Mice harboring the T316N variant in the GABAAR γ2 subunit exhibit sleep-related hypermotor epilepsy phenotypes and hypersynchronization in the thalamocortical pathway.

OBJECTIVE: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ2 subunit of γ-aminobutyric acid type A receptor (GABAAR), in patients with SHE and demonstrated that these variants impaired GABAAR function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear. METHODS: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABAAR subunits were also investigated. RESULTS: No obvious changes in gross morphology were detected in Gabrg2T316N/+ mice compared to their wild-type (Gabrg2+/+) littermates. Gabrg2T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2+/+ mice, GABAAR γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2T316N/+ mice. CONCLUSION: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.

Inactivation mechanisms on pectin methylesterase by high pressure processing combined with its recombinant inhibitor.

High pressure processing (HPP) juice often experiences cloud loss during storage, caused by the activity of pectin methylesterase (PME). The combination of HPP with natural pectin methylesterase inhibitor (PMEI) could improve juice stability. However, extracting natural PMEI is challenging. Gene recombination technology offers a solution by efficiently expressing recombinant PMEI from Escherichia coli and Pichia pastoris. Experimental and molecular dynamics simulation were conducted to investigate changes in activity, structure, and interaction of PME and recombinant PMEI during HPP. The results showed PME retained high residual activity, while PMEI demonstrated superior pressure resistance. Under HPP, PMEI's structure remained stable, while the N-terminus of PME's α-helix became unstable. Additionally, the helix at the junction with the PME/PMEI complex changed, thereby affecting its binding. Furthermore, PMEI competed with pectin for active sites on PME, elucidating. The potential mechanism of PME inactivation through the synergistic effects of HPP and PMEI.

TOM40 mediates the effect of TSPO on postpartum depression partially through regulating calcium homeostasis in microglia.

AIMS: To assess the effect of the translocator protein 18 kDa (TSPO) on postpartum depression and explore its mechanism. METHODS: Postpartum depression (PPD) mouse model was established, and flow cytometry, immunofluorescence, Western blot analysis, real-time quantitative PCR, adeno-associated virus (AAV), co-immunoprecipitation-mass spectrometry and immunofluorescence co-staining were used to detect the effect of TSPO ligand ZBD-2 on PPD mice. RESULTS: ZBD-2 inhibits the overactivation of microglia in the hippocampus and amygdala of PPD model mice. ZBD-2 not only inhibited the inflammation but also repressed the burst of reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Meanwhile, ZBD-2 protects mitochondria from LPS-induced damages through inhibiting the influx of calcium. ZBD-2 modulated the calcium influx by increasing the level of translocase of the outer mitochondrial membrane 40 (TOM40) and reducing the interaction of TSPO and TOM40. In addition, the effect of ZBD-2 was partially dependent on anti-oxidative process. Knockdown of TOM40 by adeno-associated virus (AAV) in the hippocampus or amygdala dramatically reduced the effect of ZBD-2 on PPD, indicating that TOM40 mediates the effect of ZBD-2 on PPD. CONCLUSIONS: TOM40 is required for the effect of ZBD-2 on treating anxiety and depression in PPD mice. This study reveals the role of microglia TSPO in PPD development and provides the new therapeutic strategy for PPD.

Integrative Metabolomic and Transcriptomic Landscape during Akebia trifoliata Fruit Ripening and Cracking.

Akebia trifoliata fruit is prone to crack after ripening, but little is known about the mechanism underlying the cracking process. This study integrated transcriptomic and metabolomic data, revealing significant changes in 398 metabolites and 8414 genes during ripening and cracking, mainly impacting cell-wall metabolism. Multi-omics joint analysis indicated that genes related to polygalacturonase, pectate lyase, α-amylase, and glycogen phosphorylase were up-regulated after cracking, degrading cell wall and starch. Concurrently, diminished photosynthetic metabolism and heightened phenylpropanoid metabolism suggested alterations in cuticle structure, potentially impacting cell-wall robustness. Numerous auxin and abscisic acid signaling-related genes were expressed, and we assume that they contributed to the promoting peel growth. These alterations collectively might compromise peel strength and elevate expanding pressure, potentially leading to A. trifoliata cracking. Transcription factors, predominantly ethylene response factors and helix-loop-helix family members, appeared to regulate these metabolic shifts. These findings provide valuable insights into A. trifoliata cracking mechanisms; however, direct experimental validation of these assumptions is necessary to strengthen these conclusions and expedite their commercial utilization.

Latest Advances in Active Materials for Food Packaging and Their Application.

Food packaging plays a pivotal role in preserving the quality and safety of food products while extending their shelf life [...].

Effect of pasteurization processing and storage conditions on softening of acidified chili pepper: Pectin and it related enzymes.

The softening of acidified chili peppers induced by processing and storage has become a major challenge for the food industry. This study aims to explore the impact of pasteurization techniques, thermal processing (TP), high-pressure processing (HPP), addition of sodium metabisulfite (SMS), and storage conditions (25 °C, 37 °C, and 42 °C for 30 days) on the texture-related properties of acidified chili pepper. The results showed that the textural properties of samples were destructed by TP (the hardness of samples decreased by 19.43 %) but were less affected by HPP and SMS. Compared with processing, storage temperature had a more dominant impact on texture and pectin characteristics. With increased storage temperature, water-solubilized pectin fraction content increased (increased by 160.99 %, 136.74 %, and 13.01 % in TP, HPP, and SMS-stored groups, respectively), but sodium carbonate-solubilized pectin fraction content decreased (decreased by 29.84 %, 26.81 %, and 8.60 % in TP-, HPP-, and SMS-stored groups, respectively), especially in TP-stored groups. Multivariate data analysis showed that softening was more closely related to pectin conversion induced by acid hydrolysis and pectinase depolymerization. This finding offers new perspectives for the production of acidified chili pepper.

PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice.

Hormone replacement therapy (HRT) is not recommended for treating learning and memory decline in menopausal women because it exerts adverse effects by activating classic estrogen receptors ERα and ERß. The membrane estrogen receptor G protein-coupled receptor 30 (GPR30) has been reported to be involved in memory modulation; however, the underlying mechanisms are poorly understood. Here, we found that GPR30 deletion in astrocytes, but not in neurons, impaired learning and memory in female mice. Astrocytic GPR30 depletion induced A1 phenotype transition, impairing neuronal function. Further exploration revealed that Praja1 (PJA1), a RING ubiquitin ligase, mediated the effects of astrocytic GPR30 on learning and memory by binding to Serpina3n, which is a molecular marker of neuroinflammation in astrocytes. GPR30 positively modulated PJA1 expression through the CREB signaling pathway in cultured murine and human astrocytes. Additionally, the mRNA levels of GPR30 and PJA1 were reduced in exosomes isolated from postmenopausal women while Serpina3n levels were increased in the plasma. Together, our findings suggest a key role for astrocytic GPR30 in the learning and memory abilities of female mice and identify GPR30/PJA1/Serpina3n as potential therapeutic targets for learning and memory loss in peri- and postmenopausal women.

Chemometric Classification of Apple Cultivars Based on Physicochemical Properties: Raw Material Selection for Processing Applications.

Apple cultivars exhibit significant diversity in fruit quality traits, creating distinct consumption scenarios. This study aimed to assess the physicochemical parameters and sensory attributes differences among fifteen apple cultivars and identify characteristic qualities suitable for various processed apple products using chemometric analysis. Relatively large differences were registered between cultivars for deflection, peel color, titratable acidity (TA), the ratio of total soluble solid to titratable acidity (TSS/TA), hardness, soluble sugar, and volatile organic compound contents. Sensory results showed significant differences existed among the preferences for different processed products. Based on the above results, all cultivars could be distinguished into three main clusters. Cluster I (i.e., Aziteke, Bakeai, Magic Flute, Royal Gala, Red General, Red Delicious, and Zhongqiuwang) demonstrated favorable appearance, high sensory scores, and rich aroma volatile compounds, making them suitable for direct consumption. Cluster II (i.e., Fuburuisi, Sinike, Honglu, and Huashuo) exhibited a higher sugar and acid content, making them suitable for apple juice production. Cluster III (i.e., Miqila, Honey Crisp, Shandong Fuji, and Yanfu 3) were more suitable for fresh-cut apples due to their good flavor and undesirable appearance. Several chemometric analyses effectively assessed differences among apple cultivars.

A Novel Strategy to Improve Cloud Stability of Orange-Based Juice: Combination of Natural Pectin Methylesterase Inhibitor and High-Pressure Processing.

This study investigated the prospect of producing cloud-stable orange-based juice by combining high-pressure processing (HPP) with a natural kiwifruit pectin methylesterase inhibitor (PMEI) during chilled storage. Kiwifruit is rich in a PMEI, which greatly improves the cloud loss caused by the pectin methylesterase (PME) demethylation of pectin. The results show that the cloud loss of orange juice occurred after 3 days, while the orange-kiwifruit mixed juice and kiwifruit puree were cloud stable during 28 days' storage. Although, the kiwifruit puree contained larger particles compared to the orange juice, its higher viscosity and solid-like behavior were dominant, improving the cloud stability of the juice systems. In addition, the particle size distribution and rheological properties were highly related to PME activity, PMEI activity, and pectin characterization. The kiwifruit PMEI showed higher resistance to HPP and storage time than PME. More water-solubilized pectin fractions with a high molecular mass were found in the kiwifruit puree, leading to its high viscosity and large particle size, but a more chelator-solubilized pectin fraction with a low esterification degree was observed in the orange juice, resulting in its cloud loss. In general, the outcome of this work provides a novel strategy to improve the cloud stability of orange-based juices using natural PMEIs and nonthermal processing technologies.

Preparation of garlic stem cellulose nanocrystal/leaf extract/chitosan film for black garlic preservation by electrostatic spraying.

In this study, a novel active chitosan (CH) packaging film that incorporates garlic leaf extract (GL) and stem cellulose nanocrystals (CNC) was prepared. The addition of CNC to the CH film increased its tensile strength, hydrophilicity, thermal stability, and water/oxygen barrier and decreased its water contact angle and weight-loss rate, while the addition of GL greatly enhanced its antioxidant and antibacterial activities. SEM and AFM analyses showed that the CNC agglomerates and deposits in the lower layer and the surface roughness of the film was the highest at 1.2 % concentration. The optimal composition of the film was determined to be 0.8 % CNC and 4 % GL by the fuzzy mathematics evaluation method. Then, black garlic was preserved with the optimized coating by electrostatic spraying and was found to slow water loss and migration, while its excellent antioxidant activities decreased the degree of browning during 90 d of storage.

Effect of electroacupuncture combined with rehabilitation training on hypertension: A systematic review and meta-analysis.

To evaluate the clinical effects of electroacupuncture combined with rehabilitation training (EART) versus conventional rehabilitation training (CRT) on hypertension. Multiple databases like PubMed, Embase, Web of Science and Wanfang database, China National Knowledge Internet database, and Chinese Biological Medical database were used to search for the relevant studies and full-text articles involved in evaluating EART versus CRT with hypertension. Review Manager 5.4 was used to estimate the effects of the results among included articles. Forest plots, sensitivity analysis, and funnel plots were also conducted on the included articles. In this meta-analysis study, there were 9 relevant studies were eventually satisfied the included criteria. There were significant differences between EART group and CRT group in systolic blood pressure after treatment (MD -16.62, 95 %CI = -21.84 to -11.39; P < 0.00001), diastolic blood pressure after treatment (MD = -16.03, 95 % CI = -21.55 to -10.50; P < 0.00001), and effective rate (MD = 1.22, 95 % CI = 1.13 to 1.32; P < 0.00001). Sensitivity analysis and funnel chart demonstrated that the study was robust and limited publication bias was observed. Our data showed that EART was clinically more significant than CRT in hypertension. Further studies need to be performed using large relevance references to verify the effectiveness of EART in the treatment of hypertension.

Evaluation of Radio Frequency-Assisted Enzymatic Extraction of Non-Anthocyanin Polyphenols from Akebia trifoliata Flowers and Their Biological Activities Using UPLC-PDA-TOF-ESI-MS and Chemometrics.

A new radio frequency heating-assisted enzymatic extraction (RF-E) method is applied for the determination of phenolic compounds in Akebia trifoliata flowers, compared with hot water, acidified ethanol (EtOH), and enzymatic-assisted (EA) extractions. Non-anthocyanin polyphenol profiles, antibacterial, angiotensin-converting enzyme (ACE) inhibitory, anti-inflammatory activities, and structures of extracts are evaluated. Results show no significant differences in the extraction of total flavonoid content (15.85-16.63 mg QEs/g) and ACE inhibitory activity (51.30-52.86%) between RF-E and EA extracts. RF-E extract shows the highest anti-inflammatory activities. FTIR and UV spectra reveal that acidified EtOH treatment has a significant effect on the structure of the extract due to its highest flavonoid content (20.33 mg QEs/g), thus it has the highest antibacterial activity against Staphylococcus aureus and Escherichia coli. Sixteen non-anthocyanin polyphenols are identified by UPLC-PDA-TOF-ESI-MS and RF pre-treatment did not cause significant compound degradation. The chemometric analysis shows that enzymatic hydrolysis significantly increased biological activities, and the presence of non-anthocyanin polyphenols correlates well with ACE inhibitory and anti-inflammatory activities. Accordingly, A trifoliata flowers have potential as reagents for the food and pharmaceutical industries due to their abundant polyphenols that could be extracted efficiently using RF-E.

Effects of pasteurization technologies and storage conditions on the flavor changes in acidified chili pepper.

In this study, the effects of thermal processing (TP), high pressure processing (HHP), and preservatives addition, i.e. sodium metabisulfite (SMS), on flavor changes in acidified chili peppers were compared. In addition, their changes during different storage periods (25, 37, and 42 °C for 30 days) were also investigated. The results indicate that TP clearly changed the flavor properties of acidified chili peppers compared to other processing, such as an increase in organic acid contents and titratable acid (TA) values but a decrease in pH value, free amino acid (FAA) concentrations, and some aromatic compound contents (e.g., esters and aldehydes). For SMS groups, more biter FAAs and higher alcohol concentrations were detected. Some terpenes (e.g., ß-ocimene) significantly increased in samples after HPP (P < 0.05). In addition, storage conditions also clearly affected their flavor, particularly for high storage temperature. During storage, pH fast decreased but TA values and organic acids increased; FAAs firstly increased but followed decreased; esters and terpenes were the main compounds decreasing. Furthermore, some off-flavor related compounds were produced when samples were stored at high temperature, such as furans, aldehydes, and oxides. The outcome of this study could provide new insights into the effects of processing and storage conditions on flavor changes and guide production for the acidified chili pepper industry.

Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China.

OBJECTIVE: The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes. METHODS: This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations. RESULTS: There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510-201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149-62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165-16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146-86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764-32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051-0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam. CONCLUSION: Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.

Effect of radio frequency, ultrasound, microwave-assisted papain, and alcalase hydrolysis on the structure, antioxidant activity, and peptidomic profile of Rosa roxburghii Tratt. seed protein.

Traditional enzymatic hydrolysis methods have defects such as low efficiency and poor bioactivity in the production of active peptides. In this study, radio frequency (RF) technology was innovatively used to assist the hydrolysis of Rosa roxburghii Tratt. seed protein (RTSP) by papain and alcalase. RF-assisted hydrolysis was compared with ultrasound-(US) and microwave (MW)-assisted techniques in terms of the degree of hydrolysis, structure, antioxidant properties, and changes in the peptidome of the hydrolysates to clarify the mechanism of functional change of physically-assisted hydrolysate. All three methods improved hydrolysis efficiency. The degree of hydrolysis (DH) of papain group increased from 6.38% to 7.97%, 9.97% and 8.37% after US-, MW- and RF-assisted hydrolysis, respectively, while the DH of alcalase-treated group increased from 21.13% to 25.66%, 26.03%, and 23.01%, respectively. The in vitro antioxidant capacity and intracellular antioxidant capacity of RTSP and its hydrolysates were measured and evaluated by fuzzy statistical evaluation, and MW-assisted alcalase hydrolysis had the highest in vitro and intracellular antioxidant activity scores of 0.713 and 0.820, respectively. Fourier transform infrared and amino acid composition analysis explained the enhanced antioxidant properties of the hydrolysates. Further peptide profiling showed the physical assistance led to an increase in the species and contents of small molecule antioxidant peptides compared to enzyme treatment alone. Pearson's linear correlation analysis showed that AY, LY, IY, PHW, SVL, LHL, YYV, VYY, and NHAV were significantly correlated with the antioxidant properties of hydrolysates. Our data suggested that physical assistance such as US, MW, and RF were effective to improve the efficiency of enzymatic hydrolysis and produce novel antioxidant peptides. PRACTICAL APPLICATION: In this study, it was found that electromagnetic wave-assisted enzymatic hydrolysis could improve the efficiency of hydrolysis and enhance the antioxidant activity of hydrolysates compared to unassisted means. Compared with MW treatment, RF has the comparable hydrolysis effect, but has the advantages of high penetration ability, good uniformity, and low energy consumption and has greater potential for the production of bioactive peptides.

Tanshinone IIA improves contextual fear- and anxiety-like behaviors in mice via the CREB/BDNF/TrkB signaling pathway.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.

Exploring the mechanism of Akebia trifoliata fruit cracking based on cell-wall metabolism.

Akebia trifoliata fruit cracks easily, but little is known about the underlying mechanism of this process. In this study, the changes in minerals contents, water distribution, phytohormone levels, and reactive oxygen species (ROS) metabolism were investigated to explore the effects of cell-wall metabolism in A. trifoliata fruit cracking. The micro-morphological observation confirmed that A. trifoliata fruit cracking was closely related to the cell-wall metabolism. After cracking, the higher polygalacturonase, ß-1,4-endoglucanase, and ß-glucosidase activities resulted in the depolymerization of covalently bound pectin (from 9.69% to 7.70%) and cellulose (from 57.91% to 38.05%). Moreover, the disordered ROS homeostasis resulted from the lower superoxide dismutase and ascorbate peroxidase activities, which led to cellular oxidative damage. These modifications, together with the decreases in Ca, K, and B, degradation of starch, and the movement of water, decreased cell-wall strength and degraded the cellulose network, and thus resulted in A. trifoliata cracking. The above processes were regulated by phytohormones through increased indole-3-acetic acid, salicylic acid, and jasmonic acid levels, as well as decreased cytokinin content. The findings of this study will be beneficial for further research into the preservation of A. trifoliata fruit, which is of great significance to the development of the A. trifoliata industry.

Combination of chitosan coating and heat shock treatments to maintain postharvest quality and alleviate cracking of Akebia trifoliate fruit during cold storage.

Akebia trifoliata fruit cracks easily, which shortens the shelf life and declines commercial value. This work aimed to evaluate the effects of heat shock and coating treatments on postharvest quality of A. trifoliata fruit and to elucidate the mechanism underlying retarding cracking by cell wall metabolism. Coating could decline cracking incidence (from 16.05% to 3.61%), decay incidence (from 31.21% to 18.06%), total soluble solids (TSS), and malondialdehyde (MDA) content compared to uncoated treatment during 35 days of storage. Heat shock could further decrease decay incidence but did not influence TSS, pH, firmness, and starch. Heat shock at 40 °C combined with coating treatment had the best preservation performance with the highest synthetic score (4.41). Furthermore, coated fruit displayed lower ß-glucosidase and polygalacturonase activities which resulted in higher cellulose and Na2CO3-soluble pectin. These modifications together with lower weight loss, MDA, and ion leakage contributed to the lower cracking incidence.

Activation of GIPR Exerts Analgesic and Anxiolytic-Like Effects in the Anterior Cingulate Cortex of Mice.

Background: Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. Methods: The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala2-GIP) and antagonist (Pro3-GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR. Results: In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala2-GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro3-GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice. Conclusions: GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety.

Low serum apelin levels are associated with mild cognitive impairment in Type 2 diabetic patients.

BACKGROUND: Apelin is a new adipokine that is secreted by adipocytes, and is associated with insulin resistance (IR), inflammation, and obesity. This study was designed to investigate the role of apelin in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI). METHODS: A total of 235 patients with T2DM were included. The cognitive function of patients was evaluated using Montreal Cognitive Assessment (MoCA) tool, then patients were divided into MCI group and non-MCI group according to the MoCA score. Blood sample was analyzed for the level of apelin by enzyme-linked immunosorbent assay (ELISA). RESULTS: The MCI group (n = 73) presented lower serum apelin levels compared with the patients with normal cognitive function (P < 0.001). Apelin levels showed significantly negative correlation with diabetes duration, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C, creatinine and high sensitivity C-reactive protein (hs-CRP), and positive correlation with high-density lipoprotein cholesterol (HDL-C) and brain-derived neurotrophic factor (BDNF). Multivariable logistic regression analysis indicated that serum apelin (OR = 0.304, 95%CI: 0.104-0.886, P = 0.029), as well as education levels, diabetes duration, cardiovascular disease, serum HbA1c, HDL-C, creatinine, and BDNF, were independent risk factors of MCI in patients with T2DM. CONCLUSIONS: Serum apelin level is reduced in T2DM patients with MCI. Apelin might has protective effect against cognitive impairment and serve as a serum biomarker of T2DM.