Enhanced autophagy interacting proteins negatively correlated with the activation of apoptosis-related caspase family proteins after focal ischemic stroke of young rats.

BACKGROUND: Neuronal injury induced in young rats by cerebral ischemia reperfusion (CIR) is known to differ substantially from that in adult rats. In the present study, we investigated the specific differences in neuronal injury induced by focal CIR between young and adult rats. RESULTS: 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining revealed a gradual increase in the infarct volume of both young and adult rats in accordance with I/R times and was significantly lower in young rats than in adult rats under the same conditions. The number of cells in the cortex showing immunoreactivity for neuronal nuclei (NeuN) gradually decreased in both young and adult rats in accordance with I/R times; these numbers were significantly higher in young rats than in adult rats under the same conditions. Similarly, as the duration of I/R increased, the degree of glial activation in the cortex penumbra region became more severe in both young and adult groups; however, glial activation was significantly lower in the cortex penumbra region of young rats when compared with that in adult rats. In addition, the expression of Beclin-1 was significantly higher in the infarct penumbra of young rats than adult rats and was more frequently co-expressed with neurons. The levels of autophagy-related proteins increased significantly in the penumbra region after I/R in both young and adult groups, this increase was more pronounced in young rats than in adult rats. Following CIR, analysis revealed significantly lower levels of pro-apoptosis-related factors and significantly higher levels of anti-apoptosis-related proteins in the young rats than in adult rats. CONCLUSIONS: Collectively, the present results suggest that the the reduced levels of neuronal death after CIR in young rats were closely related to enhanced levels of autophagy and reduced levels of pro-apoptosis in neurons.

Fe3O4 Nanozymes Improve Neuroblast Differentiation and Blood-Brain Barrier Integrity of the Hippocampal Dentate Gyrus in D-Galactose-Induced Aged Mice.

Aging is a process associated with blood-brain barrier (BBB) damage and the reduction in neurogenesis, and is the greatest known risk factor for neurodegenerative disorders. However, the effects of Fe3O4 nanozymes on neurogenesis have rarely been studied. This study examined the effects of Fe3O4 nanozymes on neuronal differentiation in the dentate gyrus (DG) and BBB integrity of D-galactose-induced aged mice. Long-term treatment with Fe3O4 nanozymes (10 µg/mL diluted in ddH2O daily) markedly increased the doublecortin (DCX) immunoreactivity and decreased BBB injury induced by D-galactose treatment. In addition, the decreases in the levels of antioxidant proteins including superoxide dismutase (SOD) and catalase as well as autophagy-related proteins such as Becin-1, LC3II/I, and Atg7 induced by D-galactose treatment were significantly ameliorated by Fe3O4 nanozymes in the DG of the mouse hippocampus. Furthermore, Fe3O4 nanozyme treatment showed an inhibitory effect against apoptosis in the hippocampus. In conclusion, Fe3O4 nanozymes can relieve neuroblast damage and promote neuroblast differentiation in the hippocampal DG by regulating oxidative stress, apoptosis, and autophagy.

Simvastatin Improves Behavioral Disorders and Hippocampal Inflammatory Reaction by NMDA-Mediated Anti-inflammatory Function in MPTP-Treated Mice.

The cognitive function impairment may be related to the inflammation of the hippocampus in Parkinson's disease. Simvastatin can play a positive role in Parkinson's disease. The purpose of this study was to investigate whether simvastatin could improve behavioral disorders, especially depression, anxiety and cognitive function in mouse PD models, and further explore the molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for 5 consecutive days. At the same time, simvastatin (10 mg/kg) was pretreated for 2 days before the Parkinson's disease model was established, and then continued for 5 days, and the control group underwent intraperitoneal injection of MK801 (dizocilpine, 0.2 mg/kg) and saline solution. Depression status was tested by a tail suspension test and a sucrose splash test, followed by an open-field test and an elevated plus maze test to determine anxiety levels. Spatial behavior and muscle status were measured with a water maze and a rotarod test. The expression of RNA and protein of N-methyl-D-aspartate receptor subtype 2B (NMDAR2B), nerve growth factor IB (Nur77), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF) α were assayed by real-time polymerase chain reaction and Western blot. Our results showed that simvastatin can improve the cognitive function, anxiety, and depression of PD mice with MPTP injury. Simvastatin reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice. This role of simvastatin was consistent with MK801 in increasing the expression of Nur77 and inhibiting NMDAR2B and cytokines in MPTP-lesioned PD mice. These findings suggest that reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice may be one of the mechanisms that simvastatin improves cognitive functions, depression, and anxiety in MPTP-lesioned mice.

Barrel Cortical Neuron Integrates Triple Associated Signals for Their Memory Through Receiving Epigenetic-Mediated New Synapse Innervations.

Associative learning is common way for information acquisition. Associative memory is essential to logical reasoning and associative thinking. The storages of multiple associated signals in individual neurons facilitate their integration, expand memory volume, and strengthen cognition ability. Associative memory cells that encode multiple signals have been reported, however, the mechanisms underlying their recruitment and working principle remain to be addressed. We have examined the recruitment of associative memory cells that integrate and store triple sensory signals as well as the potential mechanism of their recruitment. Paired mouse whisker, olfaction, and tail stimulations lead to odorant-induced motion and tail-induced whisker motion. In mice of expressing this cross-modal response, their barrel cortical neurons become to encode odor and tail signals alongside whisker signal. These barrel cortical neurons receive new synapse innervations from piriform and S1-tail cortical neurons. The emergence of cross-modal responses as well as the recruitments of new synapse innervations and associative memory cells in the barrel cortex need miRNA-324 and miRNA-133a, which downregulate Ttbk1 and Tet3. The co-activations of sensory cortices recruit their mutual synapse innervations and associative memory cells that integrate and store multiple associated signals through epigenetic-mediated process.

Effects of carbon nanotubes on phosphorus adsorption behaviors on aquatic sediments.

Aquatic sediments are believed to be an important sink for carbon nanotubes (CNTs). With novel properties, CNTs can potentially disturb the fate and mobility of the co-existing contaminants in the sediments. Only toxic pollutants have been investigated previously, and to the best of our knowledge, no data has been published on how CNTs influence phosphorus (P) adsorption on aquatic sediments. In this study, multi-walled carbon nanotubes (MWCNTs) were selected as model CNTs. Experimental results indicated that compared to pseudo-first order and intraparticle diffusion models, the pseudo-second-order model is better for describing the adsorption kinetics of sediments and MWCNT-contaminated sediments. Adsorption isotherm studies suggested that the Langmuir model fits the isotherm data well. With the increase in the MWCNT-to-sediment ratio from 0.0% to 5.0%, the theoretical maximum monolayer adsorption capacity (Qmax) for P increased from 0.664 to 0.996mg/g. However, the Langmuir isotherm coefficient (KL) significantly decreased from 4.231L/mg to 2.874L/mg, indicating the decrease in the adsorption free energy of P adsorbed on the sediments after MWCNT contamination. It was suggested that P was released more easily to the overlying water after the re-suspension of sediments. Moreover, the adsorption of sediments and sediment-MWCNT mixture was endothermic and physical in nature. Results obtained herein suggested that the change in the specific surface area and zeta potential of sediments is related to MWCNT contamination, and the large adsorption capacity of MWCNTs is probably the main factor responsible for the variation in the adsorption of P on aquatic sediments.

Co-adsorption of perfluorooctane sulfonate and phosphate on boehmite: Influence of temperature, phosphate initial concentration and pH.

The co-presence of perfluorooctane sulfonate (PFOS) and phosphate in wastewater of various industries has been detected. Removing PFOS and phosphate simultaneously before discharging sewage into natural water can decrease effectively the environmental risk caused by the combined pollution of PFOS and phosphate. In this study, laboratory batch experiments were conducted for investigating the co-adsorption of PFOS and phosphate on boehmite and the influences of temperature, phosphate initial concentration and pH on the co-adsorption. The adsorption thermodynamics and kinetics of PFOS and phosphate on boehmite were also investigated completely and systematically. The results showed that lower temperature favored the co-adsorptions of PFOS and phosphate. The adsorption of PFOS and phosphate on boehmite agreed well with the Langmuir isotherm and the adsorption parameters of thermodynamics are ΔH=-16.9 and -20.0kJmol-1 (PFOS and phosphate), ΔS=-5.69 and -7.63Jmol-1 K-1 (PFOS and phosphate) and ΔG <0 (PFOS and phosphate). It demonstrated that the co-adsorption of PFOS and phosphate on boehmite is a spontaneously exothermic process. Moreover, the co-adsorption process can be described well by a pseudo-second-order kinetic model. With increasing phosphate initial concentration, more phosphate could be adsorbed on boehmite, while the adsorption of PFOS decreased at phosphate initial concentration of less than 30mgL-1 and increased at that of larger than 30mgL-1. In the co-adsorption process, the adsorption amount of PFOS decreased with pH increasing, but that of phosphate changed little.

Sulfur Cycling-Related Biogeochemical Processes of Arsenic Mobilization in the Western Hetao Basin, China: Evidence from Multiple Isotope Approaches.

The role of sulfur cycling in arsenic behavior under reducing conditions is not well-understood in previous investigations. This study provides observations of sulfur and oxygen isotope fractionation in sulfate and evaluation of sulfur cycling-related biogeochemical processes controlling dissolved arsenic groundwater concentrations using multiple isotope approaches. As a typical basin hosting high arsenic groundwater, the western Hetao basin was selected as the study area. Results showed that, along the groundwater flow paths, groundwater δ34SSO4, δ18OSO4, and δ13CDOC increased with increases in arsenic, dissolved iron, hydrogen sulfide and ammonium concentrations, while δ13CDIC decreased with decreasing Eh and sulfate/chloride. Bacterial sulfate reduction (BSR) was responsible for many of these observed changes. The δ34SSO4 indicated that dissolved sulfate was mainly sourced from oxidative weathering of sulfides in upgradient alluvial fans. The high oxygen-sulfur isotope fractionation ratio (0.60) may result from both slow sulfate reduction rates and bacterial disproportionation of sulfur intermediates (BDSI). Data indicate that both the sulfide produced by BSR and the overall BDSI reduce arsenic-bearing iron(III) oxyhydroxides, leading to the release of arsenic into groundwater. These results suggest that sulfur-related biogeochemical processes are important in mobilizing arsenic in aquifer systems.

Allylsamarium Bromide-Mediated Cascade Cyclization of Homoallylic Esters. Synthesis of 2-(2-Hydroxyalkyl)cyclopropanols and 2-(2-Hydroxyethyl)bicyclo[2.1.1]hexan-1-ols.

In continuation of our previous study on the intramolecular reductive coupling of simple homoallylic esters promoted by allylSmBr/HMPA/H2O, which afforded a facile synthesis of 2-(2-hydroxyalkyl)cyclopropanols, here we report the reductive cascade cyclization of but-3-enyl but-3-enoates mediated by allylSmBr/HMPA/CuCl2·2H2O, in which the two C═C bonds were successively coupled to allow the construction of the structurally interesting bridged bicyclic tertiary alcohols. Thus, the 2-(2-hydroxyethyl)bicyclo[2.1.1]hexan-1-ols were prepared in moderate to good yields with excellent diastereoselectivity.

[Differential expression of microRNA in chronic hepatitis B patients of pi-wei dampness-heat syndrome and of gan depression Pi deficiency syndrome: a primary research].

OBJECTIVE: To explore different microRNA expression profiles between chronic hepatitis B (CHB) patients of Pi-Wei dampness-heat syndrome (PWDHS) and Gan depression Pi deficiency syndrome (GDPDS). METHODS: By applying gene chip technology, blood samples from CHB patients of PWDHS (3 cases), GDPDS (3 cases), and healthy volunteers (3 cases) were withdrawn and microRNA detected. The microRNA was screened and functional analyses performed by using SAS system. RESULTS: Totally 77 microRNAs with differential expression were screened from CHB patients of PWDHS and healthy volunteers, including 60 up-regulated microRNAs and 17 down-regulated microRNAs. Functions of target genes were mainly associated with transcription factors, gas exchange, adverse stimulating, regulation of enzyme activities, developing of the immune system, and the process of actin filaments. Totally 41 microRNAs with differential expression were screened from CHB patients of GDPDS and healthy volunteers, including 32 up-regulated microRNAs and 9 down-regulated microRNAs. Functions of target genes were mainly associated with binding to nucleotide or chromatin, inhibition and activation of transcription, biosynthesis, regulation of metabolic process, regulation of enzyme activities, developing of the immune system, the process of actin filaments, and IL-12. Totally 6 microRNAs with differential expression were screened from CHB patients of PWDHS and CHB patients of GDPDS, including 1 up-regulated microRNA and 5 down-regulated microRNAs. Functions of target genes were mainly associated with transmembrane transport, regulation of transcription factors, metabolism of hormones, developing of the immune system, the process of actin filaments, regulation of metabolic process, response to exterior stimulation, and so on. CONCLUSION: There existed differentially expressed microRNAs (spectrum) between CHB patients of PWDHS and CHB patients of GDPDS.

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.

Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.

Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.

Erbu Zhuyu decoction improves endometrial angiogenesis via uterine natural killer cells and the PI3K/Akt/eNOS pathway a mouse model of embryo implantation dysfunction.

BACKGROUND: We investigated the effect of Erbu Zhuyu decoction (EBZY) on angiogenesis via uterine natural killer (uNK) cells and the PI3K/Akt/eNOS pathway in embryo implantation dysfunction (EID) mice. METHODS: Pregnant mice were randomly divided into blank, model, EBZY, progynova, and aspirin groups. Uteri were excised on the 5th day of pregnancy for analysis. RESULTS: Mice in the model group showed pale uteri, a reduced implantation rate, and lower expression levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), endothelial nitric oxide synthase (eNOS) and nitric oxide (NO). Compared to the model group, implantation rates in the medium-dose and high-dose groups of EBZY were significantly higher (P < .05), PI3K and Akt mRNA expression levels in the low-dose group were significantly higher (P < .05, P < .01), and the expression of p-PI3K, p-Akt, and p-eNOS proteins in all treatment groups were significantly increased (P < .01, P < .05). The expression of NO was significantly increased in the low-dose and high-dose groups (P < .01, P < .05, respectively). The level of p-Akt protein in the high-dose group was significantly higher than those in the other treatment groups (P < .01, P < .05). There was no significant difference in the density of uNK cells (P > .05). CONCLUSIONS: EBZY facilitated embryo implantation in EID mice by enhancing endometrial angiogenesis via activation of the PI3K/Akt/eNOS pathway, at least in part. There was no evidence to indicate that EBZY could adjust the expression of uNK.

Combined ICP-OES and XPS analysis to evaluate the [AlO4]0 concentration in quartz: limiting the formation temperature of quartz.

A proposed quartz thermometer is based on the concentration of [AlO4]0 tetrahedra determined by combining inductively coupled plasma optical emission spectrometry (ICP-OES) with X-ray photoelectron spectroscopy (XPS) data. The concentration of [AlO4]0 tetrahedra in the quartz lattice (C[AlO4]0/ppm) and the formation temperatures of quartz (TQ/°C) from agate, gold deposits, and granodiorite are calculated by C[AlO4]0 = CAl total (ppm) × k and TQ (°C) = 3.6 × CAl total (ppm) × k + 33.0, respectively. Where CAl total is the total Al concentration of quartz measured by ICP-OES and k is the relative percentage of [AlO4]0 tetrahedra in the quartz lattice and can be obtained by fitting the Al(2p) XPS spectrum. The obtained formation temperatures of quartz (TQ) agree well with the equilibrium formation temperature (TE) calculated by oxygen isotope data. By comparing the relative positions of the two temperature curves of quartz (TQ and TE), the composition of the mineral-forming fluid can be inferred. The proposed quartz thermometer can be applied to quartz formed under equilibrium conditions and in Al-saturated environments over a wide temperature range (152-566 °C). The use of the quartz thermometer effectively eliminates interference from different fluid compositions and satisfies the requirements of convenience and economy.

Rutin Attenuates Oxidative Stress Via PHB2-Mediated Mitophagy in MPP+-Induced SH-SY5Y Cells.

Oxidative stress plays a crucial role in the occurrence and development of Parkinson's disease (PD). Rutin, a natural botanical ingredient, has been shown to have antioxidant properties. Therefore, the aim of this study was to investigate the neuroprotective effects of rutin on PD and the underlying mechanisms. MPP+(1-methyl-4-phenylpyridinium ions)-treated SH-SY5Y cells were used as an in vitro model of PD. Human PHB2-shRNA lentiviral particles were transfected into SH-SY5Y cells to interfere with the expression of Prohibitin2 (PHB2). The oxidative damage of cells was analyzed by detecting intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and mitochondrial membrane potential (MMP). Western blotting was used to detect the protein expression of antioxidant factors such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO-1), and mitophagy factors PHB2, translocase of outer mitochondrial membrane 20 (TOM20), and LC3II/LC3I (microtubule-associated protein II light chain 3 (LC3II) to microtubule-associated protein I light chain 3 (LC3I)). In addition, we also examined the expression of PHB2 and LC3II/LC3I by immunofluorescence staining. MPP+ treatment significantly increased the generation of ROS and MDA and the level of MMP depolarization and decreased the protein expression of Nrf2, HO-1, NQO1, TOM20, PHB2, and LC3II/LC3I. In MPP+-treated SH-SY5Y cells, rutin significantly decreased the generation of ROS and MDA and the level of MMP depolarization and increased the protein expression of Nrf2, HO-1, NQO-1, TOM20, PHB2, and LC3II/LC3I. However, the protective role of rutin was inhibited in PHB2-silenced cells. Rutin attenuates oxidative damage which may be associated with PHB2-mediated mitophagy in MPP+-induced SH-SY5Y cells. Rutin might be used as a potential drug for the prevention and treatment of PD.

Elucidation of the mechanism of Yiqi Tongluo Granule against cerebral ischemia/reperfusion injury based on a combined strategy of network pharmacology, multi-omics and molecular biology.

BACKGROUND: Ischemic stroke is caused by local lesions of the central nervous system and is a severe cerebrovascular disease. A traditional Chinese medicine, Yiqi Tongluo Granule (YQTL), shows valuable therapeutic effects. However, the substances and mechanisms remain unclear. PURPOSE: We combined network pharmacology, multi-omics, and molecular biology to elucidate the mechanisms by which YQTL protects against CIRI. STUDY DESIGN: We innovatively created a combined strategy of network pharmacology, transcriptomics, proteomics and molecular biology to study the active ingredients and mechanisms of YQTL. We performed a network pharmacology study of active ingredients absorbed by the brain to explore the targets, biological processes and pathways of YQTL against CIRI. We also conducted further mechanistic analyses at the gene and protein levels using transcriptomics, proteomics, and molecular biology techniques. RESULTS: YQTL significantly decreased the infarction volume percentage and improved the neurological function of mice with CIRI, inhibited hippocampal neuronal death, and suppressed apoptosis. Fifteen active ingredients of YQTL were detected in the brains of rats. Network pharmacology combined with multi-omics revealed that the 15 ingredients regulated 19 pathways via 82 targets. Further analysis suggested that YQTL protected against CIRI via the PI3K-Akt signaling pathway, MAPK signaling pathway, and cAMP signaling pathway. CONCLUSION: We confirmed that YQTL protected against CIRI by inhibiting nerve cell apoptosis enhanced by the PI3K-Akt signaling pathway.

Mineralogical and Geochemical Characteristics of Banded Agates from Placer Deposits: Implications for Agate Genesis.

The phase composition and geochemical characteristics in banded agates with different structural sequences have been investigated in detail. The results reveal that the agate bands have a combination of a pseudo-granular silica → fibrous chalcedony → crystalline quartz (type I) sequence and a newly discovered pseudo-granular silica → crystalline quartz (type II) sequence. The banded agates mainly consist of α-quartz, moganite, and a minor amount of amorphous silica, goethite, hematite, kaolinite, illite, and carbonates. With the evolution of two structural sequences, the content of α-quartz and moganite increases and decreases, respectively. There is no moganite in crystalline quartz. The increased concentration of trace elements like Li, Na, Al, K, Ca, Ti, Mn, and Fe in different bands may correspond to the decrease in the water content in the mineral-forming fluid. The increased trace elements promote the structural transformation process of silica. With the evolution of the type I sequence, the thermal gradients between adjacent bands are 17 and 51 °C, respectively. In contrast, a significantly higher thermal gradient of 53-66 °C is exhibited when pseudo-granular silica transforms directly to crystalline quartz. It is inferred that a slightly increased thermal gradient between adjacent bands promotes the structural transformation process of the type I sequence. The sharply increasing thermal gradient between adjacent bands leads to the formation of the type II sequence from pseudo-granular silica to crystalline quartz. The formation process of different structural sequences in agate may be controlled together by trace element concentrations and thermal gradients.

Artemisinin Alleviates Cerebral Ischemia/Reperfusion-Induced Oxidative Damage via Regulating PHB2-Mediated Autophagy in the Human Neuroblastoma SH-SY5Y Cell Line.

Oxidative stress plays a key role in cerebral ischemia/reperfusion injury. Artemisinin (ART) has antioxidative stress activity in addition to its powerful antimalarial effects. In this article, we investigated the effect of ART on OGD/R-induced oxidative stress injury and its underlying mechanisms. We used oxygen-glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model of cerebral ischemia/reperfusion (I/R) injury. CCK-8 and lactate dehydrogenase (LDH) release were used to assess cellular damage. Measurement of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and mitochondrial membrane potential (MMP) estimates oxidative stress-induced damage and protection from ART effect. OGD/R treatment aggravated oxidative stress damage, whereas ART reversed the effects of OGD/R. Autophagy is closely related to oxidative stress; in order to confirm whether the antioxidative stress effect of ART is related to PHB2-mediated autophagy, we examined the protein expression of prohibitin 2 (PHB2), TOMM20, p62, and the conversion of microtubule-associated protein light chain 3I (LC3I) to LC3II and found that the protein expression of PHB2, TOMM20, p62, and LC3II/LC3I was significantly correlated with OGD/R treatment. The colocalization of PHB2 and LC3, TOMM20, and LC3 was reduced after OGD/R treatment, and ART reversed this change. After silencing PHB2, the protective effect of ART against OGD/R-induced oxidative stress injury was reduced, the protein expressions of PHB2, TOMM20 and LC3II/LC3I and the colocalization of PHB2 and LC3, TOMM20, and LC3 were decreased. We used chloroquine to block the lysosomal pathway and found that ART increased the conversion of LC3I to LC3II, silencing PHB2 which inhibited the conversion of LC3I to LC3II, and impaired mitophagy. Our findings showed that ART attenuated OGD/R-induced oxidative stress damage through PHB2-mediated mitophagy. To the current knowledge, our study is the first to demonstrate that ART attenuates OGD/R-induced oxidative stress injury through PHB2-mediated autophagy in the human neuroblastoma SH-SY5Y cell line, which provided new insights into the treatment of OGD/R injury.

Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice.

The progression of Parkinson's disease (PD) is often accompanied by the loss of substantia nigra dopaminergic neurons, mitophagy damage, learning, and memory impairment. Idebenone is a therapeutic drug that targets the mitochondria of neurodegenerative diseases, but its role in Parkinson's disease and its pathological mechanism are still unclear. The purpose of this study was to investigate whether idebenone could improve behavioral disorders, especially motor, learning, and memory disorders, in mouse PD models and to explore its molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for five consecutive days. Then, a 200 mg/kg dose was given as a single daily gavage of idebenone dissolved in water for 21 days after the successful establishment of the subacute MPTP model. Motor, learning, and memory were measured by a water maze and a rotarod test. Our results showed that idebenone could reduce MPTP-induced dopaminergic neuron damage and improve movement disorders, memory, and learning ability, which may be associated with upregulating mitochondrial autophagy-related outer membrane proteins VDAC1 and BNIP3 and activating the Parkin/PINK1 mitochondrial autophagy pathway. To confirm whether idebenone promotes the smooth progression of autophagy, we used eGFP-mCherry-LC3 mice to construct a subacute model of Parkinson's disease and found that idebenone can increase autophagy in dopaminergic neurons in Parkinson's disease. In summary, our results confirm that idebenone can regulate the expression of the mitochondrial outer membrane proteins VDAC1 and BNIP3, activate Parkin/PINK1 mitophagy, promote the degradation of damaged mitochondria, reduce dopaminergic neuron damage, and improve behavioral disorders in Parkinson's disease mice.

Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson's Disease Model.

Mitophagy and oxidative stress play important roles in Parkinson's disease (PD). Dysregulated mitophagy exacerbates mitochondrial oxidative damage; however, the regulatory mechanism of mitophagy is unclear. Here, we provide a potential mechanistic link between c-Abl, a nonreceptor tyrosine kinase, and mitophagy in PD progression. We found that c-Abl activation reduces the interaction of prohibitin 2 (PHB2) and microtubule-associated protein 1 light chain 3 (LC3) and decreases the expressive level of antioxidative stress proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2), NADPH quinone oxidoreductase-1 (NQO-1), and the antioxidant enzyme heme oxygenase-1 (HO-1) in 1-methyl-4-phenylpyridinium- (MPP+-) lesioned SH-SY5Y cells. Importantly, we found that MPP+ can increase the expression of phosphorylated proteins at the tyrosine site of PHB2 and the interaction of c-Abl with PHB2. We showed for the first time that PHB2 by changing tyrosine (Y) to aspartate (D) at site 121 resulted in impaired binding of PHB2 and LC3 in vitro. Moreover, silencing of PHB2 can decrease the interaction of PHB2 and LC3 and exacerbate the loss of dopaminergic neurons. We also found that STI 571, a c-Abl family kinase inhibitor, can decrease dopaminergic neuron damage and ameliorate MPTP-induced behavioral deficits in PD mice. Taken together, our findings highlight a novel molecular mechanism for aberrant PHB2 phosphorylation as an inhibitor of c-Abl activity and suggest that c-Abl and PHB2 are potential therapeutic targets for the treatment of individuals with PD. However, these results need to be further validated in PHB2 Y121D mice.

Vivianite and Its Oxidation Products in Mammoth Ivory and Their Implications to the Burial Process.

The phase composition and distribution characteristics have been obtained from two mammoth ivory samples with typical blue and yellowish-brown outer layers. The results reveal that hydroxyapatite, newberyite, organic matter, and quartz exist in all structures of mammoth ivory. Vivianite and santabarbaraite mainly contribute to the blue and yellowish-brown oxide layers of mammoth ivory, respectively. Meanwhile, metavivianite also occurs and partly influences the appearance of oxide layers. Vivianite is a common and complex product that can be formed by the interaction of gradually infiltrated Fe2+ and the original PO4 3- in mammoth ivory. At the later stage, vivianite can be oxidized into metavivianite and santabarbaraite. As a result, mammoth tusks present dark bluish-green and yellowish-brown appearances. The multi-colored oxide layers are formed by different contents of vivianite and its oxidation products, which also provides valuable information on the relative burial intensity and time in different structures. It is inferred that the burial intensity increases in the sequence of yellowish-white dentin → blue outer layer → yellowish-brown outer layer. These observations are hopeful to be widely used in evaluating the changeable burial environment and exploring historical events that occurred on mammoth ivory.