Neuroprotective potential of Mentha piperita extract prevents motor dysfunctions in mouse model of Parkinson's disease through anti-oxidant capacities.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Neurodegeneration of the substantia nigra (SN) and diminished release of dopamine are prominent causes of this progressive disease. The current study aims to evaluate the protective potential of ethanolic extract of Mentha piperita (EthMP) against rotenone-mediated PD features, dopaminergic neuronal degeneration, oxidative stress and neuronal survival in a mouse model. Swiss albino male mice were assigned to five groups: control (2.5% DMSO vehicle), PD (rotenone 2.5 mg/kg), EthMP and rotenone (200mg/kg and 2.5mg/kg, respectively), EthMP (200 mg/kg), and Sinemet, reference treatment containing levodopa and carbidopa (20 mg/kg and rotenone 2.5mg/kg). Behavioral tests for motor functional deficit analysis were performed. Anti-oxidant capacity was estimated using standard antioxidant markers. Histopathology of the mid-brain for neurodegeneration estimation was performed. HPLC based dopamine level analysis and modulation of gene expression using quantitative real-time polymerase chain reaction was performed for the selected genes. EthMP administration significantly prevented the rotenone-mediated motor dysfunctions compared to PD group as assessed through open field, beam walk, pole climb down, stepping, tail suspension, and stride length tests. EthMP administration modulated the lipid peroxidation (LPO), reduced glutathione (GSH), and superoxide dismutase (SOD) levels, as well as glutathione-s-transferase (GST) and catalase (CAT) activities in mouse brain. EthMP extract prevented neurodegeneration in the SN of mice and partially maintained dopamine levels. The expression of genes related to dopamine, anti-oxidant potential and synapses were modulated in M. piperita (MP) extract treated mice brains. Current data suggest therapeutic capacities of MP extract and neuroprotective capacities, possibly through antioxidant capacities. Therefore, it may have potential clinical applications for PD management.

Syagrus coronata fixed oil prevents rotenone-induced movement disorders and oxidative stress in Drosophila melanogaster.

One prominent aspect of Parkinson's disease (PD) is the presence of elevated levels of free radicals, including reactive oxygen species (ROS). Syagrus coronata (S. coronata), a palm tree, exhibits antioxidant activity attributed to its phytochemical composition, containing fatty acids, polyphenols, and flavonoids. The aim of this investigation was to examine the potential neuroprotective effects of S. coronata fixed oil against rotenone-induced toxicity using Drosophila melanogaster. Young Drosophila specimens (3-4 d old) were exposed to a diet supplemented with rotenone (50 µM) for 7 d with and without the inclusion of S. coronata fixed oil (0.2 mg/g diet). Data demonstrated that rotenone exposure resulted in significant locomotor impairment and increased mortality rates in flies. Further, rotenone administration reduced total thiol levels but elevated lipid peroxidation, iron (Fe) levels, and nitric oxide (NO) levels while decreasing the reduced capacity of mitochondria. Concomitant administration of S. coronata exhibited a protective effect against rotenone, as evidenced by a return to control levels of Fe, NO, and total thiols, lowered lipid peroxidation levels, reversed locomotor impairment, and enhanced % cell viability. Molecular docking of the oil lipidic components with antioxidant enzymes showed strong binding affinity to superoxide dismutase (SOD) and glutathione peroxidase (GPX1) enzymes. Overall, treatment with S. coronata fixed oil was found to prevent rotenone-induced movement disorders and oxidative stress in Drosophila melanogaster.

A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators.

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson's disease (PD), underscores the urgency of discovering novel therapeutic strategies. Given the limitations associated with available treatments for mitochondrial dysfunction-associated diseases, the search for new potent alternatives has become imperative. In this report, we embarked on an extensive screening of 4224 fractions from 384 Australian marine organisms and plant samples to identify natural products with protective effects on mitochondria. Our initial screening using PD patient-sourced olfactory neurosphere-derived (hONS) cells with rotenone as a mitochondria stressor resulted in 108 promising fractions from 11 different biota. To further assess the potency and efficacy of these hits, the 11 biotas were subjected to a subsequent round of screening on human neuroblastoma (SH-SY5Y) cells, using 6-hydroxydopamine to induce mitochondrial stress, complemented by a mitochondrial membrane potential assay. This rigorous process yielded 35 active fractions from eight biotas. Advanced analysis using an orbit trap mass spectrophotometer facilitated the identification of the molecular constituents of the most active fraction from each of the eight biotas. This meticulous approach led to the discovery of 57 unique compounds, among which 12 were previously recognized for their mitoprotective effects. Our findings highlight the vast potential of natural products derived from Australian marine organisms and plants in the quest for innovative treatments targeting mitochondrial dysfunction in neurodegenerative diseases.

Dopamine- and Grape-Seed-Extract-Loaded Solid Lipid Nanoparticles: Interaction Studies between Particles and Differentiated SH-SY5Y Neuronal Cell Model of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, primarily associated with dopaminergic neuron depletion in the Substantia Nigra. Current treatment focuses on compensating for dopamine (DA) deficiency, but the blood-brain barrier (BBB) poses challenges for effective drug delivery. Using differentiated SH-SY5Y cells, we investigated the co-administration of DA and the antioxidant Grape Seed Extract (GSE) to study the cytobiocompability, the cytoprotection against the neurotoxin Rotenone, and their antioxidant effects. For this purpose, two solid lipid nanoparticle (SLN) formulations, DA-co-GSE-SLNs and GSE-ads-DA-SLNs, were synthesized. Such SLNs showed mean particle sizes in the range of 187-297 nm, zeta potential values in the range of -4.1--9.7 mV, and DA association efficiencies ranging from 35 to 82%, according to the formulation examined. The results showed that DA/GSE-SLNs did not alter cell viability and had a cytoprotective effect against Rotenone-induced toxicity and oxidative stress. In addition, this study also focused on the evaluation of Alpha-synuclein (aS) levels; SLNs showed the potential to modulate the Rotenone-mediated increase in aS levels. In conclusion, our study investigated the potential of SLNs as a delivery system for addressing PD, also representing a promising approach for enhanced delivery of pharmaceutical and antioxidant molecules across the BBB.

Neuroprotective potential of traditionally used medicinal plants of Manipur against rotenone-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Alternanthera sessilis (L.) R. Br. ex DC., Eryngium foetidum L., and Stephania japonica (Thunb.) Miers plants are traditionally used to treat various central nervous system disorders like paralysis, epilepsy, seizure, convulsion, chronic pain, headache, sleep disturbances, sprain, and mental disorders. However, their possible neuroprotective effects have not been evaluated experimentally so far. AIM OF THE STUDY: The study aims to examine the neuroprotective potential of the three plants against cytotoxicity induced by rotenone in SH-SY5Y neuroblastoma cells and assess its plausible mechanisms of neuroprotection. MATERIALS AND METHODS: The antioxidant properties of the plant extracts were determined chemically by DPPH and ABTS assay methods. The cytotoxicity of rotenone and the cytoprotective activities of the extracts were evaluated using MTT assays. Microtubule-associated protein 2 (MAP2) expression studies in cells were performed to assess neuronal survival after rotenone and extract treatments. Mitochondrial membrane potential and intracellular levels of reactive oxygen species were evaluated using Rhodamine 123 and DCF-DA dye, respectively. Catalase, glutathione peroxidase, and superoxide dismutase activities were also measured. Apoptotic nuclei were examined using DAPI staining. Liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS) analysis of the plant extracts was also performed. RESULTS: The methanol extracts of A. sessilis, S. japonica, and E. foetidum showed excellent free radical scavenging activities. MAP2 expression studies show that A. sessilis and S. japonica have higher neuroprotective effects against rotenone-induced neurotoxicity in SH-SY5Y cells than E. foetidum. Pre-treating cells with the plant extracts reverses the rotenone-induced increase in intracellular ROS. The plant extracts could also restore the reduced mitochondrial membrane potential induced by rotenone treatment and reinstate rotenone-induced increases in catalase, glutathione peroxidase, and superoxide dismutase activities. All the extracts inhibited rotenone-induced changes in nuclear morphology and DNA condensation, an early event of cellular apoptosis. LC-QTOF-MS analysis of the plant extracts shows the presence of neuroprotective compounds. CONCLUSIONS: The plant extracts showed neuroprotective activities against rotenone-treated SH-SY5Y cells through antioxidant and anti-apoptotic mechanisms. These findings support the ethnopharmacological uses of these plants in treating neurological disorders. They probably are a good source of neuroprotective compounds that could be further explored to develop treatment strategies for neurodegenerative diseases like Parkinson's disease.

The effect of common paralytic agents used for fluorescence imaging on redox tone and ATP levels in Caenorhabditis elegans.

One aspect of Caenorhabditis elegans that makes it a highly valuable model organism is the ease of use of in vivo genetic reporters, facilitated by its transparent cuticle and highly tractable genetics. Despite the rapid advancement of these technologies, worms must be paralyzed for most imaging applications, and few investigations have characterized the impacts of common chemical anesthetic methods on the parameters measured, in particular biochemical measurements such as cellular energetics and redox tone. Using two dynamic reporters, QUEEN-2m for relative ATP levels and reduction-oxidation sensitive GFP (roGFP) for redox tone, we assess the impact of commonly used chemical paralytics. We report that no chemical anesthetic is entirely effective at doses required for full paralysis without altering redox tone or ATP levels, and that anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. We also assess the use of cold shock, commonly used in combination with physical restraint methods, and find that cold shock does not alter either ATP levels or redox tone. In addition to informing which paralytics are most appropriate for research in these topics, we highlight the need for tailoring the use of anesthetics to different endpoints and experimental questions. Further, we reinforce the need for developing less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters.

A polarity-responsive lysosomes-nucleus translocation probe for the dual-emissive visualization of cell apoptosis.

Visualization of cell apoptosis is a critical task playing central roles in the fundamental studies in biology, pathology, and biomedicine. Dual-emissive fluorescent probes are desired molecular tools for study on apoptosis, which however were rarely reported. Herein, utilizing the polarity differences between lysosomes and nucleus, a translocation type of fluorescent probe (NA-S) was developed for the dual-color visualization of cell apoptosis. NA-S was designed to be polarity sensitive, bearing alkalescence group, and with DNA affinity. In living cells, NA-S targeted the lysosomes to give blue fluorescence, which translocated into the nucleus during cell apoptosis to give green emission. Thereby, the cell apoptosis could be visualized with NA-S in dual-emissive manner. With the unique probe, the cell apoptosis induced by oxidative stress, UV irradiation, rotenone, colchicine, and paclitaxel have been successfully visualized.

Antiviral Rotenoids and Isoflavones Isolated from Millettia oblata ssp. teitensis.

Three new (1-3) and six known rotenoids (5-10), along with three known isoflavones (11-13), were isolated from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14-18), and one known chalcone (19) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC50 values of 0.7 and 3.4 µg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC50 values of 0.4-10 µM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC50 of 4.2 µM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3, 11, and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.

The effects of Nardosinone on levodopa intervention in the treatment of Parkinson's disease.

BACKGROUND: The roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD. AIM OF THE STUDY: To investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora. MATERIAL AND METHODS: We used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora. RESULTS: The behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified. CONCLUSION: Our findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD.

Tolperisone hydrochloride improves motor functions in Parkinson's disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade.

The mitogen-activated protein kinase (MAPK) signaling pathway, particularly the p38 MAPK and ERK1/2, has been implicated in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that MAPK signaling pathway can influence the expression of matrix metalloproteinase 9 (MMP-9), known for its involvement in various physiological and pathological processes, including neurodegenerative diseases. This study explores the modulation of MMP-9 expression via the MAPK/ERK signaling cascade and its potential therapeutic implications in the context of PD-associated motor dysfunction. Here, tolperisone hydrochloride (TL), a muscle relaxant that blocks voltage-gated sodium and calcium channels, was used as a treatment to observe its effect on MAPK signaling and MMP-9 expression. Rotenone (RT) exposure in mice resulted in a significant reduction in substantia nigra and primary motor cortex neurons, which were further evidenced by impairments in motor function. When TL was administered, neuron count was restored (89.0 ± 4.78 vs 117.0 ± 4.46/mm2), and most of the motor dysfunction was alleviated. Mechanistically, TL reduced the protein expression of phospho-p38MAPK (1.06 fold vs 1.00 fold) and phospho-ERK1/2 (1.16 fold vs 1.02 fold), leading to the inhibition of MAPK signaling, as well as reduced MMP-9 concentrations (2.76 ± 0.10 vs 1.94 ± 0.10 ng/mL) in the process of rescuing RT-induced neuronal cell death and motor dysfunction. Computational analysis further revealed TL's potential inhibitory properties against MMP-9 along with N and L-type calcium channels. These findings shed light on TL's neuroprotective effects via MMP-9 inhibition and MAPK signaling downregulation, offering potential therapeutic avenues for PD-associated motor dysfunction.

Deguelin inhibits the proliferation of human multiple myeloma cells by inducing apoptosis and G2/M cell cycle arrest: Involvement of Akt and p38 MAPK signalling pathway.

Deguelin exhibits antiproliferative activity against various cancer cell types. Previous studies have reported that deguelin exhibits pro-apoptotic activity against human cancer cells. The current study aimed at further elaborating the anticancer effects of deguelin against multiple myeloma cells. Cell growth estimations were made through MTT assay. Phase contrast microscopy was used for the analysis of the viability of multiple myeloma cells. Colony formation from multiple myeloma cells was studied using a clonogenic assay. Antioxidative assays for determining levels of glutathione (GSH) and superoxide dismutase (SOD) were carried out after treating multiple myeloma cells with deguelin. The apoptosis of multiple myeloma cells was studied using AO/EB and Annexin V-FITC/PI staining methods. Multiple myeloma cell cycle analysis was performed through flow cytometry. mRNA expression levels were depicted using qRT-PCR. Migration and invasion of multiple myeloma cells were determined with the wound-healing and transwell assays, respectively. Deguelin specifically inhibited the multiple myeloma cell growth while the normal plasma cells were minimally affected. Multiple myeloma cells when treated with deguelin exhibited remarkably lower viability and colony-forming ability. Multiple myeloma cells treated with deguelin produced more SOD and had higher GSH levels. The multiple myeloma cell growth, migration, and invasion were significantly declined by in vitro administration of deguelin. In conclusion, deguelin treatment, when applied in vitro, induced apoptotic cell death and resulted in mitotic cessation at the G2/M phase through modulation of cell cycle regulatory mRNAs in multiple myeloma cells.

ASSESSMENT OF RAT BRAIN MORPHOFUNCTIONAL STATE IN A PARKINSON'S MODEL: INFLUENCE OF THERAPEUTIC AGENTS OF ANIMAL AND SYNTHETIC ORIGINS.

In neurodegenerative diseases, particularly in Parkinson's disease (PD), antinociceptive centers are often implicated in neurodegeneration, leading to persistent pain unresponsive to narcotic substances. This study investigated the periaqueductal gray matter (PAG) and the nucleus raphe magnus (NRM), components of the brain's antinociceptive system. In conditions of rotenone intoxication (an experimental PD model), morphological changes in intracellular structures were observed in PAG and NRM neurons, indicating metabolic disorders characteristic of PD (alterations in the shape and size of neuronal bodies and processes, disruption of acid phosphatase activity in neuron cytoplasm). Under the influence of bacterial melanin and in combination with synoestrol, positive changes in structural properties were observed in PAG and NRM neurons compared to the rotenone model of PD. This included the preservation of the morphological characteristics typical of these brain regions, with cells exhibiting shapes and sizes close to normal. Furthermore, under the influence of these therapeutic agents, an increase in phosphatase activity in cell cytoplasm was detected, indicating an acceleration of metabolic processes (metabolic activation) disrupted by rotenone intoxication. The data obtained suggests that bacterial melanin and synoestrol may act as potential neuroprotective agents against PAG and NRM neurons in the rat brain in the rotenone model of PD. Further research is needed to elucidate the mechanisms of action of therapeutic doses and propose their use in the treatment of PD, either in isolation or combination therapy.

Prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume.

Leber's hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.

Synthesis and biological evaluation of folic acid-rotenol conjugate as a potent targeted anticancer prodrug.

Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative-rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential.

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Demonstrates Neuroprotective Properties in Experimental Parkinson's Disease by Enhancing the Antioxidant System, Normalising Chaperone Activity and Suppressing Apoptosis.

Parkinson's disease (PD) is a neurodegenerative disease, whereby disturbances within the antioxidant defence system, increased aggregation of proteins, and activation of neuronal apoptosis all have a crucial role in the pathogenesis. In this context, exploring the neuroprotective capabilities of compounds that sustain the effectiveness of cellular defence systems in neurodegenerative disorders is worthwhile. During this study, we assessed how 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ), which has antioxidant properties, affects the functioning of the antioxidant system, the activity of NADPH-generating enzymes and chaperones, and the level of apoptotic processes in rats with rotenone-induced PD. Six groups of animals were formed for our experiment, each with 12 animals. These were: a control group, animals with rotenone-induced PD, rats with PD given HTHQ at a dose of 50 mg/kg, rats with PD given HTHQ at a dose of 25 mg/kg, animals with pathology who were administered a comparison drug rasagiline, and control animals who were administered HTHQ at a dose of 50 mg/kg. The study results indicate that administering HTHQ led to a significant decrease in oxidative stress in PD rats. The enhanced redox status in animal tissues was linked with the recovery of antioxidant enzyme activities and NADPH-generating enzyme function, as well as an upsurge in the mRNA expression levels of antioxidant genes and factors Nrf2 and Foxo1. Administering HTHQ to rats with PD normalized the chaperone-like activity and mRNA levels of heat shock protein 70. Rats treated with the compound displayed lower apoptosis intensity when compared to animals with pathology. Therefore, owing to its antioxidant properties, HTHQ demonstrated a beneficial impact on the antioxidant system, resulting in decreased requirements for chaperone activation and the inhibition of apoptosis processes triggered in PD. HTHQ at a dose of 50 mg/kg had a greater impact on the majority of the examined variables compared to rasagiline.

Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, characterized by motor and psychological dysfunction. Palliative treatment and dopamine replenishment therapy are the only available therapeutic options. Calcium channel blockers (CCBs) have been reported to protect against several neurodegenerative disorders. The current study was designed to evaluate the neuroprotective impact of Felodipine (10 mg/kg, orally) as a CCB on motor and biochemical dysfunction associated with experimentally induced PD using rotenone (2.5 mg/kg, IP) and to investigate the underlying mechanisms. Rotenone induced deleterious neuromotor outcomes, typical of those associated with PD. The striatum revealed increased oxidative burden and NO levels with decreased antioxidant capacity. Nrf2 content significantly decreased with the accumulation of α-synuclein and tau proteins in both the substantia nigra and striatum. These observations significantly improved with felodipine treatment. Of note, felodipine increased dopamine levels in the substantia nigra and striatum as confirmed by the suppression of inflammation and the significant reduction in striatal NF-κB and TNF-α contents. Moreover, felodipine enhanced mitophagy, as confirmed by a significant increase in mitochondrial Parkin and suppression of LC3a/b and SQSTM1/p62. In conclusion, felodipine restored dopamine synthesis, attenuated oxidative stress, inflammation, and mitochondrial dysfunction, and improved the mitophagy process resulting in improved PD-associated motor impairment.

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells.

Hydrogen sulfide (H2S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.

Effect of Diacetylcurcumin Manganese Complex on Rotenone-Induced Oxidative Stress, Mitochondria Dysfunction, and Inflammation in the SH-SY5Y Parkinson's Disease Cell Model.

Diacetylcurcumin manganese complex (DiAc-Cp-Mn) is a diacetylcurcumin (DiAc-Cp) derivative synthesized with Mn (II) to mimic superoxide dismutase (SOD). It exhibited superior reactive oxygen species (ROS) scavenging efficacy, particularly for the superoxide radical. The present study investigated the ROS scavenging activity, neuroprotective effects, and underlying mechanism of action of DiAc-Cp-Mn in a cellular model of Parkinson's disease. This study utilized rotenone-induced neurotoxicity in SH-SY5Y cells to assess the activities of DiAc-Cp-Mn by measuring cell viability, intracellular ROS, mitochondrial membrane potential (MMP), SOD, and catalase (CAT) activities. The mRNA expression of the nuclear factor erythroid 2 p45-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), inducible nitric oxide synthase (iNOS), and Interleukin 1ß (IL-1ß), which are oxidative and inflammatory genes, were also evaluated to clarify the molecular mechanism. The results of the in vitro assays showed that DiAc-Cp-Mn exhibited greater scavenging activity against superoxide radicals, hydrogen peroxide, and hydroxyl radicals compared to DiAc-Cp. In cell-based assays, DiAc-Cp-Mn demonstrated greater neuroprotective effects against rotenone-induced neurotoxicity when compared to its parent compound, DiAc-Cp. DiAc-Cp-Mn maintained MMP levels, reduced intracellular ROS levels, and increased the activities of SOD and CAT by activating the Nrf2-Keap1 signaling pathway. In addition, DiAc-Cp-Mn exerted its anti-inflammatory impact by down-regulating the mRNA expression of iNOS and IL-1ß that provoked neuro-inflammation. The current study indicates that DiAc-Cp-Mn protects against rotenone-induced neuronal damage by reducing oxidative stress and inflammation.

Single Fluorescent Probe for Multiple Tasks: Illuminating Lipid Droplets and Lysosomes in Dual Channels and Distinguishing Autophagy and Apoptosis.

Lipid droplets (LDs) and lysosomes play key roles in autophagy and cell apoptosis, and the discriminative visualization of the two organelles and simultaneously of autophagy and apoptosis is very helpful to understand their internal relationships. However, fluorescent probes that can concurrently achieve these tasks are not available currently. Herein, we delicately fabricate a robust probe CAQ2 for multiple tasks: illumination of LDs and lysosomes in dual emission colors as well as discriminative visualization of cell apoptosis and autophagy. The probe exhibited both lipophilic and basic properties and displayed different emission colors in neutral and protonated forms; thus, LDs and lysosomes emitted blue and red fluorescence colors, respectively. Because of the lysosomal acidification during autophagy, CAQ2 detected autophagy with evidently enhanced red emission. Because of the lysosomal alkalization during apoptosis, CAQ2 imaged apoptosis with a drastically decreased red fluorescence intensity. With the robust probe, the autophagy under starvation and lipidless conditions was visualized, and the apoptosis induced by H2O2, ultraviolet (UV) irradiation, and rotenone treatment was successfully observed. The efficient detoxification of Na2S against rotenone treatment was successfully revealed.