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    2025, 39(6): 0.
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  • ORIGINAL ARTICLES
  • ORIGINAL ARTICLES
    CHEN Xingxing, CHEN Zhengxun, ZHANG Die, JIANG Haopeng, TAO Jie, TANG Lele, YUAN Yi
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    OBJECTIVE  To investigate the effects of potassium channel Kv1.3 knockout (Kv1.3 KO) on neurological dysfunction and neuroinflammation in C57BL/6 mice following traumatic brain injury (TBI).  METHODS  C57BL/6 mice and homozygous Kv1.3 KO C57BL/6 mice were subjected to the classic controlled cortical impact model to establish a TBI model. The experimental groups included the sham surgery group, C57BL/6 TBI model group (TBI group), and a Kv1.3 KO C57BL/6 TBI model group (TBI+Kv1.3 KO group). At 1, 2, and 3 weeks post-modeling, real-time quantitative PNCR was used to measure the mRNA expression levels of Kv1.3, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TF-α), and IL-10 in hippocampal tissues. At 1 and 3 weeks post-modeling, Western blotting was performed to detect Kv1.3 protein expressions in the hippocampus. At 3 weeks post-modeling, Western blotting was used to assess the protein levels of IL-1β, IL-6, TNF-α, and IL-10 in hippocampal tissues. Additionally, immunofluorescence was employed to quantify cells co-labeled with the microglial marker ionized calcium-binding adapter molecule 1 (IBA1) and Kv1.3, IL-1β, or TNF-α in the hippocampus. Patch-clamp recordings were conducted to measure Kv1.3 channel currents in primary microglia at 3 weeks post-modeling. Neurological function was evaluated at 1 and 3 weeks post-modeling using the neurological severity score (NSS), pole climbing, and rotarod tests. Cognitive function was assessed at 3 weeks post-modeling via open field, Morris water maze, and Y-maze tests. RESULTS  Compared with the sham group, the TBI group exhibited significantly elevated mRNA expression levels of Kv1.3 and IL-1β in the hippocampus at 1, 2 and 3 weeks post-modeling, while IL-6 and IL-10 mRNA levels showed no significant changes. Notably, TNF-α mRNA expressions demonstrated a significant increase only at 2 and 3 weeks post-modeling. At 1 and 3 weeks post-modeling, Kv1.3 protein expressions in the hippocampus were significantly higher in the TBI group. At 3 weeks post-modeling, hippocampal IL-1β and TNF-α protein levels were markedly increased in the TBI group, whereas IL-6 and IL-10 protein levels did not change significantly. Moreover, Kv1.3 current density in primary microglia was significantly enhanced in the TBI group at 3 weeks post-modeling. Immunofluorescence analysis revealed that the number of IBA1-positive microglia co-labeled with Kv1.3, IL-1β, or TNF-α in the hippocampus was significantly larger in the TBI group than in the sham group at 3 weeks post-modeling. Behaviorally, the TBI group exhibited significantly higher NSS scores, lower success rates in full turn attempts, and longer times taken to descend the pole at 1 and 3 weeks post-modeling compared with the sham group. At 3 weeks post-modeling, TBI mice also demonstrated reduced total movement distance in the open field, decreased time spent in the central zone, fewer platform crossings, less time in the target quadrant, and lower spontaneous alternation rates. In contrast, the TBI+Kv1.3 KO group showed significantly improved outcomes compared with the TBI group: lower NSS scores, higher success rates in full turns, and shorter time taken to descend the pole at 1 and 3 weeks post-modeling. At 3 weeks post-modeling, the TBI+Kv1.3 KO group displayed longer rotarod endurance, increased total movement distance in the open field, more time spent in the central zone, higher platform crossings, greater target quadrant exploration time, and improved spontaneous alternation rates. Furthermore, at 1 and 3 weeks post-modeling, the TBI+Kv1.3 KO group exhibited significantly reduced mRNA expression levels of the 
    inflammatory cytokines IL-1β and TNF-α in the hippocampus compared with the TBI group. CONCLUSION  Potassium channel Kv1.3 knockout mitigates neurological dysfunction and neuroinflammation in C57BL/6 mice following TBI. 
  • ORIGINAL ARTICLES
    JIANG Xiaowei, YU Gang, SU Ruibin
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    OBJECTIVE  To investigate the role of δ-subunit-containing extrasynaptic γ-aminobutyric acid type A receptor (GABAAR) in sleep-promoting effects of zolpidem (ZPD). METHODS  ① C57BL/6J mice were implanted with skull electrodes and allowed postoperative recovery of seven days. Groups of mice were intraperitoneally (ip) administered with ZPD at 0 (vehicle control), 2.5, 5 and 10 mg·kg-1. Cortical electroencephalography (EEG) was recorded to analyze latencies of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, the percentage of wakefulness, NREM and REM sleep, sleep architecture (the proportion of NREM and REM sleep in sleep, number of times and mean duration of NREM and REM sleep, microarousals and short awakenings), EEG power density and slow-wave activity (SWA, 0.5-4 Hz) during NREM sleep. ② Wild-type (WT) and δ-subunit knockout (δ-KO) mice were ip administered with vehicle or ZPD 10 mg·kg-1 before cortical EEG parameters were analyzed to compare ZPD effects between genotypes. RESULTS  ① Compared with the vehicle, ZPD 2.5, 5 and 10 mg·kg-1 significantly shortened NREM sleep latency. ZPD 5 and 10 mg·kg-1 markedly reduced wakefulness and increased NREM sleep time. ZPD 2.5 and 10 mg·kg-1 increased NREM sleep episode frequency while ZPD 10 mg·kg-1 elevated brief awakening frequency. REM sleep remained unchanged. ② In δ-KO mice, ZPD 10 mg·kg-1 significantly shortened NREM sleep latency compared with WT mice, but its effects on increasing short awakenings and suppressing SWA were abolished. Zolpidem showed no significant differences in the proportion of each sleep phase, the average duration of NREM sleep, and the frequency of REM sleep in KO mice compared to its effects on WT mice. CONCLUSION ZPD-induced sleep fragmentation and reduced sleep depth are mediated by δ-subunit-containing extrasynaptic GABAAR, whereas its shortening of NREM sleep latency is independent of this receptor subtype.
  • ORIGINAL ARTICLES
    WANG Shengyuan, LI Xianfu, LIU Yuanyuan, ZHAO Ziming, WANG Zengming, ZHENG Aiping
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    OBJECTIVE  To establish an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of dexmedetomidine (DEX) in plasma of beagle dogs and evaluate the pharmacokinetics and sedation after nasal, buccal and sublingual mucosal administration. METHODS  A UPLC-MS/MS method was established and validated for dertermination of DEX in plasma of beagle dogs. DEX was administered to the nasal cavity, buccal and sublingual mucous membranes of beagle dogs, respectively. Blood samples were collected at different time points. The plasma concentration of DEX was measured by the established UPLC-MS/MS method. Pharmacokinetic parameters were fitted by Phoenix software and the sedative effect at different mucous membrane sites was evaluated in conjunction with behavioral and Ramsay scores. RESULTS  The linearity of DEX was fine within the range of 0.05-100 μg·L-1 (r >0.999), which was validated methodologically to meet the requirements of quantitative detection. The plasma concentration of the drug peaked the fastest with nasal administration. Tmax was 0.25 h, Cmax (4.43±1.19) μg·L-1, and the AUC0-6 h was (8.92±2.07) μg·h·L−1, compared with 0.92 and 1 h, (2.87±0.69), (2.70±0.41) μg·L−1, and (7.99±1.77), (7.01±2.09) μg·h·L−1 with buccal and sublingual administration. Nasal administration had the fastest onset at 7 min, with a Ramsay score of 4, and sedation lasted for 36 min, compared with 33 and 35 min, and 38 and 37 min for buccal and sublingual administration. CONCLUSION  The proposed method is sensitive, reliable and applicable to quantitative analysis of DEX in plasma of beagle dogs. Administration of DEX to the nasal cavity mucosa has a faster onset and a better sedative effect than to the buccal and sublingual mucosa.
  • ORIGINAL ARTICLES
    XING Huanchun, GUO Shuai, CAO Wenbing, WANG Lin, LU Kui, WAN Yongan, YANG Jun
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    OBJECTIVE  To investigate the biodistribution of lipid nanoparticles (LNPs) with different surface charges and different particle sizes in mice. METHODS  LNPs were prepared using microfluidic technology by incorporating positively charged phospholipids, negatively charged phospholipids, ionizable phospholipids, and neutral phospholipids into the formulation to create LNPs with corresponding surface charges. The particle size of the LNPs was controlled by polyethylene glycol (PEG) modification and measured using dynamic light scattering (DLS) and transmission electron microscopy (TEM), while the surface charge was analyzed using a zeta potential analyzer. The LNPs were labeled with a fluorescent dye, and the mice were intravenously injected with 0.625 μmol·kg-1 of LNPs. At 1, 4, 12 and 24 h post-injection, the brain, heart, livers, spleen, lungs and kidneys were collected. The fluorescence distribution in different organs was detected using an in vivo imaging system to reflect the distribution of LNPs in various organs. RESULTS  Particle size analysis showed that, except the ionizable lipid nanoparticles without PEG modification (LNP-MC3), which had a particle size>200 nm, the particle sizes of positively charged LNPs without PEG modification (LNP-Pos), PEG-modified positively charged LNPs (LNP-Pos-P), PEG-modified neutral LNPs (LNP-Neu-P), PEG-modified ionizable LNPs (LNP-MC3-P), and PEG-modified negatively charged LNPs (LNP-Neg-P) were all <200 nm. Zeta potential analysis revealed that the surface charges of the LNPs were the highest in LNP-Pos, followed by LNP-Pos-P, LNP-MC3-P, LNP-Neu-P, LNP-MC3 and LNP-Neg-P. In vivo imaging results indicated that LNP-Pos-P, LNP-Pos and LNP-MC3-P were primarily distributed in the livers, lungs and kidneys, respectively, while LNP-Neu-P and LNP-Neg-P in the livers, kidneys, and lungs, respectively. The distribution of LNP-MC3-P in the brain, heart, spleen and kidneys peaked at 12 h post-injection, but at 24 h in the livers. The distribution of LNP-Pos-P in the lungs peaked at 1 h post-injection. CONCLUSION  LNPs are primarily distributed in the livers. Surface charges influence the second most highly-distributed organs. LNP-Pos-P and LNP-MC3-P are the second most highly-distributed in the lungs, and LNP-Neu-P and LNP-Neg-P in the kidneys.
  • ORIGINAL ARTICLES
    HUANG Hegui, XIONG Ying, ZHANG Dingmei, HE Zheng, WANG Hui
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    OBJECTIVE  To investigate the mechanisms of adrenal dysfunction among adult offspring rats caused by prenatal ethanol exposure (PEE) aggravated by high-fat diet (HFD) and unpredictable chronic stress (UCS). METHODS  Pregnant rats were randomly divided into the control group (saline, ig, once) and PEE group (4 g·kg-1, ig, once) from gestational day (GD) 11 until delivery. At postnatal week 4 (PW4), offspring rats from the control group and PEE group were randomly assigned to three subgroups: the normal diet (ND) group, HFD group, and HFD-UCS group (n=20 per subgroup, at an equal male-to-female ratio). The rats in each group were given a corresponding diet until PW24. The HFD-UCS group received HFD until PW24, with additional UCS treatment initiated at PW21 and continued for 3 weeks. Serum adrenocorticotropic hormone (ACTH) levels were measured by radioimmunoassay, and corticosterone (CORT) levels were quantified via enzyme-linked immunosorbent assay (ELISA). Adrenal mRNA expressions of steroidogenic factor 1 (Sf1), steroidogenic acute regulatory protein (Star ), cytochrome P450 cholesterol side chain cleavage(P450scc), 3β-hydroxysteroid dehydrogenase (3β-Hsd), steroid 21-hydroxylase (P450c21), steroid 11β-hydroxylase (P450c11), 11β-hydroxysteroid dehydrogenase type 1 (11β-Hsd1), 11β-Hsd 2, mineralocorticoid receptor (Mr ), glucocorticoid receptor (Gr ), insulin-like growth factor 1 (Igf1), IGF1 receptor (Igf1r), and serine/threonine kinase 1 (Akt1) were determined using real-time quantitative PCR. Protein expressions of Akt1 and phosphorylated Akt1 (p-Akt1) were analyzed via immunohistochemistry. RESULTS  In male offspring, HFD/PEE significantly reduced serum ACTH and CORT levels, downregulated Star, P450scc, 3β-Hsd and P450c11 mRNA, decreased 
    11β-Hsd1 mRNA expressions and 11β-Hsd1/11β-Hsd2 ratio, but increased Igf1, Igf1r mRNA, and p-Akt1 protein. Conversely, HFD-UCS/PEE elevated ACTH, CORT, P450scc, 3β-Hsd and P450c11 mRNA, increased 11β-Hsd1 and 11β-Hsd1/11β-Hsd2 ratio while suppressing Igf1 mRNA, and p-Akt1 protein. In females, HFD/PEE decreased ACTH but upregulated Igf1, Akt1 mRNA, and p-Akt1 protein. HFD-UCS/PEE increased ACTH, CORT, Sf1, Star, P450scc and P450c11 mRNA, and 11β-Hsd1/11β-Hsd2 ratio, but reduced lgf1 and Igf1r mRNA. CONCLUSION  HFD/UCS can aggravate PEE-induced adrenal dysfunction in adult offspring. The adrenal "GC-IGF1 axis" is an endocrine negative feedback one, and its decompensation may increase the susceptibility of a wide range of GC-related adult chronic diseases, such as diabetes.
  • ORIGINAL ARTICLES
    ZHANG Linli, TIAN Shuting, LIU Ruixi, LIU Li
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    OBJECTIVE  To study the effects of ethanol on markers of gastric stem cells and epithelial cells, and explore the related signal pathways for stem cells differentiation in a mouse gastric mucous injury model. METHODS  Male C57BL/6 mice were randomly divided into normal control and ethanol groups. The mice in the control group were given normal drinking water while those in the ethanol group were gavaged with 10 ml·kg-1 50% (V/V) ethanol on day 1, and drinking water containing 10% (V/V ) ethanol was given on day 2-9. On the 10th day, stomach tissues were collected. HE staining was used to detect pathological changes in the stomach. Immunohistochemistry (IHC) staining was used to detect changes of such cell markers as mucin 5AC, H+/K+ATPase β and pepsin C. Immunofluorescence (IF) staining was employed to analyze changes in expression of cell markers such as  H+/K+ ATPase β, pepsin C and gastrin. ELISA assay was used to measure gastrin, somatostatin and interleukin 1β (IL-1β) concentrations in gastric tissue homogenates. Flow cytometry was adopted to measure the number of leucine rich repeat containing G protein-coupled receptor 5 positive (LGR5+) stem cells in gastric glands. Organoids was constructed to characterize stem cell activity. RNA sequencing and bioinformatics analysis were conducted to analyze the inflammatory pathways and differentiation signaling pathways during mice gastric mucous injury. RESULTS  H&E results showed multifocal necrosis of the mucosal layer appeared in the ethanol group, accompanied by pyknosis, lysis and detachment of mucosal epithelial cells and gastric gland cells. IHC results showed decreased expressions of mucin 5AC and increased expressions of H+/K+ATPase β and pepsin C. IF results revealed increased expressions of 
    H+/K+ATPase β, pepsin C, and gastrin after ethanol treatment. ELISA results demonstrated significant increases in gastrin, somatostatin and IL-1β levels in gastric tissues of the ethanol group. Flow assay results suggested that the number of LGR5+ stem cells significantly decreased in ethanol treated gastric tissues. Stem cells from stomach tissues treated with ethanol did not grow into organoids. RNA sequencing and bioinformatics analyses revealed enrichment of TNF, NF-κB and Notch pathways in the ethanol group. CONCLUSION  Administration of 50% ethanol solution on day 1, followed by continuous administration of 10% ethanol solution on day 2-9 can induce histopathological injury to the gastric gland and stem cells, and an increase in epithelial cells. These changes may be related to the up-regulation of inflammatory pathways and Notch signaling pathways triggered by ethanol.
  • REVIEWS
  • REVIEWS
    TAO Weijie, YONG Zheng, SU Ruibin
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    Commonly used anesthetic sedatives (opioids, benzodiazepines, ketamine, propofol, etc.) share the risk of inducing respiratory depression, and their multi-target mechanism of action presents significant heterogeneity. Opioids inhibit the rhythmic activity of the respiratory center of the medulla bulbar (such as the PreBötzinger complex and parbrachial nucleus) by activating both the μ-opioid receptor and the G-protein-gated inwardly-rectifying potassium channel and β-arrestin signaling pathway, resulting in decreased respiratory frequency and amplitude. Benzodiazepines enhance inhibitory neurotransmission mediated by γ-aminobutyric acid receptors, reduce the sensitivity of chemoreceptors to PaCO2 and PaO2, and lead to a decreased tidal volume and upper airway obstruction. Ketamine inhibits respiratory drive and respiratory muscle function by blocking N-methyl-D-aspartic acid  receptors and indirectly affecting the μ-opioid receptor. In addition, propofol inhibits pre-expiratory neuronal activity and relaxes upper airway muscles by activating the GABAA receptor β3 subunit. Currently, specific antagonists (naloxone/flumazenil) and respiratory stimulants (doxapram) are clinically used to treat respiratory depression, but they have defects such as short duration of action and insufficient specificity. The development of novel stimulants targeting μ-opioid receptor agonists and the D-serine release pathway of astrocytes, as well as broad-spectrum antidotes based on "molecular cage" technology, has become a new sphere of research that aims at precisely reversing respiratory depression while preserving analgesic and sedative effects. This article reviews the biological mechanisms of respiratory depression caused by sedative hypnotic anesthetic drugs, explores the advantages and disadvantages of treatments currently availabe, and proposes new strategies for improving respiratory depression in the future.
  • REVIEWS
    LIU Xiaoli, WANG Hongbo, YU Gang, SU Ruibin
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    Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors are a class of inhibitory neurotransmitter receptors that are distributed in non-synaptic structures such as cell bodies and dendrites. Extrasynaptic GABAA receptors are heteropentamers usually containing δ-subunit. Changes of δ-subunit expressions can be observed in model animals of postpartum depression and premenstrual syndrome, and δ-/- or δ+/- mice exhibit behavioral phenotypes of postpartum depression, suggesting that extrasynaptic GABAA receptors are involved in the pathogenesis of related diseases. The present review is concerned with the relationship between extrasynaptic GABAA receptors and postpartum depression as well as premenstrual syndrome in general, and the advances in research on drugs targeting extrasynaptic GABAA receptors for the treatment of these two conditions in particular. The article highlights the value of extrasynaptic GABAA receptors as a therapeutic target for female mood disorders, and may provide a reference for the development and application of related drugs.
  • REVIEWS
    ZHAO Siyu, LI Qingyu, Reham Taha, XU Yan, XIAO Li, SUN Lixin
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    The intestine in a hypoxic state is an essential physiological organ, and its primary functions include digestion, absorption, excretion, hormone secretion, and providing barrier and immune protection. Hypoxia-inducible factor-2α (HIF-2α) represents one of the important physiologicalregulators for the intestine, partaking in the regulation of iron homeostasis, oxygen homeostasis and energy metabolism in the intestinal environment. Recent studies have shown that HIF-2α is closely associated with the onset and progression of various intestinal-related diseases, including iron-relatedblood diseases, inflammatory bowel disease (IBD), colorectal cancer (CRC), and obesity-related metabolic diseases. Thus, HIF-2α may be a novel target for the treatment. HIF-2α is currently a hot topic in drug development, and numerous studies have revealed that it has therapeutic potential for intestinal-related diseases. HIF-2α is a key transcription factor that regulates intestinal iron absorption and systemic iron homeostasis. Aberrant expression of HIF-2α has been closely linked to various hematological disorders associated with iron metabolism dysregulation. In the pathological hypoxic microenvironment of the intestine, sustained activation of HIF-2α induces inflammatory response and impairs epithelial barrier function, thereby exacerbating the progression of IBD. Within the tumor microenvironment, HIF-2α contributes to CRC progression through multiple mechanisms, including metabolic reprogramming, angiogenesis, enhanced proliferation, migration, and invasion of tumor cells, as well as inflammation, iron accumulation, and immune evasion. Moreover, HIF-2α is involved in the regulation of obesity, insulin resistance, and glucose-lipid metabolism via the gut-liver axis. Although seven HIF-2α modulators have been approved for clinical use, adverse effects such as anemia and thrombosis remain concerns. Therefore, developing next-
    generation HIF-2α-targeted strategies with improved specificity and safety profiles is critical to future research.This article is an overview of the recent advancements in understanding the role and mechanisms of HIF-2α in intestinal health and associated diseases while analyzing the challenges to development and application of HIF-2α modulators in the future, in hopes of offering novel therapeutic avenues for intestinal-related ailments.