Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Optimal allocation of agricultural water and land resources integrated with virtual water trade: A perspective on spatial virtual water coordination.

Agricultural production consumes the majority of global freshwater resources. The worsening water scarcity has imposed significant stress on agricultural production when regions seek food self-sufficiency. To seek optimal allocation of spatial agricultural water and land resources in each water function zone of the objective region, a multi-objective optimization model was developed to tackle the trade-offs between the water-saving objective and the economic benefit objective considering virtual water trade (VWT). The cultivated area of each crop in each water function zone was taken into account as the decision variable, while a set of strong constraints were used to restrict land resources and water availability. Then, a decomposition-simplex method aggregation algorithm (DSMA) was proposed to solve this nonlinear, bounding-constrained, and multi-objective optimization model. Based on the quantitative analysis of the spatial blue and green virtual water in each agricultural product, the proposed methodology was applied to a real-world, provincial-scale region in China (i.e., Jiangsu Province). The optimized results provided 18 Pareto solutions to reallocate the land resources in the 21 IV-level water function zones of Jiangsu Province, considering four major rainy-season crops and two dry-season crops. Compared to the actual scenario, the superior scheme increased by 7.95% (5.6 × 109 RMB) for economic trade and decreased by 1.77% (2.0 × 109 m3) for agricultural water consumption. It was mainly because the potential of spatial blue and green virtual water in Jiangsu was fully exploited by improving spatial land resource allocation. The food security of Jiangsu could be guaranteed by achieving self-sufficiency in the superior scheme, and the total VWT in the optimal scheme was 2.2 times more than the actual scenario. The results provided a systematic decision-support methodology from the perspective of spatial virtual water coordination, yet, the methodology is widely applicable.

EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.

EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.

Hippophae rhamnoides L.: A Comprehensive Review on the Botany, Traditional Uses, Phytonutrients, Health Benefits, Quality Markers, and Applications.

Hippophae rhamnoides L. (sea buckthorn), consumed as a food and health supplement worldwide, has rich nutritional and medicinal properties. Different parts of H. rhamnoides L. were used in traditional Chinese medicines for relieving cough, aiding digestion, invigorating blood circulation, and alleviating pain since ancient times. Phytochemical studies revealed a wide variety of phytonutrients, including nutritional components (proteins, minerals, vitamins, etc.) and functional components like flavonoids (1-99), lignans (100-143), volatile oils (144-207), tannins (208-230), terpenoids (231-260), steroids (261-270), organic acids (271-297), and alkaloids (298-305). The pharmacological studies revealed that some crude extracts or compounds of H. rhamnoides L. demonstrated various health benefits, such as anti-inflammatory, antioxidant, hepatoprotective, anticardiovascular disease, anticancer, hypoglycemic, hypolipidemic, neuroprotective, antibacterial activities, and their effective doses and experimental models were summarized and analyzed in this paper. The quality markers (Q-markers) of H. rhamnoides L. were predicted and analyzed based on protobotanical phylogeny, traditional medicinal properties, expanded efficacy, pharmacokinetics and metabolism, and component testability. The applications of H. rhamnoides L. in juice, wine, oil, ferment, and yogurt were also summarized and future prospects were examined in this review. However, the mechanism and structure-activity relationship of some active compounds are not clear, and quality control and potential toxicity are worth further study in the future.

mGluR5 in hippocampal CA1 pyramidal neurons mediates stress-induced anxiety-like behavior.

Pharmacological manipulation of mGluR5 has showed that mGluR5 is implicated in the pathophysiology of anxiety and mGluR5 has been proposed as a potential drug target for anxiety disorders. Nevertheless, the mechanism underlying the mGluR5 involvement in stress-induced anxiety-like behavior remains largely unknown. Here, we found that chronic restraint stress induced anxiety-like behavior and decreased the expression of mGluR5 in hippocampal CA1. Specific knockdown of mGluR5 in hippocampal CA1 pyramidal neurons produced anxiety-like behavior. Furthermore, both chronic restraint stress and mGluR5 knockdown impaired inhibitory synaptic inputs in hippocampal CA1 pyramidal neurons. Notably, positive allosteric modulator of mGluR5 rescued stress-induced anxiety-like behavior and restored the inhibitory synaptic inputs. These findings point to an essential role for mGluR5 in hippocampal CA1 pyramidal neurons in mediating stress-induced anxiety-like behavior.

O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission.

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.

New compounds from the stems of Fissistigma acuminatissimum Merr. and their in vitro anti-inflammatory activity.

Three new compounds, 4,5,6,7-tetramethoxy-3-benzoylbenzofuran (1), 4-hydroxy-3,5,6-trimethoxydihydrochalcone-2-O-ß-D-glucopyranoside (2) and 2-hydroxy-3,4,5,6-tetramethoxyphenylethyl benzoate (3) along with five known flavonoids were isolated from the dichloromethane fraction of the stems of Fissistigma acuminatissimum Merr.'s ethanol extracts. The compounds were obtained by chromatographic methods and the structure elucidation was completed primarily on the basis of spectroscopic analyses, all of these compounds were isolated from F. acuminatissimum for the first time. All the fractions and compounds were evaluated for their anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated tumor necrosis factor α (TNF-α) production in RAW264.7 cells in vitro. The dichloromethane fraction showed the most potent inhibition(38.2%) at 60 µg/mL, compound 1 (70.2%) and 3 (65.2%) showed significant inhibition at 10 µM.

Anti-inflammatory Mechanism of Modified Erchentang on Chronic Obstructive Pulmonary Disease Through Jagged1/Notch1/Hes1 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Erchentang on the expression of key molecules in the Jagged1/Notch1/Hes1 signaling pathway in lung tissues of rats with chronic obstructive pulmonary disease （COPD） and explore its anti-inflammatory effect and molecular mechanism on COPD through the Jagged1/Notch1/Hes1 signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， low-， medium-， and high-dose modified Erchentang groups （5， 10， 20 g·kg-1）， and γ-secretase inhibitor DAPT group （0.02 g·kg-1）， with 10 rats in each group. The COPD model was induced in rats by cigarette smoking combined with intratracheal instillation of lipopolysaccharide （LPS）. Rats were treated with corresponding drugs by gavage， while those in the normal group and the model group were treated with the same amount of normal saline by gavage. The serum levels of Notch1， soluble intercellular adhesion molecule-1 （sICAM-1）， activated leukocyte cell adhesion molecule （ALCAM）， and soluble vascular adhesion molecule-1 （sVCAM-1） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression of Jagged1， Notch1， and Hes1 was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of Jagged1， Notch1， Notch1 intracellular domain （NICD1）， and Hes1 in lung tissues of rats was detected by immunohistochemistry （IHC）. ResultCompared with the normal group， the model group showed increased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.01）， increased mRNA expression of Jagged1， Notch1， and Hes1 in lung tissues （P<0.01）， and increased protein expression of Jagged1， Notch1， NICD1， and Hes1 （P<0.01）. Compared with the model group， the medium- and high-dose modified Erchentang groups and the DAPT group showed decreased serum content of Notch1， sICAM-1， ALCAM， and sVCAM-1 （P<0.05， P<0.05）， down-regulated mRNA expression of Jagged1， Notch1， and Hes1 （P<0.05， P<0.01）， and reduced protein expression of Jagged1， Notch1， NICD1， and Hes1（P<0.05， P<0.01）. ConclusionModified Erchentang may inhibit the inflammatory response in the lung of COPD rats， and its mechanism may be related to the resistance of inflammatory injury in the lung by decreasing the mRNA expression of Jagged1， Notch1， and Hes1 and inhibiting the release of Notch1， sICAM-1， ALCAM， and sVCAM-1.

Effect of Modified Erchentang on Bronchioles of Rats with Chronic Obstructive Pulmonary Disease by HMGB1/RAGE/NF-κB Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo study the effect of modified Erchentang on the expression of key molecules in the high mobility group Box 1 protein （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway in bronchioles of rats with chronic obstructive pulmonary disease （COPD）， to explore the mechanism of modified Erchentang against bronchiolar inflammation of COPD rats via HMGB1/RAGE/NF-κB signaling pathway. MethodSixty SD rats were randomly divided into normal group， model group， modified Erchentang low-， medium- and high-dose groups （5， 10， 20 g·kg-1·d-1） and ethyl pyruvate （HMGB1 inhibitor） group， with 10 in each group. The COPD rat model was prepared by cigarette smoke combined with tracheal injection of lipopolysaccharide （LPS）. After modeling， the modified Erchentang groups were given corresponding drugs （ig） and Ringer's solution （4 mL， ip）， while the EP group was treated with equal volume of normal saline （ig） and EP （0.04 g·kg-1·d-1， ip）. The normal group and the model group received equal volume of normal saline （ig） and Ringer's solution （ip） for 21 consecutive days. The contents of HMGB1， chemokine （C-X-C motif） ligand 1 （CXCL1）， CXCL2 and monocyte chemotactic protein-1 （MCP-1） in bronchoalveolar lavage fluid （BALF） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expressions of HMGB1， RAGE and NF-κB p65 were determined by Real-time polymerase chain reaction （Real-time PCR）， and the protein expressions of HMGB1， RAGE， p-NF-κB p65， and alpha-smooth muscle actin （α-SMA） in bronchioles tissue of rats were determined by immunohistochemistry （IHC）. ResultCompared with the conditions in the normal group， the forced vital capacity （FVC）， forced expiratory volume in the first second （FEV1） and FEV1/FVC in the model group were decreased （P<0.01） while the contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF were increased （P<0.01）. And the model group presented higher mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01） than the normal group. Compared with the model group， the modified Erchentang medium- and high-dose groups had increased FEV1/FVC （P<0.05， P<0.01）， lowered contents of HMGB1， CXCL1， CXCL2 and MCP-1 in BALF （P<0.05， P<0.05）， and reduced mRNA expressions of HMGB1， RAGE and NF-κB p65 （P<0.05， P<0.01） and protein expressions of HMGB1， RAGE， p-NF-κB p65 and α-SMA （P<0.05， P<0.01）. ConclusionModified Erchentang can resist bronchiolar inflammation of COPD rats. The mechanism may be related to down-regulating the mRNA expressiona of HMGB1 and RAGE， inhibiting the activity of NF-κB， and reducing the release of HMGB1， CXCL1， CXCL2 and MCP-1， thus suppressing the inflammatory injury and abnormal repair of bronchioles.

Effect of folic acid supplementation on the change of plasma S-adenosylhomocysteine level in Chinese hypertensive patients: a randomized, double-blind, controlled clinical trial.

The relationship between folic acid and S-adenosylhomocysteine (SAH) is controversial. This study aims to explore the effect of different doses of folic acid supplementation on SAH levels in hypertensive patients and the modification of methylene-tetrahydrofolate reductase (MTHFR) C677T gene polymorphism. A randomized, double-blind, controlled clinical trial was conducted. Hypertensive patients aged 45-75 years without a history of stroke and cardiovascular disease were selected, who were randomly assigned to one of 8 dose groups. This trial has been registered with Trial Number: ChiCTR1800016135. In the total population, folic acid supplementation of 0.4-2.0 mg/day had no effect on SAH level (ß = 0.47, 95% CI: -0.86-1.79, p = 0.491), while folic acid supplementation of 2.4 mg/day significantly increased SAH level (ß = 1.93, 95% CI: 0.22-3.64, p = 0.027). Stratified analysis found that MTHFR C677T genotype CC supplemented with 2.4 mg/day folic acid had no effect on SAH level (ß = 0.30, 95% CI: -2.74-3.34, p = 0.847), while CT and TT genotype supplemented with 2.4 mg/day folic acid showed a significant increase in SAH level (CT: ß = 2.98, 95% CI: 0.34-5.62, p = 0.027; TT: ß = 3.00, 95% CI: -0.51-6.51, p = 0.095; CT combined with TT: ß = 2.99, 95% CI: 0.90-5.09, p = 0.005). In conclusion, supplementation of 2.4 mg/day folic acid can lead to increased SAH levels, especially in MTHFR C677T genotype CT and TT.

Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development.

Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important "find-me" signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

P2X2 receptors in pyramidal neurons are critical for regulating vulnerability to chronic stress.

Rationale: Stress is a major risk factor for the development of depression. However, the underlying molecular mechanisms of stress vulnerability in depression are largely uncharacterized. Methods: P2X2 receptors (a major receptor for gliotransmitter-ATP) in the medial prefrontal cortex (mPFC) were identified by real-time qPCR, western blots and RNAscope in situ hybridization in chronic social defeat stress model (CSDS). We generated P2X2 conditional knockout mice and overexpressed AAV-P2X2 in CamkIIα-Cre mice. The depression-like behaviors were assessed via CSDS, subthreshold social defeat stress (SSDS), social interaction test (SI), forced interaction test (FIT), forced swimming test (FST), sucrose preference test (SPT), novel stressed feeding (NSF) and open field test (OFT). The neuronal activity and synapse function of P2X2 receptors in the mPFC were detected by in vivo fiber-photometry, patch-clamp techniques and neuronal morphometric analysis. Results: We identified that P2X2 receptors were increased in the mPFC of susceptible mice in CSDS. Conditional knockout of P2X2 receptors in pyramidal neurons promoted resilience of chronic stress-induced depressive-like behaviors, whereas pyramidal neurons - specific gain of P2X2 in the mPFC increased vulnerability to depressive-like behaviors. In vivo fiber-photometry, electrophysiology and neuronal morphometric analysis showed P2X2 receptors regulated neuronal activity and synapse function in the mPFC. Conclusions: Overall, our studies reveal a critical role of P2X2 in mediating vulnerability to chronic stress and identify P2X2 as a potential therapeutic target for treatment of stress-related mood disorders.

St13 protects against disordered acinar cell arachidonic acid pathway in chronic pancreatitis.

BACKGROUND: Early diagnosis and treatment of chronic pancreatitis (CP) are limited. In this study, St13, a co-chaperone protein, was investigated whether it constituted a novel regulatory target in CP. Meanwhile, we evaluated the value of micro-PET/CT in the early diagnosis of CP. METHODS: Data from healthy control individuals and patients with alcoholic CP (ACP) or non-ACP (nACP) were analysed. PRSS1 transgenic mice (PRSS1Tg) were treated with ethanol or caerulein to mimic the development of ACP or nACP, respectively. Pancreatic lipid metabolite profiling was performed in human and PRSS1Tg model mice. The potential functions of St13 were investigated by crossing PRSS1Tg mice with St13-/- mice via immunoprecipitation and lipid metabolomics. Micro-PET/CT was performed to evaluate pancreatic morphology and fibrosis in CP model. RESULTS: The arachidonic acid (AA) pathway ranked the most commonly dysregulated lipid pathway in ACP and nACP in human and mice. Knockout of St13 exacerbated fatty replacement and fibrosis in CP model. Sdf2l1 was identified as a binding partner of St13 as it stabilizes the IRE1α-XBP1s signalling pathway, which regulates COX-2, an important component in AA metabolism. Micro-PET/CT with 68Ga-FAPI-04 was useful for evaluating pancreatic morphology and fibrosis in CP model mice 2 weeks after modelling. CONCLUSION: St13 is functionally activated in acinar cells and protects against the cellular characteristics of CP by binding Sdf2l1, regulating AA pathway. 68Ga-FAPI-04 PET/CT may be a very valuable approach for the early diagnosis of CP. These findings thus provide novel insights into both diagnosis and treatment of CP.

α-Pyrones with glucose uptake-stimulatory activity from the twigs of Cryptocarya wrayi.

Five new α-pyrones, cryptowratones A-E (1-5), and five known congeners (6-10), together with four other known compounds 11-14 were isolated from the twigs of Cryptocarya wrayi. The structures of the new compounds were elucidated on the basis of extensive spectroscopic data analysis and ECD calculations. All α-pyrones except 6 were evaluated for their stimulatory effects on glucose uptake in vitro with CHO-K1/GLUT4 cells. The positive control insulin displayed an approximate 42 ± 0.14% promotion on glucose uptake at 25 µM, compared with the CHO-K1/GLUT4 group. Compounds 1a/2a, 2, 3, and 10 showed a more significant stimulation of glucose uptake than insulin (25 µM) by 36 ± 0.08%, 27 ± 0.12%, 28 ± 0.12%, and 25 ± 0.12% at 1.5 µM, respectively. Immunofluorescence assays indicated the glucose uptake-stimulatory activity of α-pyrones might be correlated with increased GLUT4 translocation.

Glucocorticoid Receptor-Dependent Astrocytes Mediate Stress Vulnerability.

BACKGROUND: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. METHODS: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. RESULTS: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release. CONCLUSIONS: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.

Distinct roles of astroglia and neurons in synaptic plasticity and memory.

Long-term potentiation (LTP) in the hippocampus is the most studied form of synaptic plasticity. Temporal integration of synaptic inputs is essential in synaptic plasticity and is assumed to be achieved through Ca2+ signaling in neurons and astroglia. However, whether these two cell types play different roles in LTP remain unknown. Here, we found that through the integration of synaptic inputs, astrocyte inositol triphosphate (IP3) receptor type 2 (IP3R2)-dependent Ca2+ signaling was critical for late-phase LTP (L-LTP) but not early-phase LTP (E-LTP). Moreover, this process was mediated by astrocyte-derived brain-derived neurotrophic factor (BDNF). In contrast, neuron-derived BDNF was critical for both E-LTP and L-LTP. Importantly, the dynamic differences in BDNF secretion play a role in modulating distinct forms of LTP. Moreover, astrocyte- and neuron-derived BDNF exhibited different roles in memory. These observations enriched our knowledge of LTP and memory at the cellular level and implied distinct roles of astrocytes and neurons in information integration.

Unveiling the mechanism of imidacloprid removal by ferrate(VI): Kinetics, role of oxidation and adsorption, reaction pathway and toxicity assessment.

Imidacloprid (IMI), an emerging pollutant, has high toxicity to non-target organisms. This paper presents the kinetics of IMI removal by ferrate(VI) at different pH (6.0-9.0), molar ratios ([ferrate(VI)]:[IMI]) and added Fe(III) ions. The apparent second-order rate constant (kapp) decreased with increase in pH from pH 6.0 to 9.0 (i.e., (1.2 ± 0.1) × 102 M-1 s-1 to (8.3 ± 0.3) M-1 s-1). The species-specific rate constants were obtained as k (HFeO4-) = 1.3 × 102 M-1 s-1 and k (FeO42-) = 6.9 M-1 s-1. The decreases in the concentration of HFeO4- with increase in pH caused the observed pH dependence in kapp. At pH 7.0, the removal of IMI increased with the molar ratio from 1.0 to 10.0 with complete removal at the highest ratio. The variation in pH from 6.0 to 9.0 had no obvious effect on removal of IMI. Experiments indicate that IMI removal is mainly by ferrate(VI) oxidation and to a lesser extent by Fe(III) adsorption. Mineralization of IMI was also observed (20-26%). The addition of Fe(III) ions to ferrate(VI)-IMI at pH 7.0 and 8.0 resulted in enhanced removal of IMI, but the presence of Ca2+, SO42-, HCO3-, and humic acid (HA) has negative effects. The presence of coexisting substances in river water slightly decreased IMI removal by ferrate(VI) by less than 10%. Identification of products and frontier electron density (FED) calculations demonstrated involvement of opening of the five-membered heterocyclic moiety of IMI by ferrate(VI). Toxicity assessment with NIH 3T3 fibroblasts and ECOSAR analysis indicated lower toxicity of oxidized products than parent IMI.

Effect and Mechanism of Cxcr4 Gene-Modified BMSC-Derived Exosomes on Aplastic Anemia / 中国实验血液学杂志

OBJECTIVE@#To explore the improvement effect of CXC chemokine receptor 4 (Cxcr4) gene-modified bone marrow mesenchymal stem cell (BMSC)-derived exosomes on aplastic anemia (AA), and make a preliminary exploration of the mechanism.@*METHODS@#Mouse BMSCs were isolated and cultured, then infected by recombinant lentivirus carrying Cxcr4 gene. The expression of green fluorescence was observed through fluorescence microscope, the expression of Cxcr4 mRNA was detected by real-time fluorescence quantitative PCR, and the BMSC-derived exosomes modified with Cxcr4 gene were extracted. Mouse models of AA were constructed, and control group, model group (AA), AA+BMSC group, AA+NC-BMSC group, AA+Cxcr4-BMSC group were set up. Except control group and model group, the other three groups of mice were injected 400 μl exosomes from different sources via the tail vein, after 2 weeks, the routine blood indices and the number of bone marrow nucleated cells were detected, the pathological changes of bone marrow were observed by HE staining, and the expression level of Treg cells was detected by flow cytometry.@*RESULTS@#Mouse BMSCs were successfully isolated, and BMSCs with high expression of Cxcr4 and their exosomes were obtained. Compared with the control group, the number of red blood cell (RBC), white blood cell (WBC), and platelet (PLT), the hemoglobin (Hb) content and proportion of Treg cells in the peripheral blood of mice in the model group significantly decreased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01). The proliferation level of nucleated cells was low, and the medullary cavity was filled with a large number of fat cells. Compared with the model group, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+BMSC group, AA+NC-BMSC group, and AA+Cxcr4-BMSC group significantly increased (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01), and pathological changes of bone marrow were improved. In addition, the number of RBC, WBC, PLT, the Hb content and proportion of Treg cells in the peripheral blood of mice in the AA+Cxcr4-BMSC group were significantly higher than those in the AA+BMSC group (P<0.01), as well as the number of bone marrow nucleated cells (P<0.01).@*CONCLUSION@#Injection of Cxcr4 gene-modified BMSC-derived exosomes has a certain improvement effect on AA mice, and the mechanism may be related to an increase of the proportion of Treg cells.

Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD.