mRNA m5C inhibits adipogenesis and promotes myogenesis by respectively facilitating YBX2 and SMO mRNA export in ALYREF-m5C manner.

Although 5-methylcytosine (m5C) has been identified as a novel and abundant mRNA modification and associated with energy metabolism, its regulation function in adipose tissue and skeletal muscle is still limited. This study aimed at investigating the effect of mRNA m5C on adipogenesis and myogenesis using Jinhua pigs (J), Yorkshire pigs (Y) and their hybrids Yorkshire-Jinhua pigs (YJ). We found that Y grow faster than J and YJ, while fatness-related characteristics observed in Y were lower than those of J and YJ. Besides, total mRNA m5C levels and expression rates of NSUN2 were higher both in backfat layer (BL) and longissimus dorsi muscle (LDM) of Y compared to J and YJ, suggesting that higher mRNA m5C levels positively correlate with lower fat and higher muscle mass. RNA bisulfite sequencing profiling of m5C revealed tissue-specific and dynamic features in pigs. Functionally, hyper-methylated m5C-containing genes were enriched in pathways linked to impaired adipogenesis and enhanced myogenesis. In in vitro, m5C inhibited lipid accumulation and promoted myogenic differentiation. Furthermore, YBX2 and SMO were identified as m5C targets. Mechanistically, YBX2 and SMO mRNAs with m5C modification were recognized and exported into the cytoplasm from the nucleus by ALYREF, thus leading to increased YBX2 and SMO protein expression and thereby inhibiting adipogenesis and promoting myogenesis, respectively. Our work uncovered the critical role of mRNA m5C in regulating adipogenesis and myogenesis via ALYREF-m5C-YBX2 and ALYREF-m5C-SMO manners, providing a potential therapeutic target in the prevention and treatment of obesity, skeletal muscle dysfunction and metabolic disorder diseases.

Constraining the Symmetron Model with the HUST-2020 Torsion Pendulum Experiment.

The search for dynamically screening the coupling between the scalar field and matter in high-density environment is achievable with the symmetron model. The high-accuracy and short-range gravity experiment is proposed to test the symmetron model. In this Letter, the data of the HUST-2020 torsion pendulum experiment testing the inverse-square law at submillimeter range is analyzed to constrain the symmetron model. The results show that the HUST-2020 experiment is uniquely sensitive to probe the symmetron model with a mass scale of µ=7.2×10^{-3} eV, and the self-coupling parameter λ≲105 is excluded at mass scale M=0.3 TeV. Especially, at the dark energy scale µ=2.4×10^{-3} eV, the constraint at M=1.3 TeV is improved by about 10 times the previous constraints on the torsion pendulum experiment.

Conversion of Land Use from Upland to Paddy Field Changes Soil Bacterial Community Structure in Mollisols of Northeast China.

Mollisols are extremely important soil resource for crop and forage production. In northeast China, it is a major land use management practice from dry land crops to irrigated rice. However, there is few data regarding soil quality and microbial composition in Mollisols during land use transition. Here, we analyzed the upper 30 cm of soil from land with more than 30 years of paddy use and from adjacent areas with upland crops. Our results showed that land use and soil depth had a significant effect on soil properties and enzyme activities. Soil moisture (SM) and soil organic carbon (SOC) contents were substantially higher in paddy fields than in upland crop lands, while nitrogen-related enzyme activities were lower. Following the land use change, bacterial diversity was increased and bacterial community composition changed. Taxonomic analyses showed that Proteobacteria, Chloroflexi, Firmicutes, and Bacteroidetes were the dominant phyla present. At family level, Gemmatimonadaceae decreased with land use change, while Syntrophorhabdaceae and Syntrophacea that play a part in methane cycling and nitrifying bacteria such as Nitrospiraceae increased, indicating that the structure and composition of the bacterial community might be a promising indicator of Mollisol health. Redundancy analysis indicated that land use type had a stronger effect on the soil bacterial community composition than soil depth. Additionally, bacterial community composition was closely associated with soil parameters such as soil moisture, pH, SOC, NO3--N, and NH4+-N. Overall, land use change affects the physical and chemical properties of the soil, resulting in changes in the composition of the soil bacterial community and flora. These changes could provide a view of the bacterial community assembly and functional shifts following land use change.

mRNA m5C controls adipogenesis by promoting CDKN1A mRNA export and translation.

5-Methylcytosine (m5C) is a type of RNA modification that exists in tRNAs and rRNAs and was recently found in mRNA. Although mRNA m5C modification has been reported to regulate diverse biological process, its function in adipogenesis remains unknown. Here, we demonstrated that knockdown of NOL1/NOP2/Sun domain family member 2 (NSUN2), a m5C methyltransferase, increased lipid accumulation of 3T3-L1 preadipocytes through accelerating cell cycle progression during mitotic clonal expansion (MCE) at the early stage of adipogenesis. Mechanistically, we proved that NSUN2 directly targeted cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA, a key inhibitory regulator of cell cycle progression, and upregulated its protein expression in an m5C-dependent manner. Further study identified that CDKN1A was the target of Aly/REF export factor (ALYREF), a reader of m5C modified mRNA. Upon NSUN2 deficiency, the recognition of CDKN1A mRNA by ALYREF was suppressed, resulting in the decrease of CDKN1A mRNA shuttling from nucleus to cytoplasm. Thereby, the translation of CDKN1A was reduced, leading to the acceleration of cell cycle and the promotion of adipogenesis. Together, these findings unveiled an important function and mechanism of the m5C modification on adipogenesis by controlling cell cycle progression, providing a potential therapeutic target to prevent obesity.

Possible repair mechanisms of renin-angiotensin system inhibitors, matrix metalloproteinase-9 inhibitors and protein hormones on methamphetamine-induced neurotoxicity.

Methamphetamine is a highly addictive central stimulant with extensive and strong neurotoxicity. The neurotoxicity of methamphetamine is closely related to the imbalance of dopamine levels and the destruction of the blood-brain barrier. An increase in dopamine may induce adverse effects such as behavioral sensitization and excessive locomotion. Damage to the blood-brain barrier can cause toxic or harmful substances to leak to the central nervous system, leading to neurotoxicity. The renin-angiotensin system is essential for the regulation of dopamine levels in the brain. Matrix metalloproteinase-9 causes reward effects and behavioral sensitization by inducing dopamine release. Prolactin has been shown to be involved in the regulation of tight junction proteins and the integrity of the blood-brain barrier. At present, the treatment of methamphetamine detoxification is still based on psychotherapy, and there is no specific medicine. With the rapid increase in global seizures of methamphetamine, the treatment of its toxicity has attracted more and more attention. This review intends to summarize the therapeutic mechanisms of renin-angiotensin inhibitors, matrix metalloproteinase-9 inhibitors and protein hormones (prolactin) on methamphetamine neurotoxicity. The repair effects of these three on methamphetamine may be related to the maintenance of brain dopamine balance and the integrity of the blood-brain barrier. This review is expected to provide the new therapeutic strategy of methamphetamine toxicity.

METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPß pathway via an m6A-YTHDF2-dependent manner.

Bone marrow stem cells (BMSCs) are multipotent stem cells that can regenerate mesenchymal tissues, such as adipose tissue, bone, and muscle. Recent studies have shown that N6-methyladenosine (m6A) methylation, one of the most prevalent epigenetic modifications, is involved in the development process. However, whether it plays roles in BMSC differentiation is still elusive. Here, we found that the deletion of m6A "writer" protein methyltransferase-like (METTL)3 in porcine BMSCs (pBMSCs) could promote adipogenesis and janus kinase (JAK)1 protein expression via an m6A-dependent way. Knockdown of METTL3 decreased mRNA m6A levels of JAK1, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2)-dependent JAK1 mRNA stability. We further demonstrated that JAK1 activated signal transducer and activator of transcription (STAT) 5 through regulation of its phosphorylation to bind to the promoter of CCAAT/enhancer binding protein (C/EBP) ß, which could ultimately lead to a modulated adipogenic process. Collectively, our results reveal an orchestrated network linking the m6A methylation and JAK1/STAT5/C/EBPß pathway in pBMSCs adipogenic differentiation. Our findings provide novel insights into the underlying molecular mechanisms of m6A modification in the regulation of BMSCs differentiating into adipocytes, which may pave a way to develop more effective therapeutic strategies in stem cell regenerative medicine and the treatment of obesity.-Yao, Y., Bi, Z., Wu, R., Zhao, Y., Liu, Y., Liu, Q., Wang, Y., Wang, X. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPß pathway via an m6A-YTHDF2-dependent manner.

A dynamic reversible RNA N6 -methyladenosine modification: current status and perspectives.

N6 -methyladenosine (m6 A), as the most abundant RNA epigenetic modifications, has been shown to play critical roles in various biological functions. Research about enzymes that can catalyze and remove m6 A have revealed its comprehensive roles in messenger RNA (mRNA) metabolism and other physiological processes. The "readers" including YTH domain-containing proteins, hnRNPC, hnRNPG, hnRNPA2B1, IGF2BP1, IGF2BP2, and IGF2BP3, which can affect the fates of mRNA in an m6 A-dependent manner. In this review, we focus on recent advances in the research of the m6 A modifications, especially about the latest functions of its writers, erasers, readers in RNA metabolism, cancer, and lipid metabolism. In the end, we provide insights into the underlying molecular mechanisms of m6 A modifications.

ZFP217 regulates adipogenesis by controlling mitotic clonal expansion in a METTL3-m6A dependent manner.

Obesity is becoming a global problem. Research into the detailed mechanism of adipocyte development is crucial for the treatment of excess fat. Zinc finger protein 217 plays roles in adipogenesis. However, the underlying mechanism remains unclear. Here, we demonstrated that ZFP217 knockdown prevented the mitotic clonal expansion process and caused adipogenesis inhibition. Depletion of ZFP217 increased the expression of the m6A methyltransferase METTL3, which upregulated the m6A level of cyclin D1 mRNA. METTL3 knockdown rescued the siZFP217-inhibited MCE and promoted CCND1 expression. YTH domain family 2 recognized and degraded the methylated CCND1 mRNA, leading to the downregulation of CCND1. Consequently, cell-cycle progression was blocked, and adipogenesis was inhibited. YTHDF2 knockdown relieved siZFP217-inhibited adipocyte differentiation. These findings reveal that ZFP217 knockdown-induced adipogenesis inhibition was caused by CCND1, which was mediated by METTL3 and YTHDF2 in an m6A-dependent manner. We have provided novel insight into the underlying molecular mechanisms by which m6A methylation is involved in the ZFP217 regulation of adipogenesis.

Rhodococcus daqingensis sp. nov., isolated from petroleum-contaminated soil.

A novel Gram-stain positive, aerobic, non-motile bacterial strain, designated Z1T, was isolated from a sample of petroleum-contaminated soil collected in Daqing, Heilongjiang province, China and characterised with a series of taxonomic approaches. The morphological and chemotaxonomic properties of the isolate were typical of those of members of the genus Rhodococcus. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Z1T belongs to the genus Rhodococcus and clustered with Rhodococcus maanshanensis DSM 44675T (99.2%, sequence similarity) and Rhodococcus tukisamuensis JCM 11308T (97.9%), respectively. However, the DNA-DNA hybridizations between strain Z1T and R. maanshanensis DSM 44675T and R. tukisamuensis JCM 11308T were both less than 70%. The optimal growth temperature and pH for strain Z1T were found to be at 28 °C and at pH 7.0. The peptidoglycan was found to contain meso-diaminopimelic acid; arabinose, galactose and glucose were detected as diagnostic sugars. The main polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and an unidentified lipid; MK-8(H2) was found as the major menaquinone. The major fatty acids were identified as C16:0, 10-methyl C18:0 and C18:1ω9c. Mycolic acids were found to be present. The G + C content of the genomic DNA was determined to be 66.7 mol%. Based on a comparative analysis of phenotypic and genotypic characteristics, in combination with DNA-DNA hybridization results, strain Z1T can be distinguished from the type strains of its two close neighbours as a novel species of the genus Rhodococcus, for which the name Rhodococcus daqingensis sp. nov. is proposed. The type strain is Z1T (= CGMCC 1.13630T = DSM 107227T).

Dissipation and safety evaluation of afidopyropen and its metabolite residues in supervised cotton field.

The novel insecticidal mechanism of afidopyropen can be substituted for traditional pesticides to control sap-sucking pests in cotton field. The data of residue amounts of afidopyropen and its metabolite M440I007 in cotton matrix and the environment soil are important to evaluate the safe use of the target compound and establish maximum residue limit (MRL). In this work, the dissipation and residue of afidopyropen and its metabolite M440I007 in cotton and field soils were investigated. The analytical methods of the target compound in cotton plants, cottonseed, crude cottonseed oil, cottonseed oil and soil were developed and quantified by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), which satisfied the rules of pesticide residue determination. The dissipation half-lives of afidopyropen in cotton plants and soil ranged from 1 to 3 days and 4-13 days, respectively. After 14 days from the last application, the residues of afidopyropen were below 0.01 mg/kg in cottonseed and were <0.005-0.0099 mg/kg in soil, and the residues of M440I007 were below 0.02 mg/kg in cottonseed and below 0.01 mg/kg in soil. The total national estimated daily intake (NEDI) of afidopyropen was 1.41 mg and the risk quotient (RQ) was 28.0%. The results showed that the risk of application of afidopyropen with the recommended dosage was acceptable.

Geodermatophilus daqingensis sp. nov., isolated from petroleum-contaminated soil.

A novel Gram-positive actinobacterium, designated WT-2-1T, was isolated from a sample of petroleum-contaminated soil collected in Daqing, Heilongjiang province, China and characterised using a polyphasic taxonomic approach. The optimal growth for strain WT-2-1T was found to be at 25-35 °C and at pH 6.0-9.0 and with 0-4% (w/v) NaCl, forming blackish green-coloured colonies. Chemotaxonomic and molecular characteristics of the isolate match those described for members of the genus Geodermatophilus. The peptidoglycan was found to contain meso-diaminopimelic acid; galactose, glucose and xylose were detected as diagnostic sugars. The main phospholipids were identified as diphosphatidylglycerol, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and phosphatidylglycerol; MK-9(H4) was the dominant menaquinone present. The major cellular fatty acids were identified as iso-C16:0 and iso-C15:0. 16S rRNA gene sequence analysis showed that strain WT-2-1T is a member of the genus Geodermatophilus, with high sequence similarities to Geodermatophilus aquaeductus BMG801T (98.4%), Geodermatophilus saharensis CF5/5T (98.4%), Geodermatophilus bullaregiensis BMG841T (98.3%) and Geodermatophilus normandii CF5/3T (98.3%). Based on the phenotypic characteristics, phylogenetic data and DNA-DNA hybridization results, the isolate is concluded to represent a novel species of the genus Geodermatophilus, for which the name Geodermatophilus daqingensis sp. nov. is proposed. The type strain is WT-2-1T (=CGMCC 4.7381T = DSM 104001T).

Ovate family protein1 interaction with BLH3 regulates transition timing from vegetative to reproductive phase in Arabidopsis.

Three-Amino-acid-Loop-Extension(TALE) homeodomain transcription factor BLH3 regulates timing of transition from vegetative to reproductive phase. Previous preliminary results obtained using large-scale yeast two-hybrids indicate that BLH3 protein possibly interact with Ovate Family Proteins(OFPs) transcription co-regulators. Nevertheless, it is uncertain whether OFP1-BLH3 complex is involved in regulation of timing of transition from vegetative to reproductive phase in Arabidopsis. The interaction between BLH3 and OFP1 was re-tested and verified by a yeast two-hybrid system. We found that the BLH3-OFP1 interaction was mainly mediated through the BLH3 homeodomain. Meanwhile, this interaction was further confirmed by bimolecular fluorescence complementation (BiFC) in vivo. Further, by establishing protoplast transient expression, we discovered that BLH3 acts as a transcriptional activator, whereas OFP1 functioned as a repressor. The interactions between OFP1 and BLH3 can reduce BLH3 transcriptional activity. The ofp1 mutant lines and blh3 mutant lines, OFP1 overexpress lines and BLH3 overexpress lines can both influence timing of transition from vegetative to reproductive phase. Furthermore, 35s:OFP1/blh3 plants exhibited flowering and leaf quantity similar to that of the wild-type controls. 35s:BLH3/ofp1 plants flowered earlier and had less leaves than wild-type controls, indicating that OFP1 protein might depend partially on BLH3 in its function to regulate the timing of transition from vegetative to reproductive phase. These results support our assumption that, by interacting with OFP1, BLH3 forms a functional protein complex that controls timing of progression from vegetative to reproductive phase, and OFP1 might negatively regulate BLH3 or the BLH-KNOX complex, an important interaction for sustaining the normal transition from vegetative to reproductive phase.

Overexpression of TCP9-like gene enhances salt tolerance in transgenic soybean.

TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factors are a plant-specific family and play roles in plant growth, development, and responses to biotic and abiotic stresses. However, little is known about the functions of the TCP transcription factors in the soybean cultivars with tolerance to salt stress. In this study, TCP9-like, a TCP transcription factor, was identified in the soybean cultivars exposed to salt stress. The expression of TCP9-like gene in the roots of salt-tolerant soybean cultivars was higher than that in salt-sensitive cultivars treated with NaCl. The overexpression of TCP9-like enhanced the salt tolerance of the salt-sensitive soybean cultivar 'DN50'. In T2 generation, the plants with TCP9-like overexpression had significantly lower Na+ accumulation and higher K+ accumulation than the WT plants exposed to 200 or 250 mmol/L NaCl. The K+/Na+ ratio in the plants overexpressing TCP9-like was significantly higher than that in WT plants treated with 200 mmol/L NaCl. Meanwhile, the overexpression of TCP9-like up-regulated the expression levels of GmNHX1, GmNHX3, GmSOS1, GmSOS2-like, and GmHKT1, which were involved in the K+/Na+ homeostasis pathway. The findings indicated that TCP9-like mediated the regulation of both Na+ and K+ accumulation to improve the tolerance of soybean to salt stress.

Analysis of airborne particulate matter (PM2.5) over Hong Kong using remote sensing and GIS.

Airborne fine particulates (PM(2.5); particulate matter with diameter less than 2.5 µm) are receiving increasing attention for their potential toxicities and roles in visibility and health. In this study, we interpreted the behavior of PM(2.5) and its correlation with meteorological parameters in Hong Kong, during 2007-2008. Significant diurnal variations of PM(2.5) concentrations were observed and showed a distinctive bimodal pattern with two marked peaks during the morning and evening rush hour times, due to dense traffic. The study observed higher PM(2.5) concentrations in winter when the northerly and northeasterly winds bring pollutants from the Chinese mainland, whereas southerly monsoon winds from the sea bring fresh air to the city in summer. In addition, higher concentrations of PM(2.5) were observed in rush hours on weekdays compared to weekends, suggesting the influence of anthropogenic activities on fine particulate levels, e.g., traffic-related local PM(2.5) emissions. To understand the spatial pattern of PM(2.5) concentrations in the context of the built-up environment of Hong Kong, we utilized MODerate Resolution Imaging Spectroradiometer (MODIS) Aerosol Optical Thickness (AOT) 500 m data and visibility data to derive aerosol extinction profile, then converted to aerosol and PM(2.5) vertical profiles. A Geographic Information Systems (GIS) prototype was developed to integrate atmospheric PM(2.5) vertical profiles with 3D GIS data. An example of the query function in GIS prototype is given. The resulting 3D database of PM(2.5) concentrations provides crucial information to air quality regulators and decision makers to comply with air quality standards and in devising control strategies.

Multi-residue analysis, dissipation behavior, and final residues of four insecticides in supervised eggplant field.

In this study, the residues of four insecticides, spirotetramat, flonicamid, thiamethoxam, and tolfenpyrad, and their metabolites, including spirotetramat-enol, spirotetramat-mono-hydroxy, spirotetramat-keto-hydroxy, spirotetramat-enol-glucoside, 4-trifluoromethylnicotinamide, 4-trifluoromethylnicotinic acid, N-(4-trifluoromethylnicotinoyl) glycine, and clothianidin, were assessed using a single analysis method. The samples were extracted by acetonitrile, then purified by dispersive solid phase extraction and quantified using high performance liquid chromatography tandem mass spectrometry. The average recovery rate of 12 target compounds was 73.5-103.7%, the relative standard deviation was 1.1-18.3%, and the limit of quantification was 0.01-0.05 mg/kg. The results showed good linearity (R2 >0.99), meeting the requirements of the pesticide residue analysis. The dissipation half-lives of the four insecticides in eggplant were 3.4-14.5 days. After the last applications at 7 and 10 days, the final residues of the four insecticides in eggplant were <0.01-0.21, 0.085-0.26, <0.05-0.078, and <0.01-0.21 mg/kg, respectively. The dissipation and final residue results could provide a theoretical basis for the rational application of four insecticides in eggplant fields.HighlightsHPLC-MS/MS for simultaneous determination of four insecticides and their metabolites in eggplant fields.The dissipation dynamics and final residue of the target compounds in field eggplant were studied.Guidance for the safe use of four insecticides on eggplant.

Tetrahydropalmatine Regulates BDNF through TrkB/CAM Interaction to Alleviate the Neurotoxicity Induced by Methamphetamine.

Tetrahydropalmatine (THP) has analgesic, hypnotic, sedative, and other pharmacological effects. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, growth, and development. However, their mechanism of action in methamphetamine (MA)-induced neurotoxicity remains unclear. This study aims to explore the important role of BDNF in MA neurotoxicity and whether THP can regulate BDNF through the interaction between tyrosine kinase receptor B (TrkB)/calmodulin (CAM) to alleviate the neurotoxicity induced by MA. SD rats were randomly divided into control, MA, and MA + THP groups. Stereotyped behavior test, captive rejection test, open field test (OFT), and Morris water maze (MWM) were used to evaluate the anxiety, aggression, cognition, learning, and memory. Extracted hippocampus and mesencephalon tissue were detected by Western blot, HE staining, and immunohistochemistry. TUNEL staining was used to detect apoptosis. MOE was used for bioinformatics prediction, and coimmunoprecipitation was used to confirm protein interactions. Long-term abuse of MA resulted in lower weight gain ratio and nerve cell damage and caused various neurotoxicity-related behavioral abnormalities: anxiety, aggression, cognitive motor disorders, and learning and memory disorders. MA-induced neurotoxicity is related to the down-regulation of BDNF and apoptosis. THP attenuated the MA-induced neurotoxicity by decreasing CAM, increasing TrkB, phosphorylating Akt, up-regulating NF-κB and BDNF, and inhibiting cell apoptosis. MA can induce neurotoxicity in rats. BDNF may play a vital role in MA-induced neurotoxicity. THP regulates BDNF through TrkB/CAM interaction to alleviate the neurotoxicity induced by MA. THP may be a potential therapeutic drug for the neurotoxic and neurodegenerative diseases related to MA.

Levo-tetrahydropalmatine: A new potential medication for methamphetamine addiction and neurotoxicity.

Levo-tetrahydropalmatine (l-THP) is mainly derived from the dried tuber of the Papaveraceae plant Corydalis, also called Corydalis B, which is a drug with analgesic, hypnotic, sedative and other effects. Methamphetamine (METH) belongs to the central nervous stimulant and is a highly addictive drug. It is an urgent problem to study the mechanism of methamphetamine neurotoxicity and to search for the therapeutic targets of the METH addiction. This review is aimed to discuss the pharmacological mechanism and the protective effects of l-THP on METH-induced neurotoxicity, and to explore the therapeutic prospects of l-THP for METH addiction to provide an innovative application of l-THP in clinic. It was found that exposure to METH leads to the compulsive drug-seeking and drug-taking behavior, which is ultimately resulted in METH addiction and neurotoxicity. L-THP has the inhibitory effects on the incidence, maintenance and relapse of METH addiction. L-THP can effectively enhance the plasticity of nerve cells and improve the function of nerve cells where brain-derived neurotrophic factor (BDNF) and its pathways play a protective role. Therefore, l-THP has the potential to become an important therapeutic drug for METH addiction and neurotoxicity.

TBHQ-Overview of Multiple Mechanisms against Oxidative Stress for Attenuating Methamphetamine-Induced Neurotoxicity.

Methamphetamine is a derivative of amphetamines, a highly addictive central stimulant with multiple systemic toxicity including the brain, heart, liver, lung, and spleen. It has adverse effects such as apoptosis and breakdown of the blood-brain barrier. Methamphetamine is a fatal and toxic chemical substance, and its lethal mechanism has been widely studied in recent years. The possible mechanism is that methamphetamine can cause cardiotoxicity and neurotoxicity mainly by inducing oxidative stress so as to generate heat, eliminate people's hunger and thirst, and maintain a state of excitement so that people can continue to exercise. According to many research, there is no doubt that methamphetamine triggers neurotoxicity by inducing reactive oxygen species (ROS) production and redox imbalance. This review summarized the mechanisms of methamphetamine-induced neurotoxicity including apoptosis and blood-brain barrier breakdown through oxidative stress and analyzed several possible antioxidative mechanisms of tert-butylhydroquinone (TBHQ) which is a kind of food additive with antioxidative effects. As a nuclear factor E2-related factor 2 (Nrf2) agonist, TBHQ may inhibit neurotoxicity caused by oxidative stress through the following three mechanisms: the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, the astrocytes activation, and the glutathione pathway. The mechanism about methamphetamine's toxic effects and its antioxidative therapeutic drugs would become a research hotspot in this field and has very important research significance.

m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7.

N: 6-methyladenosine (m6A), the most abundant internal modification on mRNAs in eukaryotes, play roles in adipogenesis. However, the underlying mechanism remains largely unclear. Here, we show that m6A plays a critical role in regulating macroautophagy/autophagy and adipogenesis through targeting Atg5 and Atg7. Mechanistically, knockdown of FTO, a well-known m6A demethylase, decreased the expression of ATG5 and ATG7, leading to attenuation of autophagosome formation, thereby inhibiting autophagy and adipogenesis. We proved that FTO directly targeted Atg5 and Atg7 transcripts and mediated their expression in an m6A-dependent manner. Further study identified that Atg5 and Atg7 were the targets of YTHDF2 (YTH N6-methyladenosine RNA binding protein 2). Upon FTO silencing, Atg5 and Atg7 transcripts with higher m6A levels were captured by YTHDF2, which resulted in mRNA degradation and reduction of protein expression, thus alleviating autophagy and adipogenesis. Furthermore, we generated an adipose-selective fto knockout mouse and find that FTO deficiency decreased white fat mass and impairs ATG5- and ATG7-dependent autophagy in vivo. Together, these findings unveil the functional importance of the m6A methylation machinery in autophagy and adipogenesis regulation, which expands our understanding of such interplay that is essential for development of therapeutic strategies in the prevention and treatment of obesity. ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin, beta; ATG: autophagy-related; Baf A1: bafilomycin A1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; CEBPB: CCAAT/enhancer binding protein (C/EBP), beta; FABP4: fatty acid binding protein 4, adipocyte; FTO: fat mass and obesity associated; HFD: high-fat diet; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; m6A: N6-methyladenosine; MEFs: mouse embryo fibroblasts; MeRIP-qPCR: methylated RNA immunoprecipitation-qPCR; PPARG: peroxisome proliferator activated receptor gamma; RIP: RNA-immunoprecipitation; SAT: subcutaneous adipose tissue; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like kinase 1; VAT: visceral adipose tissue; WAT: white adipose tissue; YTHDF: YTH N6-methyladenosine RNA binding protein.

Chronic toxicity of methamphetamine: Oxidative remodeling of pulmonary arteries.

Methamphetamine (MA) has a high uptake in lung, but the precise mechanism of MA-induced lung toxicity remains unclear. The aim of this study is to investigate the role of MA abuse in remodeling of pulmonary arteries and to explore the possible correlation of the association of the remodeling with the redox imbalance in pulmonary arterial smooth muscle cells (PASMCs). Wistar rats were randomly divided into control group and MA group for the experimental study. We employed H&E staining, western blot, immunofluorescence, knockdown, flow in our experimental approach. Our studies shows that chronic exposure to MA led to weight loss, increased pulmonary arterial pressure, hypertrophy of right ventricle and remodeling of pulmonary arterial wall of rats. Our cell culture study with PASMCs indicates that MA significantly induced the imbalance between proliferation and apoptosis by upregulating the level of PCNA, Bcl-2 and reduction in the expression of BAX and Caspase 3. MA markedly prevented the nuclear translocation of Nrf2 to inhibit antioxidation. The knockdown of Nrf2 expression using siRNA significantly elevated the expression of SOD2/GCS and the production of ROS in PASMCs and even scaled up the amount of PASMCs induced by MA. Linear regression analysis showed that knockdown of Nrf2 promoted the positive correlation of relative ROS level with proliferation of PASMCs. Therefore, chronic exposure to MA induces pulmonary arterial remodeling by Nrf2-mediated imbalance of redox system to aggravate oxidative stress, and Nrf2 is a possible target for the treatment of MA-lung toxicity.