BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α.

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

Formation and removal of 1,N6-dimethyladenosine in mammalian transfer RNA.

RNA molecules harbor diverse modifications that play important regulatory roles in a variety of biological processes. Over 150 modifications have been identified in RNA molecules. N6-methyladenosine (m6A) and 1-methyladenosine (m1A) are prevalent modifications occurring in various RNA species of mammals. Apart from the single methylation of adenosine (m6A and m1A), dual methylation modification occurring in the nucleobase of adenosine, such as N6,N6-dimethyladenosine (m6,6A), also has been reported to be present in RNA of mammals. Whether there are other forms of dual methylation modification occurring in the nucleobase of adenosine other than m6,6A remains elusive. Here, we reported the existence of a novel adenosine dual methylation modification, i.e. 1,N6-dimethyladenosine (m1,6A), in tRNAs of living organisms. We confirmed that m1,6A is located at position 58 of tRNAs and is prevalent in mammalian cells and tissues. The measured level of m1,6A ranged from 0.0049% to 0.047% in tRNAs. Furthermore, we demonstrated that TRMT6/61A could catalyze the formation of m1,6A in tRNAs and m1,6A could be demethylated by ALKBH3. Collectively, the discovery of m1,6A expands the diversity of RNA modifications and may elicit a new tRNA modification-mediated gene regulation pathway.

Role of adenosine A2A receptors in the loss of consciousness induced by propofol anesthesia.

The mechanism of propofol-anesthesia-induced loss of consciousness (LOC) remains largely unknown. We speculated that the adenosine A2A receptor serves as a vital molecular target in regulating LOC states under propofol anesthesia. c-Fos staining helped observe the changes in the neuronal activity in the nucleus accumbens (NAc). Initially, the adenosine signals in the NAc were measured under propofol anesthesia using fiber photometry recordings. Then, behavior tests and electrophysiological recordings were used to verify the effect of systemic A2A R agonist or antagonist treatment on propofol anesthesia. Next, the microinjection technique was used to clarify the role of the NAc A2A R under propofol anesthesia. Fiber photometry recordings were applied to assess the effect of A2A R agonist or antagonist systemic treatment on adenosine signal alterations in the NAc during propofol anesthesia. Then, as the GABAergic neurons are the main neurons in the NAc, we further measured the neuronal activity of GABAergic neurons. In our study, propofol anesthesia enhanced the neuronal activity in the NAc, and the adenosine signals were increased in the NAc. SCH58261 reduced the LOC time and sedative depth, while CGS21680 increased those via intraperitoneal injection. Additionally, CGS21680 increased the changes in delta, theta, alpha, beta, and low-gamma oscillations in the NAc. Moreover, microinjection of SCH58261 significantly shortened the LOC time, whereas microinjection of CGS21680 into the NAc significantly prolonged the LOC duration. The results illustrated that after A2A R agonist administration, the level of extracellular adenosine signals in the NAc was decreased and the neuronal activity of GABAergic neurons was enhanced, whereas after A2A R antagonist administration via intraperitoneal injection, the opposite occurred. This study reveals the vital role of the A2A R in propofol-induced LOC and that the A2A R could affect the maintenance of propofol anesthesia.

Research on Channel Characteristics and Electrode Electrical Performance of Earth Current Field Information Transmission Technology.

Starting from the need for emergency rescue information transmission in tunnel engineering accidents, this article focuses on researching and solving the technical problems of information transmission between rescue personnel and trapped personnel after tunnel engineering collapse accidents, before and during the rescue process. The research objects are the information transmission channel and grounding electrode in the earth current field information transmission technology, and the electromagnetic characteristics of the earth medium and the electrical performance of the grounding electrode are studied and analyzed using the electromagnetic simulation software Maxwell based on finite element algorithm, establish a three-dimensional model based on the transmission of current field information of the ground electrode, analyze the effects of the electrode array, electrode depth, and radius on impedance. Research has shown that the impedance of the earth is related to the resistivity of the medium and is not a human-controllable factor. To reduce the contact impedance of an electric dipole antenna, one should start with the contact impedance of the earth electrode. The impedance of the transmitting end is an important factor affecting the efficiency of information transmission; parallel connection of multiple grounding electrodes, increasing the depth of grounding electrode penetration into the soil layer, and increasing the radius between grounding electrode pairs are all effective methods to reduce the contact impedance of electric dipole antennas, thereby improving information transmission capacity. To achieve wireless information transmission through the stratum, by appropriately selecting the operating frequency of electromagnetic waves, a certain distance of signal transmission can be achieved.

Changes in α-Farnesene and Phenolic Metabolism and the Expression of Associated Genes during the Development of Superficial Scald in Two Distinct Pear Cultivars.

Superficial scald is a postharvest physiological disorder that occurs in pear during and after cold storage. In this study, the superficial scald index; α-farnesene and its oxidation products, conjugated trienols (CTols); phenolic content; and the expression of its related genes were investigated in two different pear cultivars, 'Wujiuxiang' (Pyrus communis L.) and 'Yali' (Pyrus bretschneideri R.), following 115 days of cold storage at 0 °C followed by 7 days of shelf life at 20 °C. The results indicated that the superficial scald occurred after 115 days of cold storage and became more severe during the shelf life of the 'Wujiuxiang' pear, whereas no scald was observed in 'Yali'. The α-farnesene levels increased rapidly at first and then decreased, while the CTols contents increased significantly in 'Wujiuxiang' as compared to 'Yali', and the expression levels of the genes involved in α-farnesene and CTols metabolism (HMGR1, HMGR2, GSTU7, GPX5, and GPX6), as well as the phenolic synthesis (PAL1, PAL2, C4H1, 4CL2, C3H, and ANR) of the peel, were significantly up-regulated at the onset of the superficial scald. In addition, the relative conductivity and contents of catechin and epicatechin were higher, and the expression level of the laccase gene (LAC7) significantly increased with the development of superficial scald, while lower contents of chlorogenic acid, arbutin, and isorhamnetin-3-3-glucoside, as well as the lower expression levels of a phenolic-synthesis-related gene (C4H3) and polyphenol oxidase genes (PPO1 and PPO5), were noticed in 'Wujiuxiang' as compared to 'Yali'. The results indicated that the onset and progression of superficial scald were associated with the accumulation of CTols, cell membrane breakdown, and higher catechin, epicatechin, and rutin contents, as well as the expression of associated genes of the peels of pear fruit.

Neuronal HMGB1 in nucleus accumbens regulates cocaine reward memory.

Cocaine is a common abused drug that can induce abnormal synaptic and immune responses in the central nervous system (CNS). High mobility group box 1 (HMGB1) is one kind of inflammatory molecules that is expressed both on neurons and immune cells. Previous studies of HMGB1 in the CNS have largely focused on immune function, and the role of HMGB1 in neurons and cocaine addiction remains unknown. Here, we show that cocaine exposure induced the translocation and release of HMGB1 in the nucleus accumbens (NAc) neurons. Gain and loss of HMGB1 in the NAc bidirectionally regulate cocaine-induced conditioned place preference. From the nucleus to the cytosol, HMGB1 binds to glutamate receptor subunits (GluA2/GluN2B) on the membrane, which regulates cocaine-induced synaptic adaptation and the formation of cocaine-related memory. These data unveil the role of HMGB1 in neurons and provide the evidence for the HMGB1 involvement in drug addiction.

Celastrol protects human retinal pigment epithelial cells against hydrogen peroxide mediated oxidative stress, autophagy, and apoptosis through sirtuin 3 signal pathway.

Age-related macular degeneration (AMD), one of the most common causes of visual impairment, often occurrs in the elderly in developed countries. Oxidative stress, autophagy, and apoptosis of retinal pigment epithelial (RPE) cells play roles in the pathogenesis of AMD. In the current study, the protective effect of celastrol against hydrogen peroxide (H2 O2 )-induced oxidative stress and apoptosis was investigated using a human RPE cell line (ARPE-19). H2 O2 inhibited ARPE-19 cells' survival and autophagy and induced their oxidative stress and apoptosis. Compared with the H2 O2 group, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay showed that celastrol increased ARPE-19 cells' survival in a dose- and time-dependent manner. Further, studies have suggested that celastrol has antioxidative stress and antiapoptosis effects in H2 O2 -treated ARPE-19 cells. Also, cell autophagy is activated by celastrol in H2 O2 -treated ARPE-19 cells. Reverse transcription polymerase chain reaction and Western blot showed that celastrol elevated the messenger RNA (mRNA) and protein expression of sirtuin 3 (SIRT3) in H2 O2 -induced ARPE-19 cells. Inhibition of the level of SIRT3 by SIRT3 small interfering RNA (siRNA) reversed the effects of celastrol on oxidative stress, autophagy, and apoptosis in H2 O2 -induced ARPE-19 cells. In conclusion, these observations suggest that celastrol activates the SIRT3 pathway in RPE cells and protects against H2 O2 -induced oxidative stress and apoptosis.

Musashi2 modulates K562 leukemic cell proliferation and apoptosis involving the MAPK pathway.

The RNA-binding protein Musashi2 (Msi2) has been identified as a master regulator within a variety of stem cell populations via the regulation of translational gene expression. A recent study has suggested that Msi2 is strongly expressed in leukemic cells of acute myeloid leukemia patients, and elevated Msi2 is associated with poor prognosis. However, the potential role of Msi2 in leukemogenesis is still not well understood. Here, we investigated the effect of Msi2 knockdown on the biological properties of leukemic cells. High expression of Msi2 was found in K562 and KG-1a leukemic cell lines, and low expression was observed in the U937 cell line. We transduced K562 cells with two independent adenoviral shRNA vectors targeting Msi2 and confirmed knockdown of Msi2 at the mRNA and protein levels. Msi2 silencing inhibited cell growth and caused cell cycle arrest by increasing the expression of p21 and decreasing the expression of cyclin D1 and cdk2. In addition, knockdown of Msi2 promoted cellular apoptosis via the upregulation of Bax and downregulation of Bcl-2 expression. Furthermore, Msi2 knockdown resulted in the inactivation of the ERK/MAPK and p38/MAPK pathways, but no remarkable change in p-AKT was observed. These data provide evidence that Msi2 plays an important role in leukemogenesis involving the MAPK signaling pathway, which indicates that Msi2 may be a novel target for leukemia treatment.

Study on the Structure-Activity Relationship and Oil Displacement Characteristics of the Polysurfactant Agent.

This study examines a versatile polymer known as polysurfactant, which is synthesized by co-polymerizing flexible acrylamide and sodium acrylate hydrocarbon chain. The polymer serves as a backbone and possesses active functional groups. Notably, the polysurfactant exhibits superior plugging and flooding abilities compared to conventional polymers. The primary objective of this paper is to investigate the properties and oil displacement characteristics of the polysurfactant through indoor physical simulation experiments. The results demonstrate that the multi-branched structure of the polysurfactant enhances its ability to associate, leading to the formation of a unique spatial network structure. The inclusion of multi-branched structures notably amplifies the association effect. The critical concentration for the association is estimated to be around 800 mg/L, at which juncture the polysurfactant exhibits a viscosity retention rate surpassing 90% subsequent to shearing. Furthermore, this spatial network structure exhibits self-recovery capabilities after experiencing shear failure and displaying strong viscosity and shear resistance. In addition, the concentration of the polysurfactant can control the hydrodynamic feature size, which shows its adaptability in regulation and oil-repelling functions at reservoir permeabilities ranging from 500 to 2000 × 10-3 µm2 with resistance coefficients ranging from 108 to 320. During the microscopic oil displacement process, the polysurfactant exerts a significant impact on mobility control, while the elastic pull clearly demonstrates a commendable viscoelastic oil displacement effect. The polysurfactant exhibits a specific degree of emulsification capability towards crude oil, leading to the emulsion exhibiting typical pseudoplastic fluid characteristics. The utilization of emulsification transportation and emulsification blockage contributes to the enhancement of oil recovery. As a result, the polysurfactant exhibits multifaceted capabilities, encompassing profile control, flooding, and plugging, owing to its unique structural characteristics. Through the implementation of a field test focused on flooding in the Daqing Oilfield, a significant enhancement in the recovery rate of 10.85% is observed, accompanied by a favorable input-output ratio of 1:3.86, thereby generating significant economic advantages.

Circadian Regulation of the Lactate Metabolic Kinetics in Mice Using the [1H-13C]-NMR Technique.

Lactate is not only the energy substrate of neural cells, but also an important signal molecule in brain. In modern societies, disturbed circadian rhythms pose a global challenge. Therefore, exploring the influence of circadian period on lactate and its metabolic kinetics is essential for the advancement of neuroscientific research. In the present study, the different groups of mice (L: 8:00 a.m.; D: 20:00 p.m.; SD: 20:00 p.m. with 12 h acute sleep deprivation) were infused with [3-13C] lactate through the lateral tail vein for a duration of 2 min. After 30-min lactate metabolism, the animals were euthanized and the tissues of brain and liver were obtained and extracted, and then, the [1H-13C] NMR technology was employed to investigate the kinetic information of lactate metabolism in different brain regions and liver to detect the enrichment of various metabolic kinetic information. Results revealed the fluctuating lactate concentrations in the brain throughout the day, with lower levels during light periods and higher levels during dark periods. Most metabolites displayed strong sensitivity to circadian rhythm, exhibiting significant day-night variations. Conversely, only a few metabolites showed changes after acute sleep deprivation, primarily in the temporal brain region. Interestingly, in contrast to brain lactate metabolism, liver lactate metabolism exhibited a significant increase following acute sleep deprivation. This study explored the kinetics of lactate metabolism, hinted at potential clinical implications for disorders involving circadian rhythm disturbances, and providing a new research basis for clinical exploration of brain and liver lactate metabolism.

The HMGB1-RAGE axis in nucleus accumbens facilitates cocaine-induced conditioned place preference via modulating microglial activation.

INTRODUCTION: Repeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box-1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown. METHODS: Rats were trained by intraperitoneal cocaine administration and cocaine-induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide. RESULTS: Cocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine-induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1-RAGE interaction suppressed cocaine-induced microglial activation, as well as the consolidation of cocaine-induced memory. CONCLUSION: All above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1-RAGE axis as a new target for the treatment of drug addiction.

Study on the Alkali-Free Three-Component Flooding System in the Daqing Oilfield.

ASP flooding is an important method to further improve oil recovery by a large margin. At present, it has entered the stage of industrial application, but there are still problems of scaling in the injection production system and high production maintenance costs. Based on the industrialized mature technology of weak alkali ASP flooding, sodium chloride is used to replace sodium carbonate, and the alkali-free three-component flooding (TC) system in the Daqing Oilfield is developed by mixing with petroleum sulfonate and partially hydrolyzed polyacrylamide. Based on the experiments of viscosity increasing, interface performance, stability, adsorption, and oil displacement effect, the differences between the alkali-free TC system and the weak alkali ASP system are compared and analyzed. The laboratory research results show that both systems are basically the same in terms of viscosity, viscoelasticity, shear resistance, interfacial activity, stability, and flowability. Due to the lack of alkaline water, the adsorption, emulsification, and oil displacement performance of the alkali-free TC system is slightly lower than that of the weak alkali ASP system. The recovery factor of core flooding can be increased by 27.31% over water flooding, which is 2.56 percentage points lower than that of the weak alkali ASP system. On the premise of the same 1% EOR effect, the agent cost of the alkali-free system is 17.02% lower than that of the alkali ASP system. This article innovatively verifies the feasibility of using NaCl instead of Na2CO3 and explains the mechanism of significantly improving oil recovery in composite systems under alkali-free conditions from the ion level. However, the emulsification effect of the alkali-free TC system is relatively weak. The next step of research would be to consider adding an E-surfactant to enhance the emulsification performance of the composite system. By improving the system composition, technical references are provided for the efficient development of other terrestrial sandstone oilfields.

Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury.

Mild traumatic brain injury (mTBI)-induced post-traumatic headache (PTH) is a pressing public health concern and leading cause of disability worldwide. Although PTH is often accompanied by neurological disorders, the exact underlying mechanism remains largely unknown. Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH. In this study, a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery. Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage. Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum, temporal lobe/cortex, and hippocampal regions during the early stages of PTH. Additionally, variations in brain functional activities and connectivity were further detected in the early stage of PTH, particularly in the cerebellum and temporal cortex, suggesting that these regions play central roles in the mechanism underlying PTH. Moreover, our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH. Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Melatonin Ameliorates Depressive-Like Behaviors in Ovariectomized Mice by Improving Tryptophan Metabolism via Inhibition of Gut Microbe Alistipes Inops.

Melatonin (N-acetyl-5-methoxytryptamine) is reported to improve mood disorders in perimenopausal women and gut microbiome composition is altered during menopausal period. The possible role of microbiome in the treatment effect of melatonin on menopausal depression remains unknown. Here, it is shown that melatonin treatment reverses the gut microbiota dysbiosis and depressive-like behaviors in ovariectomy (OVX) operated mice. This effect of melatonin is prevented by antibiotic cocktails (ABX) treatment. Transferring microbiota harvested from adolescent female mice to OVX-operated mice is sufficient to ameliorate depressive-like behaviors. Conversely, microbiota transplantation from OVX-operated mice or melatonin-treated OVX-operated mice to naïve recipient mice exhibits similar phenotypes to donors. The colonization of Alistipes Inops, which is abundant in OVX-operated mice, confers the recipient with depressive-like behaviors. Further investigation indicates that the expansion of Alistipes Inops induced by OVX leads to the degradation of intestinal tryptophan, which destroys systemic tryptophan availability. Melatonin supplementation restores systemic tryptophan metabolic disorders by suppressing the growth of Alistipes Inops, which ameliorates depressive-like behaviors. These results highlight the previously unrecognized role of Alistipes Inops in the modulation of OVX-induced behavioral disorders and suggest that the application of melatonin to inhibit Alistipes Inops may serve as a potential strategy for preventing menopausal depressive symptoms.

Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

Dysfunction of Glutamatergic Synaptic Transmission in Depression: Focus on AMPA Receptor Trafficking.

Pharmacological and anatomical evidence suggests that abnormal glutamatergic neurotransmission may be associated with the pathophysiology of depression. Compounds that act as NMDA receptor antagonists may be a potential treatment for depression, notably the rapid-acting agent ketamine. The rapid-acting and sustained antidepressant effects of ketamine rely on the activation of AMPA receptors (AMPARs). As the key elements of fast excitatory neurotransmission in the brain, AMPARs are crucially involved in synaptic plasticity and memory. Recent efforts have been directed toward investigating the bidirectional dysregulation of AMPAR-mediated synaptic transmission in depression. Here, we summarize the published evidence relevant to the dysfunction of AMPAR in stress conditions and review the recent progress toward the understanding of the involvement of AMPAR trafficking in the pathophysiology of depression, focusing on the roles of AMPAR auxiliary subunits, key AMPAR-interacting proteins, and posttranslational regulation of AMPARs. We also discuss new prospects for the development of improved therapeutics for depression.

Chinese Traditional Pear Paste: Physicochemical Properties, Antioxidant Activities and Quality Evaluation.

As a traditional folk medicine, pear paste has important nutritional and health effects. The physicochemical properties and antioxidant activities of pear pastes prepared from 23 different cultivars were investigated, including color parameters ( L*, a*, b* and h°), transmittance, pH, titratable acidity (TA), soluble sugar content, total phenolics content (TPC), total flavonoids content (TFC), DPPH and •OH radical scavenging activity (RSA), and ferric reducing antioxidant power (FRAP). It was demonstrated that the physicochemical properties and antioxidant activities of pear pastes from various cultivars differed significantly. Pear cultivars of "Mantianhong", "Xiangshui" and "Anli" possessing higher TPC and TFC exhibited excellent antioxidant activity determined by DPPH RSA, •OH RSA and FRAP, while the lowest TPC and TFC was observed for the cultivars of "Xueqing", "Nansui", "Hongxiangsu", and "Xinli No. 7", which also demonstrated the poor antioxidant activity. Multivariate analyses, including factor and cluster analysis, were used for the quality evaluation and separation of pear pastes based on their physicochemical and antioxidant properties. Factor analysis reduced the above thirteen parameters to final four effective ones, i.e. DPPH RSA, color b*, FRAP and TA, and subsequently these four parameters were used to construct the comprehensive evaluation prediction model for evaluating the quality of pear pastes. The pear pastes could be separated into three clusters and differentiated for the diverse of pear cultivars via cluster analysis. Consistently, "Mantianhong", "Xiangshui" and "Anli" pear with higher quality clustered into one group, in contrast, "Xueqing", "Nansui", "Hongxiangsu", and "Xinli No. 7" with lower quality clustered into the other group. It provided a theoretical method to evaluate the quality of pear paste and may help the fruit processing industry select the more suitable pear cultivars for pear paste making.

A strategy for screening and identification of new amino acid-conjugated bile acids with high coverage by liquid chromatography-mass spectrometry.

Bile acids (BAs) are a class of vital gut microbiota-host cometabolites, and they play an important role in maintaining gut microbiota-host metabolic homeostasis. Very recently, a new mechanism of BA anabolic metabolism mediated by gut microbiota (BA-amino acid conjugation) has been revealed, which provides a perspective for the research on BA metabolism and gut metabolome. In this study, we established a polarity-switching multiple reaction monitoring mass spectrometry-based screening method to mine amino acid-conjugated bile acids (AA-BAs) derived from host-gut microbiota co-metabolism. In addition, a retention time-based annotation strategy was further proposed to identify the AA-BA isomers and epimers. Using the developed methods, we successfully screened 118 AA-BA conjugates from mouse and human feces, 28 of them were confirmed by standards, and 62 putatively identified based on their predicted retention times. Moreover, we observed that the levels of most AA-BAs were significantly downregulated in the feces of chronic sleep deprivation mice, suggesting that the AA-BA metabolism was closely related to the physiological state of the host.

Decoding the contributions of gut microbiota and cerebral metabolism in acute liver injury mice with and without cognitive dysfunction.

AIMS: Patients with acute liver injury (ALI) can develop cognitive dysfunction (CD). The study investigated the role of gut microbiota and cerebral metabolism in ALI mice with and without CD. METHODS: Male C57BL/6 mice that received thioacetamide were classified into ALI mice with (susceptible) or without (unsusceptible) CD-like phenotypes by hierarchical cluster analysis of behavior. The role of gut microbiota was investigated by 16S ribosomal RNA gene sequencing and feces microbiota transplantation (FMT). 1 H-[13 C] NMR and electrophysiology were used to detect the changes in cerebral neurotransmitter metabolic and synaptic transition in neurons or astrocytes. RESULTS: Apromixlay 55% (11/20) of mice developed CD and FMT from the susceptible group transmitted CD to gut microbiota-depleted mice. Alloprevotella was enriched in the susceptible group. GABA production was decreased in the frontal cortex, while hippocampal glutamine was increased in the susceptible group. Altered Escherichia. Shigella and Alloprevotella were correlated with behaviors and cerebral metabolic kinetics and identified as good predictors of ALI-induced CD. The frequencies of both miniature inhibitory and excitatory postsynaptic currents in hippocampal CA1 and prefrontal cortex were decreased in the susceptible group. CONCLUSION: Altered transmitter metabolism and synaptic transmission in the hippocampus and prefrontal cortex and gut microbiota disturbance may lead to ALI-induced CD.

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice.

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.