Emerging role of gut microbiota in autoimmune diseases.

Accumulating studies have indicated that the gut microbiota plays a pivotal role in the onset of autoimmune diseases by engaging in complex interactions with the host. This review aims to provide a comprehensive overview of the existing literatures concerning the relationship between the gut microbiota and autoimmune diseases, shedding light on the complex interplay between the gut microbiota, the host and the immune system. Furthermore, we aim to summarize the impacts and potential mechanisms that underlie the interactions between the gut microbiota and the host in autoimmune diseases, primarily focusing on systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes mellitus, ulcerative colitis and psoriasis. The present review will emphasize the clinical significance and potential applications of interventions based on the gut microbiota as innovative adjunctive therapies for autoimmune diseases.

CD300e: Emerging role and mechanism as an immune-activating receptor.

As a transmembrane protein, CD300e is primarily expressed in myeloid cells. It belongs to the CD300 glycoprotein family, functioning as an immune-activating receptor. Dysfunction of CD300e has been suggested in many diseases, such as infections, immune disorders, obesity, and diabetes, signifying its potential as a key biomarker for disease diagnosis and treatment. This review is aimed to explore the roles and potential mechanisms of CD300e in regulating oxidative stress, immune cell activation, tissue damage and repair, and lipid metabolism, shedding light on its role as a diagnostic marker or a therapeutic target, particularly for infections and autoimmune disorders.

Gut microbiota and microbiota-derived metabolites in colorectal cancer: enemy or friend.

Colorectal cancer (CRC) is a highly prevalent gastrointestinal cancer worldwide. Recent research has shown that the gut microbiota plays a significant role in the development of CRC. There is mounting evidence supporting the crucial contributions of bacteria-derived toxins and metabolites to cancer-related inflammation, immune imbalances, and the response to therapy. Besides, some gut microbiota and microbiota-derived metabolites have protective effects against CRC. This review aims to summarize the current studies on the effects and mechanisms of gut microbiota and microbiota-produced metabolites in the initiation, progression, and drug sensitivity/resistance of CRC. Additionally, we explore the clinical implications and future prospects of utilizing gut microbiota as innovative approaches for preventing and treating CRC.

Ferritinophagy activation and sideroflexin1-dependent mitochondrial iron overload contribute to patulin-induced cardiac inflammation and fibrosis.

Patulin (PAT) is a mycotoxin that is commonly present throughout the ecosystem where fungi grow and mainly contaminates food, soil, and water. PAT was found to be cardiotoxic in previous studies. However, the detailed mechanism has not been fully elucidated. The present study aimed to explore the role and underlying mechanism of ferroptosis in PAT-induced cardiac injury. Here, we confirmed in vivo and in vitro that ferroptosis is involved in PAT-induced myocardial inflammation and fibrosis. Mice exposed to PAT (1 and 2 mg/kg body weight/day for 14 days) exhibited myocardial inflammation and fibrosis along with disrupted iron homeostasis, elevated lipid peroxidation, depletion of glutathione peroxidase 4, and abnormal mitochondrial morphology. When primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells were exposed to PAT, ferroptosis was initiated in a dose-dependent manner, and this process could be significantly attenuated by ferrostatin-1. Mechanistically, we found that nuclear receptor coactivator (NCOA) 4, a master regulator of ferritinophagy, bound to and degraded ferritin in response to PAT treatment, thereby releasing large amounts of ferrous iron and further leading to sideroflexin (SFXN) 1-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN1 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation. Furthermore, myocardial inflammation and fibrosis in PAT-exposed mice was alleviated by the mitochondrial iron chelator deferiprone. Overall, our findings underscore that ferritinophagy activation and SFXN1-dependent mitochondrial iron overload play critical roles in PAT-induced myocardial ferroptosis and consequent cardiotoxicity.

circRNA_17725 Promotes Macrophage Polarization towards M2 by Targeting FAM46C to Alleviate Arthritis.

Accumulating studies have implicated that circular RNAs (circRNAs) play vital roles in the pathogenesis of rheumatoid arthritis (RA). Dysregulation of macrophage polarization leads to immune homeostatic imbalance in RA. However, the altering effects and mechanisms of circRNAs on macrophages polarization and immune homeostatic balance remain largely unclear. We aimed to investigate the potential role of circRNA_17725 in RA. The high-throughput sequence was performed to identify the dysregulated circRNAs in RA. We confirmed the data by CCK-8, EdU, and Annexin V/PI staining to elucidate the proliferation and apoptosis. The expressions of M1/M2-associated markers were confirmed using real-time PCR and flow cytometry analysis. Luciferase reporter assay and RNA Binding Protein Immunoprecipitation (RIP) were used to demonstrate the underlying mechanism of circRNA_17725. The altering effect of circRNA_17725 on macrophages in vivo was evaluated using collagen-induced arthritis (CIA) mouse model. circRNA_17725 was demonstrated to be downregulated in peripheral blood mononuclear cells and CD14+ monocytes from RA cases in contrast to healthy controls. The negative association between circRNA_17725 and the disease activity indexes (CRP, ESR, and DAS28) was observed, suggesting a vital role of circRNA_17725 in RA disease activity. Besides, after a coexpression analysis based on high-input sequencing and the bioinformatics analysis in MiRanda and TargetScan databases, a circRNA_17725-miR-4668-5p-FAM46C competing endogenous RNA (ceRNA) network was hypothesized. A series of cytology experiments in vitro have implicated that circRNA_17725 could inhibit the proliferation but enhance the apoptosis of macrophages. Decreased expression of TNF-α, IL-1ß, and MMP-9 were observed in the supernatant of circRNA_17725-overexpressed Raw264.7 macrophages, implicating the inhibitory effect of circRNA_17725 on macrophage inflammatory mediators. Furthermore, circRNA_17725 could promote macrophage polarization towards M2 by targeting miR-4668-5p/FAM46C as a miRNA sponge. Additionally, circRNA_17725-overexpressed macrophages alleviated arthritis and protected against joint injuries and bone destruction by inducing macrophage polarization towards M2 in collagen-induced arthritis (CIA) mice. This study has suggested that circRNA_17725 regulated macrophage proliferation, apoptosis, inflammation, and polarization by sponging miR-4668-5p and upregulating FAM46C in RA.

Lignocelluloses-Based Furan-Acetone Adducts as Wood Adhesives for Plywood Production.

Plywood is made of wood veneers that are bonded with adhesives such as urea-formaldehyde, phenol-formaldehyde and melamine-formaldehyde resins. The plywood made from formaldehyde-based adhesives not only releases formaldehyde but also relies on fossil resources. In this article, we synthesized furan-acetone adducts from lignocellulosic biomass in one pot. The furan-acetone adducts could be directly used as adhesives with the addition of phosphoric acid as a curing catalyst. Particularly, with the addition of 5 wt% diphenylmethane diisocyanate (MDI) as a crosslinking agent, both the wet and dry bonding strength of the plywood prepared from the adhesives could meet the minimum requirement of 0.7 MPa (Chinese National Standard GB/T 9846-2015). The possible adhesion mechanism is that the penetration of furan-acetone adhesives into vessels and cell lumens followed by crosslinking during hot-pressing forms mechanical interlocking at the interface of wood veneers, which provides the main bonding strength of plywood. The findings presented here could provide a new way for the efficient preparation of aldehyde-free green wood adhesives and the value-added utilization of woody biomass.

Updated insight into the role of Th2-associated immunity in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organs involvement, abundant autoantibodies, complement activation, and immune complexes depositions. By regulating inflammation and immune homeostasis, cytokines have been well documented to participate in the pathogenesis of SLE. A number of studies have shown that T helper 2 (Th2)-associated immunity plays an important role in autoimmune diseases, including SLE. Key molecules underlying Th2-related immunity are expected to serve as promising targets for the diagnosis and targeted treatment of SLE. Current progress in SLE pathogenesis and biological treatment strategies has been reviewed, focusing on the latest development in Th2-associated immunity.

Lanthanum Chloride Induces Axon Abnormality Through LKB1-MARK2 and LKB1-STK25-GM130 Signaling Pathways.

Lanthanum (La) is a natural rare-earth element that can damage the central nervous system and impair learning and memory. However, its neurotoxic mechanism remains unclear. In this study, adult female rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, and 0.5% LaCl3, respectively, and this was done from conception to the end of the location. Their offspring rats were used to establish animal models to investigate LaCl3 neurotoxicity. Primary neurons cultured in vitro were treated with LaCl3 and infected with LKB1 overexpression lentivirus. The results showed that LaCl3 exposure resulted in abnormal axons in the hippocampus and primary cultured neurons. LaCl3 reduced the expression of LKB1, p-LKB1, STRAD and MO25 proteins, and directly or indirectly affected the expression of LKB1, leading to decreased activity of LKB1-MARK2 and LKB1-STK25-GM130 pathways. This study indicated that LaCl3 exposure could interfere with the normal effects of LKB1 in the brain and downregulate LKB1-MARK2 and LKB1-STK25-GM130 signaling pathways, resulting in abnormal axon in offspring rats.

Alterations of the Gut Microbiota in Patients with Diabetic Nephropathy.

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease. Accumulating studies have implied a critical role for the gut microbiota in diabetes mellitus (DM) and DN. However, the precise roles and regulatory mechanisms of the gut microbiota in the pathogenesis of DN remain largely unclear. In this study, metagenomics sequencing was performed using fecal samples from healthy controls (CON) and type 2 diabetes mellitus (T2DM) patients with or without DN. Fresh fecal samples from 15 T2DM patients without DN, 15 DN patients, and 15 age-, gender-, and body mass index (BMI)-matched healthy controls were collected. The compositions and potential functions of the gut microbiota were estimated. Although no difference of gut microbiota α and ß diversity was observed between the CON, T2DM, and DN groups, the relative abundances of butyrate-producing bacteria (Clostridium, Eubacterium, and Roseburia intestinalis) and potential probiotics (Lachnospira and Intestinibacter) were significantly reduced in T2DM and DN patients. Besides, Bacteroides stercoris was significantly enriched in fecal samples from patients with DN. Moreover, Clostridium sp. 26_22 was negatively associated with serum creatinine (P < 0.05). DN patients could be accurately distinguished from CON by Clostridium sp. CAG_768 (area under the curve [AUC] = 0.941), Bacteroides propionicifaciens (AUC = 0.905), and Clostridium sp. CAG_715 (AUC = 0.908). DN patients could be accurately distinguished from T2DM patients by Pseudomonadales, Fusobacterium varium, and Prevotella sp. MSX73 (AUC = 0.889). Regarding the potential bacterial functions of the gut microbiota, the citrate cycle, base excision repair, histidine metabolism, lipoic acid metabolism, and bile acid biosynthesis were enriched in DN patients, while selenium metabolism and branched-chain amino acid biosynthesis were decreased in DN patients. IMPORTANCE Gut microbiota imbalance is found in fecal samples from DN patients, in which Roseburia intestinalis is significantly decreased, while Bacteroides stercoris is increased. There is a significant correlation between gut microbiota imbalance and clinical indexes related to lipid metabolism, glucose metabolism, and renal function. The gut microbiota may be predictive factors for the development and progression of DN, although further studies are warranted to illustrate their regulatory mechanisms.

Mesenchymal Stem Cells-derived Exosomes Ameliorate Lupus by Inducing M2 Macrophage Polarization and Regulatory T Cell Expansion in MRL/lpr Mice.

Previous studies have implicated that the transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) effectively alleviates systemic lupus erythematosus (SLE) primarily due to immunomodulatory effects. However, little is known about the role of hUC-MSC-derived exosomes in SLE. This study is carried out to investigate the modifying effects of hUC-MSC-exosomes on the differentiation and function of immune cells in SLE. hUC-MSC-derived exosomes were extracted from the cultural supernatant of hUC-MSCs by ultrahigh speed centrifugation. Quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and flow cytometry were performed to estimate the effect of hUC-MSC-derived exosomes on macrophage and regulatory T cell (Treg) polarization. In vivo, hUC-MSC-exosomes were injected intravenously into 28-week-old MRL/lpr mice. We had found that exosomes derived from hUC-MSC restrained the proliferation and inflammation of macrophages in vitro. Besides, MSC-exosomes inhibited CD68+M1 and HLA-DR+M1 but promoted CD206+M2 and CD163+M2 in vitro. Moreover, MRL/lpr mice administrated by intravenous injection of MSC-exosomes had less infiltration of CD14+CD11c+M1 cells but more CD14+CD163+M2 cells as well as Tregs in spleens compared with those in MRL/lpr mice treated by PBS. Additionally, MSC-exosomes could alleviate nephritis, liver and lung injuries of MRL/lpr mice. The survival of lupus mice could be improved after MSC-exosome treatment. This study has suggested that MSC-derived exosomes exert anti-inflammatory and immunomodulatory effects in SLE. MSC-exosomes ameliorate nephritis and other key organ injuries by inducing M2 macrophages and Tregs polarization. As natural nanocarriers, MSC-exosomes may serve as a promising cell-free therapeutic strategy for SLE.Abbreviations: SLE: Systemic lupus erythematosus; hUC-MSCs: Human umbilical cord mesenchymal stem cells; MSCs: Mesenchymal stem cells; qRT-PCR: Quantitative real-time polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; Tregs: Regulatory cells; TNF-α: Tumor necrosis factor alfa; IL: Interleukin; COVID-19: Coronavirus disease 2019; pTHP-1: PMA-induced THP-1 macrophages; TEM: Transmission electron microscopy; LPS: Lipopolysaccharide; EVs: Extracellular vesicles; TRAF1: Tumor necrosis factor receptor-associated factor 1; IRAK1: Interferon-α-interleukin-1 receptor-associated kinase 1; NF-κB: Nuclear factor-κB; BLyS: B lymphocyte stimulator; APRIL: A proliferation-inducing ligand.

Lanthanum Impairs Learning and Memory by Activating Microglia in the Hippocampus of Mice.

Lanthanum can induce neurotoxicity and impair cognitive function; therefore, research on the mechanism by which the ability to learning and memory is decreased by lanthanum is vitally important for protecting health. Microglia are a type of neuroglia located throughout the brain and spinal cord that play an important role in the central nervous system. When overactive, these cells can cause the excessive production of inflammatory cytokines that can damage neighboring neurons. The purpose of this study was to explore the effect of lanthanum in the form of lanthanum chloride (LaCl3) on learning and the memory of mice and determine whether there is a relationship between hippocampal neurons or learning and memory damage and excessive production of inflammatory cytokines. Four groups of pregnant Chinese Kun Ming mice were exposed to 0, 18, 36, or 72 mM LaCl3 in their drinking water during lactation. The offspring were then exposed to LaCl3 in the breast milk at birth until weaning and then exposed to these concentrations in their drinking water for 2 months after weaning. The results showed that LaCl3 impaired learning and memory in mice and injured their neurons, activated the microglia, and significantly overregulated the mRNA and protein expression of tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein-1, and nitric oxide in the hippocampus. The results of this study suggest that lanthanum can impair learning and memory in mice, possibly by over-activating the microglia.

Lanthanum decreased VAPB-PTPP51, BAP31-FIS1, and MFN2-MFN1 expression of mitochondria-associated membranes and induced abnormal autophagy in rat hippocampus.

Lanthanum is one of REEs documented to have neurotoxicity that led to learning and memory ability impairments. However, the mechanisms underlying La-induced neurotoxicity remain largely unexplored. Autophagy is a self-balancing and self-renewal process that degrades damaged organelles and macromolecules through lysosomal pathway. Importantly, appropriate autophagy levels have protective effects against harmful stress, while excessive autophagy has been demonstrated to be implicated in neurological diseases. ER is close to mitochondria at specific sites with a reported distance of 10-30 nm. The functional domains between the two organelles, called MAM, have been associated with autophagosome synthesis. In this study, the pregnant Wistar rats were randomly divided into four groups and given distilled water solution containing 0%, 0.125%, 0.25%, and 0.5% LaCl3 for drinking during gestation and lactation. The pups were exposed to LaCl3 via the maternal placenta and three-week lactation. Experimental results showed that LaCl3 decreased spatial learning and memory ability of offspring rats, decreased tethering protein complexes expression of MAM, damaged MAM structure, up-regulated NOX4 expression which led to active ROS-AMPK-mTOR signaling pathway. Our findings suggest that decreased spatial learning and memory ability induced by LaCl3 may be related to the abnormally autophagy regulated by tethering protein complexes of MAM.

Lanthanum chloride induces autophagy in primary cultured rat cortical neurons through Akt/mTOR and AMPK/mTOR signaling pathways.

Autophagy is a lysosome dependent degradation pathway occurring in eukaryotic cells. Autophagy ensures balance and survival mechanism of cells during harmful stress. Excessive or weak autophagy leads to abnormal function and death in some cases. Lanthanum (La), a rare earth element (REE), damages the central nervous system (CNS) and promotes learning and memory dysfunction. However, underlying mechanism has not been fully elucidated. La induces oxidative stress, inhibits Nrf2/ARE and Akt/mTOR signaling pathways, and activates JNK/c-Jun and JNK/Foxo signaling pathways, resulting in abnormal induction of autophagy in rat hippocampus. In addition, La activates PINK1- Parkin signaling pathway and induces mitochondrial autophagy. However, the relationship between La and autophagy in rat neurons at the cellular level has not been explored previously. The aim of this study was to explore adverse effects of La. Primary culture of rat neurons were exposed to 0 mmol/L, 0.025 mmol/L, 0.05 mmol/L and 0.1 mmol/L lanthanum chloride (LaCl3). The results showed that La upregulates p-AMPK, inhibits levels of p-Akt and p-mTOR, increases levels of autophagy related proteins (Beclin1 and LC3B-II), and downregulates expression of p-Bcl-2 and p62. Upstream and downstream intervention agents of autophagy were used to detect autophagy flux to verify accuracy of our results. Electron microscopy results showed significant increase in the number of autophagosomes in LaCl3 exposed groups. These findings imply that LaCl3 inhibits Akt/mTOR signaling pathway and activates AMPK/mTOR signaling pathway, resulting in abnormal autophagy in primary cultured rat cortical neurons. In addition, LaCl3 induces neuronal damage through excessive autophagy.

SOCS3 Negatively Regulates Cardiac Hypertrophy via Targeting GRP78-Mediated ER Stress During Pressure Overload.

Pressure overload-induced hypertrophic remodeling is a critical pathological process leading to heart failure (HF). Suppressor of cytokine signaling-3 (SOCS3) has been demonstrated to protect against cardiac hypertrophy and dysfunction, but its mechanisms are largely unknown. Using primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) or overexpression mice, we demonstrated that modulation of SOCS3 level influenced cardiomyocyte hypertrophy, apoptosis and cardiac dysfunction induced by hypertrophic stimuli. We found that glucose regulatory protein 78 (GRP78) was a direct target of SOCS3, and that overexpression of SOCS3 inhibited cardiomyocyte hypertrophy and apoptosis through promoting proteasomal degradation of GRP78, thereby inhibiting activation of endoplasmic reticulum (ER) stress and mitophagy in the heart. Thus, our results uncover SOCS3-GRP78-mediated ER stress as a novel mechanism in the transition from cardiac hypertrophy to HF induced by sustained pressure overload, and suggest that modulating this pathway may provide a new therapeutic approach for hypertrophic heart diseases.

Bi-Functional Paraffin@Polyaniline/TiO2/PCN-222(Fe) Microcapsules for Solar Thermal Energy Storage and CO2 Photoreduction.

A novel type of bi-functional microencapsulated phase change material (MEPCM) microcapsules with thermal energy storage (TES) and carbon dioxide (CO2) photoreduction was designed and fabricated. The polyaniline (PANI)/titanium dioxide (TiO2)/PCN-222(Fe) hybrid shell encloses phase change material (PCM) paraffin by the facile and environment-friendly Pickering emulsion polymerization, in which TiO2 and PCN-222(Fe) nanoparticles (NPs) were used as Pickering stabilizer. Furthermore, a ternary heterojunction of PANI/(TiO2)/PCN-222(Fe) was constructed due to the tight contact of the three components on the hybrid shell. The results indicate that the maximum enthalpy of MEPCMs is 174.7 J·g-1 with encapsulation efficiency of 77.2%, and the thermal properties, chemical composition, and morphological structure were well maintained after 500 high-low temperature cycles test. Besides, the MEPCM was employed to reduce CO2 into carbon monoxide (CO) and methane (CH4) under natural light irradiation. The CO evolution rate reached up to 45.16 µmol g-1 h-1 because of the suitable band gap and efficient charge migration efficiency, which is 5.4, 11, and 62 times higher than pure PCN-222(Fe), PANI, and TiO2, respectively. Moreover, the CO evolution rate decayed inapparently after five CO2 photoreduction cycles. The as-prepared bi-functional MEPCM as the temperature regulating building materials and air purification medium will stimulate a potential application.

Lanthanum chloride causes blood-brain barrier disruption through intracellular calcium-mediated RhoA/Rho kinase signaling and myosin light chain kinase.

Rare earth elements (REEs) have caused bioaccumulation and adverse health effects attributed to extensive application. The penetrability of REEs across the blood-brain barrier (BBB) contributes to their neurotoxicity process, but potential mechanisms affecting BBB integrity are still obscure. The present study was designed to investigate the effects of lanthanum on BBB adheren junctions and the actin cytoskeleton in vitro using bEnd.3 cells. After lanthanum chloride (LaCl3, 0.125, 0.25 and 0.5 mM) treatment, cytotoxicity against bEnd.3 cells was observed accompanied by increased intracellular Ca2+. Higher paracellular permeability presented as decreased TEER (transendothelial electrical resistance) and increased HRP (horse radish peroxidase) permeation, and simultaneously reduced VE-cadherin expression and F-actin stress fiber formation caused by LaCl3 were reversed by inhibition of ROCK (Rho-kinase) and MLCK (myosin light chain kinase) using inhibitor Y27632 (10 µM) and ML-7 (10 µM). Moreover, chelating overloaded intracellular Ca2+ by BAPTA-AM (25 µM) remarkably abrogated RhoA/ROCK and MLCK activation and downstream phosphorylation of MYPT1 (myosin phosphatase target subunit 1) and MLC2 (myosin light chain 2), therefore alleviating LaCl3-induced BBB disruption and dysfunction. In conclusion, this study indicated that lanthanum caused endothelial barrier hyperpermeability accompanied by loss of VE-cadherin and rearrangement of the actin cytoskeleton though intracellular Ca2+-mediated RhoA/ROCK and MLCK pathways.

Lanthanum chloride impairs spatial learning and memory by inducing [Ca2+]m overload, mitochondrial fission-fusion disorder and excessive mitophagy in hippocampal nerve cells of rats.

Lanthanum (La) is a kind of rare earth element (REE) widely found in nature. La has neurotoxicity and can impair learning and memory, but the underlying mechanism is still not completely clear. The mitochondrial calcium uniporter (MCU) complex can cause the uptake of cytoplasmic calcium ([Ca2+]c) into mitochondria and thereby resist [Ca2+]c overload. However, the abnormal increase of calcium in the mitochondrial matrix ([Ca2+]m) can also disturb the mitochondrial fission-fusion balance, and then induce excessive mitophagy, and disrupt mitochondrial quality control (MQC). It is unclear whether La can interfere with the function of nerve cells through the above-mentioned mechanism and thus impair learning and memory. In this study, four groups of Wistar rats were treated with 0%, 0.25%, 0.5% and 1.0% (w/v) lanthanum chloride (LaCl3) from the embryonic phase to 1 month after weaning. The results showed that La could impair the spatial learning and memory of rats, promote the uptake of [Ca2+]c by MCU, induce the abnormal increase of [Ca2+]m, up-regulate p-Drp1 Ser616 expression and inhibit Mfn1/2 expression, enhance mitochondrial fission and lead to mitochondrial fission-fusion disturbance in hippocampal nerve cells. Meanwhile, La could also activate the PINK1-Parkin signaling pathway, up-regulate LC3B-II expression and decrease p62 expression, and thereby induce excessive mitophagy. These results suggested that learning and memory impairment caused by La may be related to MQC disturbance. The present data provide some novel clues for elucidating the neurotoxic effect mechanism of La.

Lanthanum Chloride Impairs Learning and Memory and Induces Dendritic Spine Abnormality by Down-Regulating Rac1/PAK Signaling Pathway in Hippocampus of Offspring Rats.

Lanthanum (La) is a natural rare earth element. It has neurotoxic effects which can impair learning and memory in humans. However, its mechanism of neurotoxicity is unclear. Learning and memory are coordinated by dendritic spines which form tiny protruding structures on the dendritic branches of neurons. This study investigated the effect of LaCl3 exposure to pregnant and lactating rats on the offspring rats' learning and memory ability. In this study, rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, 0.5% LaCl3, respectively, and this was done from conception to the end of the location. The effects of LaCl3 on spatial learning and memory ability in offspring rats and in the development of dendritic spines in CA1 pyramidal cells were investigated. The results showed that LaCl3 impaired spatial learning and memory ability in offspring rats, and decreased dendritic spine density during development. In addition, LaCl3 can affect the expression of CaMKII, miRNA132, p250GAP, Tiam1, PARD3, and down-regulated the activation of Rac1 which led to a decrease in the expression of Rac1/PAK signaling pathway and downstream regulatory proteins Cortactin and actin-related protein 2/3 complex (Arp2/3 complex). This study indicated that the learning and memory impairment and the decrease of dendritic spine density in the offspring of LaCl3 exposure may be related to the down-regulation of the Rac1/PAK signaling pathway regulated by Tiam1 and p250GAP.

2,5-Hexanedione increases the percentage of proliferative Sox2+ cells in rat hippocampus.

n-Hexane is an organic solvent widely used in industry. 2,5-Hexanedione (2,5-HD), the major neurotoxic metabolite of n-hexane, decreases the levels of neurofilaments (NFs) in neurons. Neurogenesis occurs throughout life, and the hippocampal dentate gyrus is one of two major brain areas showing neurogenesis in adulthood. In the current study, rats were intraperitoneally injected with normal saline solution or 2,5-HD five times per week for five continuous weeks. 2,5-HD was administered to the low-dose and high-dose groups at 200 and 400 mg/kg/day, respectively. Then, immunoreactive cells were counted in the hippocampal granule cell layer (GCL) and subgranular zone (SGZ). Ki67+ cells significantly decreased in the high-dose group, while the percentage of proliferative Sox2+ cells significantly increased, consistent with high hippocampal Sox2 expression. Additionally, western blotting showed that exposure to high doses of 2,5-HD led to decreased NF-L in both the cortex and hippocampus, whereas low doses led to a significant reduction in the cortex only. In conclusion, 2,5-HD increases the percentage of proliferating neural stem and progenitor (Sox2+) cells in the SGZ/GCL.