3 inhibited Bcl-2 expression and increased caspase 3 and PARP cleavage. RNA-seq analysis revealed that MYB may be a potential target of RSL3. Rescue experiments showed that overexpression of MYB can rescue MDS cell proliferation inhibition caused by RSL3. Cellular thermal shift assay showed that RSL3 binds to MYB to exert its function. Furthermore, RSL3 inhibited tumor growth and decreased MYB and Bcl-2 expression in vivo. More importantly, RSL3 decreased the viability of bone marrow mononuclear cells (BMMCs) isolated from MDS patients, and RSL3 had a synergistic effect with DAC in MDS cells. Our studies have uncovered RSL3 as a promising compound and MYB/Bcl-2 signaling pathway as a potential target for MDS treatment.
Topics: Myelodysplastic Syndromes; Humans; Apoptosis; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Proto-Oncogene Proteins c-myb; Reactive Oxygen Species; Animals; Mice; Cell Proliferation; Mice, Nude; Male; Female
PubMed: 38956026
DOI: 10.1038/s41419-024-06866-5 -
Nature Communications Jul 2024Goal-directed tasks involve acquiring an internal model, known as a predictive map, of relevant stimuli and associated outcomes to guide behavior. Here, we identified...
Goal-directed tasks involve acquiring an internal model, known as a predictive map, of relevant stimuli and associated outcomes to guide behavior. Here, we identified neural signatures of a predictive map of task behavior in perirhinal cortex (Prh). Mice learned to perform a tactile working memory task by classifying sequential whisker stimuli over multiple training stages. Chronic two-photon calcium imaging, population analysis, and computational modeling revealed that Prh encodes stimulus features as sensory prediction errors. Prh forms stable stimulus-outcome associations that can progressively be decoded earlier in the trial as training advances and that generalize as animals learn new contingencies. Stimulus-outcome associations are linked to prospective network activity encoding possible expected outcomes. This link is mediated by cholinergic signaling to guide task performance, demonstrated by acetylcholine imaging and systemic pharmacological perturbation. We propose that Prh combines error-driven and map-like properties to acquire a predictive map of learned task behavior.
Topics: Animals; Mice; Perirhinal Cortex; Memory, Short-Term; Male; Learning; Mice, Inbred C57BL; Vibrissae; Acetylcholine; Behavior, Animal; Female
PubMed: 38956015
DOI: 10.1038/s41467-024-47365-7 -
East Asian Archives of Psychiatry :... Jun 2024We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment-refractory posttraumatic stress disorder (PTSD). The Preferred... (Review)
Review
We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment-refractory posttraumatic stress disorder (PTSD). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE were searched using key words: 'rivastigmine' OR 'Exelon' OR 'rivastigmine augmentation' OR 'Exelon augmentation' AND 'posttraumatic stress disorder*' OR 'post-traumatic stress disorder*' OR 'PTSD' OR 'combat disorder*' OR 'post-traumatic symptoms'. The asterisk specified plural forms of the relevant word. Four papers were identified, comprising one double-blind randomised controlled trial, one non-controlled open trial, one case series (presenting three case studies), and one paper with two case studies. The randomised controlled trial found no statistically significant difference in efficacy, using the PTSD CheckList-Military Version as the relevant outcomes measure, between the active add-on rivastigmine interventions and placebo or treatment as usual. The open trial, although reporting relatively positive outcomes, had a weak study design and lacked reporting of key information, including participant sex and age and pre-rivastigmine PTSD measures. The assessment of efficacy was based on participants' reporting of subjective benefits, and clinician-rating using a Clinical Global Impression, rather than established PTSD assessments scales. Although the five case studies reported improvement in PTSD symptoms, there were confounding factors and limitations in clinical and demographic data, warranting caution regarding attributed benefits. There is a lack of methodologically robust evidence supporting the efficacy of add-on rivastigmine for the treatment of refractory PTSD. Additional research may help in further evaluating its possible clinical efficacy.
Topics: Rivastigmine; Humans; Stress Disorders, Post-Traumatic; Neuroprotective Agents; Cholinesterase Inhibitors
PubMed: 38955788
DOI: 10.12809/eaap2353