Pharmacological mechanism of natural antidepressants: The role of mitochondrial quality control.

BACKGROUND: Depression is a mental illness characterized by persistent sadness and a reduced capacity for pleasure. In clinical practice, SSRIs and other medications are commonly used for therapy, despite their various side effects. Natural products present distinct advantages, including synergistic interactions among multiple components and targeting multiple pathways, suggesting their tremendous potential in depression treatment. Imbalance in mitochondrial quality control (MQC) plays a significant role in the pathology of depression, emphasizing the importance of regulating MQC as a potential intervention strategy in addressing the onset and progression of depression. However, the role and mechanism through which natural products regulate MQC in depression treatments still need to be comprehensively elucidated, particularly in clinical and preclinical settings. PURPOSE: This review was aimed to summarize the findings of recent studies and outline the pharmacological mechanisms by which natural products modulate MQC to exert antidepressant effects. Additionally, it evaluated current research limitations and proposed new strategies for future preclinical and clinical applications in the depression domain. METHODS: To study the main pharmacological mechanisms underlying the regulation of MQC by natural products in the treatment of depression, we conducted a thorough search across databases such as PubMed, Web of Science, and ScienceDirect databases to classify and summarize the relationship between MQC and depression, as well as the regulatory mechanisms of natural products. RESULTS: Numerous studies have shown that irregularities in the MQC system play an important role in the pathology of depression, and the regulation of the MQC system is involved in antidepressant treatments. Natural products mainly regulate the MQC system to induce antidepressant effects by alleviating oxidative stress, balancing ATP levels, promoting mitophagy, maintaining calcium homeostasis, optimizing mitochondrial dynamics, regulating mitochondrial membrane potential, and enhancing mitochondrial biogenesis. CONCLUSIONS: We comprehensively summarized the regulation of natural products on the MQC system in antidepressants, providing a unique perspective for the application of natural products within antidepressant therapy. However, extensive efforts are imperative in clinical and preclinical investigations to delve deeper into the mechanisms underlying how antidepressant medications impact MQC, which is crucial for the development of effective antidepressant treatments.

Comparative efficacy and safety of ginkgo-based Chinese patent medicines in patients with hypertension: A systematic review and network meta-analysis of randomized clinical trials.

BACKGROUND: The efficacy and safety of different oral ginkgo-based Chinese patent medicines (CPMs) regimens for hypertension patients were analyzed based on the network meta-analysis of the frequency framework. METHODS: We conducted a comprehensive search of PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, and Chinese Biomedical Literature Database to gather data on randomized controlled trials (RCTs) evaluating the efficacy of 8 ginkgo biloba oral preparations for the treatment of hypertension. The trials included in the analysis were conducted from the inception of the databases up to September 2023. Methodological quality and risk of bias were assessed using the RoB 2.0 evaluation tool, and a reticulated meta-analysis was conducted using STATA MP 14 software. The RCTs included in this study were published studies and therefore did not require ethics committee review or patient consent. RESULTS: We ultimately included 46 RCTs covering 8 CPMs including ginkgo biloba tablet (GBT), GB capsule (GBC), ginkgo biloba drop (GBD), ginkgo biloba ketone ester drop, Fufangyinxing capsule, fufangyinxingtongmai oral liquid, Yinxingmihuan oral liquid, Yindanxinanotong softgel capsule (YDXNT). GBD + CT demonstrated the highest effectiveness in reducing systolic blood pressure (surface under the cumulative ranking [SUCRA] = 78.7%) and improving total effective rate (SUCRA = 86.7%). GBC + CT exhibited the greatest efficacy in reducing diastolic blood pressure (SUCRA = 92.6%). GBT + CT was identified as the most effective in lowering total cholesterol (TC) (SUCRA = 100%). Additionally, YDXNT + CT demonstrated notable improvements in triglyceride levels (SUCRA = 92.2%), Nitric oxide (NO) (SUCRA = 93.9%), and ET-1 (SUCRA = 67.5%). In terms of safety, 14 studies reported the occurrence of adverse reactions with a high degree of clinical heterogeneity, which was only qualitatively analyzed in this study. CONCLUSION SUBSECTIONS: We found that a combination of 8 ginkgo-based CPMs + CT was effective in hypertension compared with CT. The evidence showed that GBD + CT were the best in improving systolic blood pressure and total effective rate, GBC + CT improved diastolic blood pressure, GBT + CT were the most effective in improving TC, and YDXNT + CT was the most effective in improving TG, NO, and ET-1. Adverse effects were only analyzed qualitatively, and the number of adverse effects of CPMs treatment was relatively low compared to CT. In addition, the quality of the literature included in the study was low, and further validation through RCTs with larger sample sizes, higher quality, and more rigorously designed is needed.

Carotenoid isomerase regulates rice tillering and grain productivity by its biosynthesis pathway.

Carotenoid isomerase activity and carotenoid content maintain the appropriate tiller number, photosynthesis, and grain yield. Interactions between the strigolactone and abscisic acid pathways regulates tiller formation.

Plasma membrane-localized hexose transporter OsSWEET1b, affects sugar metabolism and leaf senescence.

KEY MESSAGE: OsSWEET1b is a hexose transporter protein, which localized in cell membranes and interacting with itself to form homodimer and knockout of OsSWEET1b resulted in reduced leaves sugar content and accelerating leaf senescence. In the rice genome, the SWEET gene family contains 21 homologous members, but the role of some of them in rice growth and development is still unknown. The function of the sugar transporter OsSWEET1b protein in rice was identified in this research. Expression analysis showed that the expression levels of OsSWEET1b in leaves were higher than that in other tissues. The hexose transport experiment confirmed that OsSWEET1b has glucose and galactose transporter activity in yeast. Subcellular localization indicates that OsSWEET1b protein was targeted to the plasma membrane and BiFC analysis showed that OsSWEET1b interacts with itself to form homodimers. Functional analysis demonstrated that the ossweet1b mutant plants were have reduced the sucrose, glucose, fructose, starch and galactose contents, and induced carbon starvation-related gene expression, which might lead to carbon starvation in leaves at filling stage. The ossweet1b knockout plants showed decreased chlorophyll content and antioxidant enzyme activity, and increased ROS accumulation in leaves, leading to leaf cell death and premature senescence phenotype at filling stage. In ossweet1b mutants, the leaf senescence-related gene expression levels were increased and the abundance of photosynthesis-related proteins was decreased. Loss of OsSWEET1b were affected the starch, sucrose metabolism and carbon fixation in photosynthetic organelles pathway by RNA-seq analysis. The destruction of OsSWEET1b function will cause sugar starvation, decreased photosynthesis and leaf senescence, which leading to reduced rice yield. Collectively, our results suggest that the OsSWEET1b plays a key role in rice leaves carbohydrate metabolism and leaf senescence.

GR5 acts in the G protein pathway to regulate grain size in rice.

Grain size is an important determinant of grain yield in rice. Although dozens of grain size genes have been reported, the molecular mechanisms that control grain size remain to be fully clarified. Here, we report the cloning and characterization of GR5 (GRAIN ROUND 5), which is allelic to SMOS1/SHB/RLA1/NGR5 and encodes an AP2 transcription factor. GR5 acts as a transcriptional activator and determines grain size by influencing cell proliferation and expansion. We demonstrated that GR5 physically interacts with five Gγ subunit proteins (RGG1, RGG2, DEP1, GS3, and GGC2) and acts downstream of the G protein complex. Four downstream target genes of GR5 in grain development (DEP2, DEP3, DRW1, and CyCD5;2) were revealed and their core T/CGCAC motif identified by yeast one-hybrid, EMSA, and ChIP-PCR experiments. Our results revealed that GR5 interacts with Gγ subunits and cooperatively determines grain size by regulating the expression of downstream target genes. These findings provide new insight into the genetic regulatory network of the G protein signaling pathway in the control of grain size and provide a potential target for high-yield rice breeding.

GW9 determines grain size and floral organ identity in rice.

Grain weight is an important determinant of grain yield. However, the underlying regulatory mechanisms for grain size remain to be fully elucidated. Here, we identify a rice mutant grain weight 9 (gw9), which exhibits larger and heavier grains due to excessive cell proliferation and expansion in spikelet hull. GW9 encodes a nucleus-localized protein containing both C2H2 zinc finger (C2H2-ZnF) and VRN2-EMF2-FIS2-SUZ12 (VEFS) domains, serving as a negative regulator of grain size and weight. Interestingly, the non-frameshift mutations in C2H2-ZnF domain result in increased plant height and larger grain size, whereas frameshift mutations in both C2H2-ZnF and VEFS domains lead to dwarf and malformed spikelet. These observations indicated the dual functions of GW9 in regulating grain size and floral organ identity through the C2H2-ZnF and VEFS domains, respectively. Further investigation revealed the interaction between GW9 and the E3 ubiquitin ligase protein GW2, with GW9 being the target of ubiquitination by GW2. Genetic analyses suggest that GW9 and GW2 function in a coordinated pathway controlling grain size and weight. Our findings provide a novel insight into the functional role of GW9 in the regulation of grain size and weight, offering potential molecular strategies for improving rice yield.

Adult hippocampal neurogenesis: pharmacological mechanisms of antidepressant active ingredients in traditional Chinese medicine.

Depression is characterized by prominent indicators and manifestations, such as anhedonia, which refers to the inability to experience pleasure, and persistent feelings of hopelessness. In clinical practice, the primary treatment approach involves the utilization of selective serotonin reuptake inhibitors (SSRIs) and related pharmacological interventions. Nevertheless, it is crucial to recognize that these agents are associated with significant adverse effects. Traditional Chinese medicine (TCM) adopts a multifaceted approach, targeting diverse components, multiple targets, and various channels of action. TCM has potential antidepressant effects. Anomalies in adult hippocampal neurogenesis (AHN) constitute a pivotal factor in the pathology of depression, with the regulation of AHN emerging as a potential key measure to intervene in the pathogenesis and progression of this condition. This comprehensive review presented an overview of the pharmacological mechanisms underlying the antidepressant effects of active ingredients found in TCM. Through examination of recent studies, we explored how these ingredients modulated AHN. Furthermore, we critically assessed the current limitations of research in this domain and proposed novel strategies for preclinical investigation and clinical applications in the treatment of depression in future.

Antidepressant pharmacological mechanisms: focusing on the regulation of autophagy.

The core symptoms of depression are anhedonia and persistent hopelessness. Selective serotonin reuptake inhibitors (SSRIs) and their related medications are commonly used for clinical treatment, despite their significant adverse effects. Traditional Chinese medicine with its multiple targets, channels, and compounds, exhibit immense potential in treating depression. Autophagy, a vital process in depression pathology, has emerged as a promising target for intervention. This review summarized the pharmacological mechanisms of antidepressants by regulating autophagy. We presented insights from recent studies, discussed current research limitations, and proposed new strategies for basic research and their clinical application in depression.

OsSTS, a Novel Allele of Mitogen-Activated Protein Kinase Kinase 4 (OsMKK4), Controls Grain Size and Salt Tolerance in Rice.

Soil salinization is one of the most common abiotic stresses of rice, which seriously affects the normal growth of rice. Breeding salt-tolerant varieties have become one of the important ways to ensure food security and sustainable agricultural development. However, the mechanisms underlying salt tolerance control still need to be clarified. In this study, we identified a mutant, termed salt-tolerant and small grains(sts), with salt tolerance and small grains. Gene cloning and physiological and biochemical experiments reveal that sts is a novel mutant allele of Mitogen-activated protein Kinase Kinase 4 (OsMKK4), which controls the grain size, and has recently been found to be related to salt tolerance in rice. Functional analysis showed that OsSTS is constitutively expressed throughout the tissue, and its proteins are localized to the nucleus, cell membrane, and cytoplasm. It was found that the loss of OsSTS function enhanced the salt tolerance of rice seedlings, and further studies showed that the loss of OsSTS function increased the ROS clearance rate of rice seedlings, independent of ionic toxicity. In order to explore the salt tolerance mechanism of sts, we found that the salt tolerance of sts is also regulated by ABA through high-throughput mRNA sequencing. Salt and ABA treatment showed that ABA might alleviate the inhibitory effect of salt stress on root length in sts. These results revealed new functions of grain size gene OsMKK4, expanded new research ideas related to salt tolerance mechanism and hormone regulation network, and provided a theoretical basis for salt-tolerant rice breeding.

NLG1, encoding a mitochondrial membrane protein, controls leaf and grain development in rice.

BACKGROUND: Mitochondrion is the key respiratory organ and participate in multiple anabolism and catabolism pathways in eukaryote. However, the underlying mechanism of how mitochondrial membrane proteins regulate leaf and grain development remains to be further elucidated. RESULTS: Here, a mitochondria-defective mutant narrow leaf and slender grain 1 (nlg1) was identified from an EMS-treated mutant population, which exhibits narrow leaves and slender grains. Moreover, nlg1 also presents abnormal mitochondria structure and was sensitive to the inhibitors of mitochondrial electron transport chain. Map-based cloning and transgenic functional confirmation revealed that NLG1 encodes a mitochondrial import inner membrane translocase containing a subunit Tim21. GUS staining assay and RT-qPCR suggested that NLG1 was mainly expressed in leaves and panicles. The expression level of respiratory function and auxin response related genes were significantly down-regulated in nlg1, which may be responsible for the declination of ATP production and auxin content. CONCLUSIONS: These results suggested that NLG1 plays an important role in the regulation of leaf and grain size development by maintaining mitochondrial homeostasis. Our finding provides a novel insight into the effects of mitochondria development on leaf and grain morphogenesis in rice.

Relationship between nonalcoholic fatty liver disease and bone mineral density in elderly Chinese.

OBJECTIVE: As our society grows older, both bone loss and fatty liver have become important issues. However, the relationship between reduced bone mineral density and fatty liver remains controversial. The purpose of this study was to investigate the relationship between nonalcoholic fatty liver disease and less bone mineral density in the ankles of Chinese people over 65. METHODS: The research included 716 older adults over the age of 65 who underwent a comprehensive health screening. A logistic regression model was used to investigate the relationship between nonalcoholic fatty liver disease (NAFLD) and ankle bone mineral density. RESULTS: A logistic regression model was used to analyze the odds ratios of reduced bone mineral density between patients with fatty liver and controls. In the adjusted model, adjustments were made for age, sex, systolic blood pressure, diastolic blood pressure, overweight rate, history of hypertension, history of diabetes, history of smoking, history of alcohol consumption, fasting glucose, hemoglobin, urea, creatinine, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, waist circumference, total protein, albumin, and globulin. The adjusted OR (aOR) for reduced bone mineral density was 0.66 [95% confidence interval (CI) = 0.45-0.97, P = 0.034 < 0.05]. In subgroup analysis by age, sex, and BMI, women, age > 75 years, and BIM < 25 were statistically significant. CONCLUSION: This study suggested that NAFLD is associated with a reduced risk of reduced heel bone mass. More research needs to be done to back up the results of this study and look into possible problems.

miR-1-3p Inhibits Osteosarcoma Cell Proliferation and Cell Cycle Progression While Promoting Cell Apoptosis by Targeting CDK14 to Inactivate Wnt/Beta-Catenin Signaling.

Osteosarcoma (OS) is a common bone malignancy and is diagnosed frequently in children and young adults. According to previous RNA sequencing, miR-1-3p is downregulated in OS clinical samples. Nevertheless, the functions of miR-1-3p in OS cell process and the related mechanism have not been revealed yet. In the current study, miR-1-3p expression in OS tissues and cells were evaluated using quantitative polymerase chain reaction. CCK-8 assays were conducted to measure OS cell viability in response to miR-1-3p overexpression. Colony forming assays and EdU staining were conducted for measurement of cell proliferation, and flow cytometry analysis was performed to determine cell apoptosis and cell cycle progression. Protein levels of apoptotic markers, beta-catenin, and Wnt downstream targets were quantified using western blotting. The binding relation between miR-1-3p and cyclin dependent kinase 14 (CDK14) was validated utilizing luciferase reporter assays. Experimental results revealed that miR-1-3p expression was decreased in OS tissues and cells. Additionally, miR-1-3p inhibited cell proliferation and cell cycle progression while enhancing OS cell apoptosis. Moreover, miR-1-3p directly targeted CDK14 and inversely regulated CDK14 expression in OS cells. Furthermore, miR-1-3p inactivated the Wnt/beta-catenin signaling. CDK14 overexpression partially rescued the inhibitory impact of miR-1-3p on OS cell growth. Overall, miR-1-3p inhibits OS cell proliferation and cell cycle progression while promoting cell apoptosis by targeting CDK14 and inactivating the Wnt/beta-catenin signaling.

SEMI-ROLLED LEAF 10 stabilizes catalase isozyme B to regulate leaf morphology and thermotolerance in rice (Oryza sativa L.).

Plant architecture and stress tolerance play important roles in rice breeding. Specific leaf morphologies and ideal plant architecture can effectively improve both abiotic stress resistance and rice grain yield. However, the mechanism by which plants simultaneously regulate leaf morphogenesis and stress resistance remains elusive. Here, we report that SRL10, which encodes a double-stranded RNA-binding protein, regulates leaf morphology and thermotolerance in rice through alteration of microRNA biogenesis. The srl10 mutant had a semi-rolled leaf phenotype and elevated sensitivity to high temperature. SRL10 directly interacted with catalase isozyme B (CATB), and the two proteins mutually increased one other's stability to enhance hydrogen peroxide (H2 O2 ) scavenging, thereby contributing to thermotolerance. The natural Hap3 (AGC) type of SRL10 allele was found to be present in the majority of aus rice accessions, and was identified as a thermotolerant allele under high temperature stress in both the field and the growth chamber. Moreover, the seed-setting rate was 3.19 times higher and grain yield per plant was 1.68 times higher in near-isogenic line (NIL) carrying Hap3 allele compared to plants carrying Hap1 allele under heat stress. Collectively, these results reveal a new locus of interest and define a novel SRL10-CATB based regulatory mechanism for developing cultivars with high temperature tolerance and stable yield. Furthermore, our findings provide a theoretical basis for simultaneous breeding for plant architecture and stress resistance.

OsPPR11 encoding P-type PPR protein that affects group II intron splicing and chloroplast development.

KEY MESSAGE: OsPPR11 belongs to the P-type PPR protein family and can interact with OsCAF2 to regulate Group II intron splicing and affect chloroplast development in rice. Pentatricopeptide repeat (PPR) proteins participate in chloroplasts or mitochondria group II introns splicing in plants. The PPR protein family contains 491 members in rice, but most of their functions are unknown. In this study, we identified a nuclear gene encoding the P-type PPR protein OsPPR11 in chloroplasts. The qRT-PCR analysis demonstrated that OsPPR11 was expressed in all plant tissues, but leaves had the highest expression. The osppr11 mutants had yellowing leaves and a lethal phenotype that inhibited chloroplast development and photosynthesis-related gene expression and reduced photosynthesis-related protein accumulation in seedlings. Moreover, photosynthetic complex accumulation decreased significantly in osppr11 mutants. The OsPPR11 is required for ndhA, and ycf3-1 introns splicing and interact with CRM family protein OsCAF2, suggesting that these two proteins may form splicing complexes to regulate group II introns splicing. Further analysis revealed that OsCAF2 interacts with OsPPR11 through the N-terminus. These results indicate that OsPPR11 is essential for chloroplast development and function by affecting group II intron splicing in rice.

Ferroptosis: a new antidepressant pharmacological mechanism.

The incidence rate of depression, a mental disorder, is steadily increasing and has the potential to become a major global disability factor. Given the complex pathological mechanisms involved in depression, the use of conventional antidepressants may lead to severe complications due to their side effects. Hence, there is a critical need to explore the development of novel antidepressants. Ferroptosis, a newly recognized form of cell death, has been found to be closely linked to the onset of depression. Several studies have indicated that certain active ingredients can ameliorate depression by modulating the ferroptosis signaling pathway. Notably, traditional Chinese medicine (TCM) active ingredients and TCM prescriptions have demonstrated promising antidepressant effects in previous investigations owing to their unique advantages in antidepressant therapy. Building upon these findings, our objective was to review recent relevant research and provide new insights and directions for the development and application of innovative antidepressant strategies.

Development and validation of a ferroptosis-related lncRNAs signature to predict prognosis and microenvironment for melanoma.

Ferroptosis plays an important role in cancer. However, studies about ferroptosis-related lncRNAs (FRLs) in skin cutaneous melanoma (SKCM) are scarce. Moreover, the relationship between prognostic FRLs and tumor microenvironment (TME) in melanoma remains unclear. This study investigates the potential prognostic value of FRLs and their association with TME in SKCM. The RNA-sequencing data of SKCM were downloaded from The Cancer Genome Atlas (TCGA) database. Melanoma patients were randomly divided into training and testing groups in a 1:1 ratio. A signature composed of 19 FRLs was developed by the least absolute shrinkage and selection operator (LASSO) regression analysis to divide patients into a low-risk group with a better prognosis and a high-risk group with a poor prognosis. Multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor. The Area Under Curve (AUC) value of the risk score reached 0.768 in the training group and 0.770 in the testing group. Subsequent analysis proved that immune-related signaling pathways were significantly enriched in the low-risk group. The tumor immune cell infiltration analysis demonstrated that melanoma in the high-risk group tended to be immunologically "cold". We identified a novel FRLs signature which could accurately predict the prognosis of patients with melanoma.

Genome-Wide Association Study Reveals Novel QTLs and Candidate Genes for Grain Number in Rice.

Grain number per panicle (GNPP), determined mainly by panicle branching, is vital for rice yield. The dissection of the genetic basis underlying GNPP could help to improve rice yield. However, genetic resources, including quantitative trait loci (QTL) or genes for breeders to enhance rice GNPP, are still limited. Here, we conducted the genome-wide association study (GWAS) on the GNPP, primary branch number (PBN), and secondary branch number (SBN) of 468 rice accessions. We detected a total of 18 QTLs, including six for GNPP, six for PBN, and six for SBN, in the whole panel and the indica and japonica subpanels of 468 accessions. More importantly, qPSG1 was a common QTL for GNPP, PBN, and SBN and was demonstrated by chromosome segment substitution lines (CSSLs). Considering gene annotation, expression, and haplotype analysis, seven novel and strong GNPP-related candidate genes were mined from qPSG1. Our results provide clues to elucidate the molecular regulatory network of GNPP. The identified QTLs and candidate genes will contribute to the improvement of GNPP and rice yield via molecular marker-assisted selection (MAS) breeding and genetic engineering techniques.

Genome-wide association study reveals novel QTLs and candidate genes for seed vigor in rice.

Highly seed vigor (SV) is essential for rice direct seeding (DS). Understanding the genetic mechanism of SV-related traits could contribute to increasing the efficiency of DS. However, only a few genes responsible for SV have been determined in rice, and the regulatory network of SV remains obscure. In this study, the seed germination rate (GR), seedling shoot length (SL), and shoot fresh weight (FW) related to SV traits were measured, and a genome-wide association study (GWAS) was conducted to detect high-quality loci responsible for SV using a panel of 346 diverse accessions. A total of 51 significant SNPs were identified and arranged into six quantitative trait locus (QTL) regions, including one (qGR1-1), two (qSL1-1, qSL1-2), and three (qFW1-1, qFW4-1, and qFW7-1) QTLs associated with GR, SL, and FW respectively, which were further validated using chromosome segment substitution lines (CSSLs). Integrating gene expression, gene annotation, and haplotype analysis, we found 21 strong candidate genes significantly associated with SV. In addition, the SV-related functions of LOC_Os01g11270 and LOC_Os01g55240 were further verified by corresponding CRISPR/Cas9 gene-edited mutants. Thus, these results provide clues for elucidating the genetic basis of SV control. The candidate genes or QTLs would be helpful for improving DS by molecular marker-assisted selection (MAS) breeding in rice.

Molecular Events of Rice AP2/ERF Transcription Factors.

APETALA2/ethylene response factor (AP2/ERF) is widely found in the plant kingdom and plays crucial roles in transcriptional regulation and defense response of plant growth and development. Based on the research progress related to AP2/ERF genes, this paper focuses on the classification and structural features of AP2/ERF transcription factors, reviews the roles of rice AP2/ERF genes in the regulation of growth, development and stress responses, and discusses rice breeding potential and challenges. Taken together; studies of rice AP2/ERF genes may help to elucidate and enrich the multiple molecular mechanisms of how AP2/ERF genes regulate spikelet determinacy and floral organ development, flowering time, grain size and quality, embryogenesis, root development, hormone balance, nutrient use efficiency, and biotic and abiotic response processes. This will contribute to breeding excellent rice varieties with high yield and high resistance in a green, organic manner.

Activation of PI3k/Akt/mTOR Signaling Induces Deposition of p-tau to Promote Aluminum Neurotoxicity.

Aluminum neurotoxicity impairs learning and memory ability, but the molecular mechanism has not been elucidated. The aim of this study was to examine the role of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling in regulating the expression of synaptic plasticity-related proteins (PRPs) and p-tau deposition to explore the mechanism underlying aluminum-induced neurotoxicity. We constructed a sub-chronic aluminum-exposed Sprague Dawley (SD) rat model to assess aluminum neurotoxicity in vivo. The learning and memory abilities of rats were examined using the Morris water maze test. We also assessed the effect of aluminum in vitro using rat pheochromocytoma (PC12) cells. To explore the role of PI3K/Akt/mTOR signaling in aluminum neurotoxicity, we used the PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin in aluminum-treated PC12 cells. Protein expression was examined by western blotting. Aluminum disrupted the learning and memory abilities of SD rats. Mechanistically, aluminum reduced the levels of the synaptic PRPs (cAMP-response element binding protein (CREB), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), and postsynaptic density protein 95 (PSD-95), and it increased p-tau deposition in the hippocampus of SD rats. We observed similar results in aluminum-treated PC12 cells. Further, PI3K/Akt/mTOR signaling was abnormally activated in aluminum-treated PC12 cells, and treatment with rapamycin reversed the decrease in synaptic PRPs levels and the increase in p-tau deposition. In conclusion, the activation of PI3K/Akt/mTOR signaling reduces the levels of synaptic PRPs and increases p-tau deposition induced by aluminum. Therefore, the PI3K/Akt/mTOR pathway participates in the mechanism of aluminum neurotoxicity.