ObjectiveBased on transcriptomics， to explore the mechanism of Hei Xiaoyaosan regulating the phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway to improve the learning and memory ability of insomnia rats with liver depression syndrome. MethodsSixty 8-week-old male SD rats were randomly divided into the blank group， model group， eszopiclone group （0.09 mg·kg^-1）， and low， medium， and high dose groups of Hei Xiaoyaosan （3.82， 7.65， 15.30 g·kg^-1）， with ten rats in each group. Except for the blank group， the other groups were induced insomnia rat model with liver depression by chronic restraint， tail clamping stimulation and intraperitoneal injection of p-chlorophenylalanine （PCPA）. Each treatment group received intragastric administration according to the specified dosage， once a day for 14 consecutive days. The pentobarbital sodium cooperative sleep test， open field test， and Morris water maze test were used to test the sleep quality， depressive-like behavior， and learning and memory abilities of rats. Additionally， enzyme-linked immunosorbent assay （ELISA） was used to detect the contents of 5-hydroxytryptamine （5-HT）， γ-aminobutyric acid （GABA）， brain-derived neurotrophic factor （BDNF）， glial cell line-derived neurotrophic factor （GDNF） and nitric oxide （NO） in hippocampus. Hematoxylin-eosin （HE） staining was performed to observe pathological changes of the hippocampal tissue， while terminal deoxynucleotidyl transferase deoxyuridine triphosphate （dUTP） nick end labeling （TUNEL） was used to evaluate apoptosis of hippocampal neurons. Transcriptomic sequencing technology was employed to identify differentially expressed genes in hippocampus between the model group and the blank group， as well as between the medium-dose group of Hei Xiaoyaosan and the model group. Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis were performed on the intersecting genes. Subsequently， the enriched key genes and signaling pathways were analyzed and verified. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was utilized to assess the mRNA expression levels of phosphatase and tensin homolog （PTEN）， B-cell lymphoma-2 （Bcl-2）-like protein 11 （BCL2L11）， and mitogen-activated protein kinase 1 （MAPK1） in hippocampus， and Western blot was employed to evaluate the protein expressions of PI3K， phosphorylation （p）-PI3K， Akt， p-Akt， Bcl-2， Bcl-2-associated X protein （Bax）， and cleaved Caspase-3 in the same tissue. ResultsCompared with the blank group， the model group exhibited a reduction in body weight， an increase in sleep latency， and a decrease in sleep duration （P<0.01）. Additionally， rats showed obvious depression-like behavior， and their learning and memory abilities decreased. Furthermore， the contents of 5-HT， GABA， NO， BDNF and GDNF in hippocampus decreased （P<0.01）. Histological examination revealed a disorganized cell arrangement in the CA1 region of the hippocampus， characterized by irregular cell shapes， a reduced cell count， deeply stained and pyknotic nuclei， increased vacuolar degeneration， and an elevated apoptosis rate （P<0.01）. Compared with the model group， the body weight of the high and medium dose groups of Hei Xiaoyaosan increased， the sleep latency shortened and the sleep time prolonged （P<0.05， P<0.01）. Additionally， depression-like behavior and learning and memory abilities of rats were significantly improved， the levels of 5-HT， GABA， NO， BDNF and GDNF in the hippocampus increased （P<0.05， P<0.01）. These interventions also ameliorated pathological damage in the hippocampal CA1 area and reduced the apoptosis of hippocampal neurons （P<0.01）. Transcriptomic sequencing results indicated that Hei Xiaoyaosan might exert a therapeutic effect by regulating PI3K/Akt pathway through key mRNAs such as PTEN， BCL2L11， and MAPK1. The roles of these key mRNAs and proteins within PI3K/Akt pathway were further validated. In comparison to the blank group， the expression levels of PTEN， BCL2L11 and MAPK1 mRNA in the hippocampus of rats in the model group were increased （P<0.01）， while the protein expression levels of p-PI3K， p-Akt and Bcl-2 were decreased （P<0.01）， and the protein expression levels of PTEN， Bax and cleaved Caspase-3 were increased （P<0.01）. Compared with the model group， the high-dose and medium-dose groups of Hei Xiaoyaosan could down-regulate the expressions of PTEN， BCL2L11 and MAPK1 mRNAs （P<0.01）， up-regulate the expressions of p-PI3K， p-Akt and Bcl-2 proteins （P<0.01）， and down-regulate the protein expressions of PTEN， Bax and cleaved Caspase-3 （P<0.05， P<0.01）. ConclusionHei Xiaoyaosan may regulate PI3K/Akt signaling pathway by down-regulating expressions of key genes such as PTEN， BCL2L11 and MAPK1， and thus improve the learning and memory abilities of insomnia rats with liver depression syndrome.

Objective: Exploring the effect and mechanism of Xinyang Tablet on reduction of ferroptosis in myocardial cells from mice with chronic heart failure. Methods: Sixty C57BL/6J mice were randomly assigned to the sham, model, Xinyang Tablet low-dose (0.34 g/kg), Xinyang Tablet medium-dose (0.68 g/kg), Xinyang Tablet high-dose (1.36 g/kg), and perindopril (0.607 mg/kg) groups using a random number table method (10 mice in each group). Except for the sham group, all other groups underwent aortic arch constriction surgery to construct a chronic heart failure model. On the third day after completion of the modeling, each treatment group was administered the corresponding medication by gavage, while the sham and model groups were administered equal volumes of water by gavage once a day for eight consecutive weeks. After treatment, cardiac ultrasound was used to detect the structure and function of the mouse heart. Hematoxylin and eosin staining was used to detect pathological changes in mouse heart tissue. Masson staining was used to detect the proportion of fibrotic area of mouse heart tissue. Realtime fluorescence PCR was used to detect the mRNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), collagen 3α (Col3α), and myosin heavy chain 7 (MYH7) in mouse myocardial tissue. Transmission electron microscope was used to detect the ultrastructure of myocardial cell mitochondria. Reactive oxygen species (ROS) staining was used to detect the mean fluorescence intensity of ROS in myocardial tissue. Micro-determination was used to detect superoxide dismutase (SOD) activity in myocardial tissue. An immunofluorescence assay was used to detect the mean fluorescence intensity of phosphorylated histone deacetylase 2 (p-HDAC2) in myocardial cell. Western blotting was used to detect the protein expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), p-HDAC2, nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), glutathione peroxidase 4 (GPX4), and cystine glutamate reverse transporter (xCT) in mouse myocardial tissue. Results: Compared to the sham group, the model group showed a decrease in left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), an increase in left ventricular end-systolic diameter(LVESD) and left ventricular end-diastolic diameter (LVEDD), an increase in the proportion of cardiac fibrosis area, an increase in relative expression levels of ANP, BNP, Col3α, and MYH7 mRNA, an increase in ROS mean fluorescence intensity, a decrease in SOD activity, an increase in mean fluorescence intensity of p-HDAC2, an increase in relative expression levels of p-HDAC2 and NOX1 proteins, and a decrease in relative expression levels of Nrf2, GPX4, and xCT proteins (P<0.05). Myocardial fibrosis lesions are obvious, with disordered mitochondrial arrangement, decreased volume and shrinkage, increased membrane density, and reduced mitochondrial cristae. Compared to the model group, the LVEF and LVFS of mice in each dose group of Xinyang Tablet and the perindopril group increased, LVESD and LVEDD decreased, the proportion of fibrotic area of heart tissue decreased, the relative expression levels of ANP, BNP, Col3α, MYH7 mRNA decreased, ROS mean fluorescence intensity decreased, SOD activity increased, mean fluorescence intensity of p-HDAC2 decreased, relative expression levels of p-HDAC2 and NOX1 proteins decreased, and relative expression levels of Nrf2 and xCT proteins increased (P<0.05). Myocardial fibrosis was reduced, the mitochondrial arrangement was more regular, the mitochondria enlarged, the membrane density was reduced, and mitochondrial cristae increased. Compared to the model group, the relative expression level of the GPX4 protein in myocardial tissue increased in the Xinyang Tablet medium-, high-dose, and the perindopril groups (P<0.05). Conclusion Xinyang Tablet can improve ferroptosis and ventricular remodeling in mice with chronic heart failure by regulating the HDAC2-mediated Nrf2 antioxidant pathway.

Objective: To analyze the trends in new diagnosis rates of HIV/AIDS cases in Huzhou City, Zhejiang Province from 2009 to 2023, so as to provide the basis for improving HIV/AIDS prevention and control strategies. Methods: Data of newly reported HIV/AIDS cases in Huzhou City from 2009 to 2023 were collected through the Chinese Disease Prevention and Control Information System. The new diagnosis rate was calculated as the ratio of newly reported HIV/AIDS cases within one year to the permanent resident population during the same period. The gender, age, and regional distribution characteristics of new diagnosis rates of HIV/AIDS cases were described. The trends were analyzed using average annual percent change (AAPC) and annual percent change (APC). Results: A total of 2 088 new HIV/AIDS cases were reported in Huzhou City from 2009 to 2023, with an average annual new diagnosis rate of 4.53/105. The new diagnosis rates showed an overall increasing trend from 2009 to 2023 (AAPC=12.745%, P<0.05), with rapid growth during 2009 to 2015 (APC=32.734%, P<0.05) but no significant trend during 2015 to 2023 (P>0.05). The average annual new diagnosis rate was significantly higher in males than in females (7.54/100 000 vs. 1.40/100 000, P<0.05). Male new diagnosis rate trend closely mirrored the overall population pattern, while females showed a continuous upward trend without clear inflection point (AAPC=12.575%, P<0.05). Age-specific analysis revealed average annual new diagnosis rates of 2.75/100 000, 6.16/100 000 and 3.83/100 000 for AIDS/HIV cases aged <25, 25-<50 and ≥50 years, respectively. The cases aged <25 years showed no significant trend (P>0.05), while the cases aged 25-<50 and ≥50 years followed patterns similar to the overall population. The average annual new diagnosis rates of HIV/AIDS cases in Wuxing District, Nanxun District, Deqing County, Changxing County and Anji County were 6.54/100 000, 3.43/100 000, 3.45/100 000, 3.56/100 000 and 4.94/100 000, respectively, showing overall upward trends (AAPC=9.672%, 27.599%, 11.800%, 18.896% and 10.254%, all P<0.05). Conclusions The new diagnosis rate of HIV/AIDS cases showed an overall upward trend in Huzhou City from 2009 to 2023. Cases are mainly concentrated among males, people aged 25-<50 years and Wuxing District, making them key targets for HIV/AIDS prevention and control.

Objective:To investigate the potential characteristic manifestations and application value of the Dynamic Visual Acuity Test（DVAT） in vestibular migraine（VM）. Methods:A total of 50 VM patients（case group） and 50 healthy subjects（control group） diagnosed at the Department of Otorhinolaryngology Head and Neck Surgery, First Hospital of Shanxi Medical University between November 1, 2023, and December 31, 2024, were enrolled. The case group underwent DVAT, video head impulse test（vHIT）, caloric test, and Dizziness Handicap Inventory（DHI） assessment, whereas the control group only received DVAT. Group-based analyses were conducted to examine the effect of age on Dynamic Visual Acuity Loss（DVALoss）, as well as the correlations of DVALoss with vestibular function tests and DHI scores. Results:DVALoss in the case group was significantly higher than that in the control group（P<0.001）. In both groups, age was significantly and positively correlated with DVALoss（P<0.001）. Within the case group, DVALoss was strongly and positively correlated with DHI scores（r=0.807, P<0.001）; it was negatively correlated with the vestibulo-ocular reflex（VOR） gain in vHIT, though without clinical significance, and showed no significant association with the caloric test. Age and DVALoss collectively accounted for 71.3% of the variance in DHI scores（R²=0.713）, with age exerting a relatively minor actual impact. Conclusion:DVAT can sensitively identify the core functional impairments of VM. DVALoss, as a direct functional reflection of the pathological mechanism of VM, is strongly correlated with DHI scores. Incorporating DVALoss into standardized assessments may provide an objective basis for the diagnosis and management of VM.
Humans ; Migraine Disorders/diagnosis* ; Visual Acuity ; Case-Control Studies ; Head Impulse Test ; Vestibular Function Tests ; Female ; Male ; Adult ; Vestibular Diseases/physiopathology* ; Middle Aged ; Caloric Tests

Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.

The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

Advanced atherosclerosis is the major global cause of death, as featured by the aggregation of apoptotic cells (ACs) in necrotic cores. The defective efferocytosis and dysfunctional cholesterol efflux of macrophages are the main reasons for forming necrotic cores in advanced atherosclerosis. In this study, we constructed self-assembled procyanidins (PC) NPs for loading pitavastatin (Pita). The designed HA@PC@Pita NPs with hyaluronic acid (HA) modification combined the advantages of efferocytosis restoration of Pita and cholesterol efflux enhancement of PC. In vitro assay indicated that HA@PC@Pita NPs could induce M1/M2 repolarization and upregulate ERK5/Mertk expression to restore efferocytosis of macrophages. Simultaneously, HA@PC@Pita NPs notably promoted cholesterol efflux by promoting macrophage lipophagy, a selective autophagy of lipid droplets. In vivo study showed that HA@PC@Pita NPs cleared necrotic core and enhanced plaque stability in the ApoE ^-/- mice model with advanced atherosclerosis. Taken together, this study demonstrated the potential of HA@PC@Pita NPs for the treatment of advanced atherosclerosis.

High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

OBJECTIVE: To analyze the imaging and clinical features of diaphragm dysfunction in patients who underwent selective cardiac sternotomy with diaphragm ultrasound and chest CT. METHODS: A prospective cohort study was conducted. The patients undergoing selective cardiac sternotomy in the cardiac and vascular surgery department of Tianjin Medical University General Hospital from June to September 2023 were enrolled. Bedside ultrasound was performed on the day before surgery, within 24 hours of extubation, and on the 7th day after surgery to measure diaphragm excursion (DE) and diaphragm thickness (DT), and to calculate the diaphragm thickening fraction (DTF). The distance from the diaphragm's apex to the thorax's apex in the chest CT scout view was measured before and after the operation, and the diaphragm elevating fraction (DEF) was calculated. Patients were divided into two groups based on whether diaphragm dysfunction (DE < 1 cm) occurred on the 7th day after surgery. The change patterns of imaging indicators were analyzed in both groups. The clinical data of both groups before, during, and after surgery were compared. RESULTS: In total, 67 patients who underwent cardiac sternotomy were enrolled. Among them, 24 patients developed diaphragm dysfunction within 24 hours after extubation; on the 7th day after surgery, 19 patients (28.4%) still exhibited diaphragm dysfunction, while 48 patients (71.6%) did not. Ultrasonic examination of the diaphragm revealed that, compared with the non-diaphragm dysfunction group, patients in the diaphragm dysfunction group exhibited varying degrees of decrease in DE and DTF before and after surgery, with a more significant decrease on the left side, and the differences were statistically significant on the 7th day after surgery [DE (cm): 1.06±0.77 vs. 1.59±0.63, DTF: 19.3% (14.8%, 21.1%) vs. 21.3% (18.3%, 26.1%), both P < 0.05]. There was no statistically significant difference in DT between the two groups at each time point. Changes in bilateral DE and DTF revealed that the non-diaphragm dysfunction group experienced early transient postoperative weakening of diaphragm function, followed by rapid recovery to the preoperative level on the 7th day after surgery, unlike the diaphragm dysfunction group. There were no significant differences between bilateral DE in the two groups on the day before surgery, and the left DE was significantly lower than the right DE within 24 hours after extubation and on the 7th day after surgery in the diaphragm dysfunction group (cm: 0.93±0.72 vs. 1.45±0.70 within 24 hours after extubation, 1.06±0.77 vs. 1.70±0.92 on the 7th day after surgery, both P < 0.05) but no significant difference was found in bilateral DT or DTF. The chest CT scan showed that, the incidence of postoperative diaphragm elevation was 61.2% (41/67), and 38.8% (26/67) did not, while no statistically significant difference in DEF was found between the two groups, nor within each group on both sides. Analysis of the clinical data showed a higher proportion of atrial fibrillation and pulmonary hypertension before surgery [atrial fibrillation: 36.8% (7/19) vs. 10.4% (5/48), pulmonary hypertension: 15.8% (3/19) vs. 2.1% (1/48), both P < 0.05], a higher incidence of high-flow oxygenation and pneumonia during surgery [high-flow oxygenation: 52.6% (10/19) vs. 25.0% (12/48), pneumonia: 73.7% (14/19) vs. 45.8% (22/48), both P < 0.05], and a longer duration of mechanical ventilation and length of intensive care unit (ICU) stay [duration of mechanical ventilation (hours): 47.0 (38.0, 73.0) vs. 24.5 (20.0, 48.0), length of ICU stay (hours): 69.0 (65.0, 117.5) vs. 60.0 (42.3, 90.6), both P < 0.05] in the diaphragm dysfunction group as compared with those in the non-diaphragm dysfunction group. CONCLUSIONS There was a high incidence of diaphragm dysfunction after cardiac sternotomy, which reflected the early transient postoperative weakening of diaphragm function, followed by rapid recovery to the preoperative level in most patients, predominantly on the left side. Diaphragm dysfunction, which was associated with atrial fibrillation and pulmonary hypertension significantly increased the incidence of postoperative pneumonia and prolonged the duration of mechanical ventilation and length of ICU stay.
Humans ; Diaphragm/physiopathology* ; Prospective Studies ; Sternotomy/adverse effects* ; Ultrasonography ; Postoperative Complications/diagnostic imaging* ; Tomography, X-Ray Computed ; Male ; Female ; Middle Aged ; Aged ; Cardiac Surgical Procedures/adverse effects*

Objective:To evaluate the self-assessed and proxy-assessed quality of life among disabled elderly individuals aged 60 and above in Chengdu,analyze the factors influencing these assessments,and assess the consistency between these two types of outcomes and the feasibility of proxy assessments.Methods:The quality of life for disabled elderly individuals is measured using the EQ-5D-5L for both self-assessments and proxy assessments.Consistency testing is conducted using weighted Kappa and Intraclass Correlation Coefficient(ICC).Univariate and differential analyses are performed with the Mann-Whitney/Wilcoxon and Kruskal-Wallis tests,respectively.The analysis of influencing factors employs generalized linear model regression.Results:The results of proxy assessments are slightly higher than those of self-assessments.The consistency between self-assessed and proxy-assessed health utility values and EQ-VAS scores is good(with ICC values exceeding 0.7),while the consistency across various dimensions is fair to moderate(with weighted Kappa values approximately between 0.4 and 0.5).The degree of disability,economic status,outdoor activities and sleep,the relationship between caregivers and the elderly,and whether caregivers possess relevant caregiving knowledge,all have a statistically significant impact on the quality of life of disabled elderly individuals and the differences between self-assessed and proxy-assessed outcomes(P＜0.05).Conclusion:The quality of life of disabled elderly individuals is significantly lower than that of the general population.It is essential to consider various related factors to enhance the quality of life for these individuals.The EQ-5D-5L proxy assessment results from their primary caregivers can serve as a supplement to the self-assessment results of disabled elderly individuals.However,individual dimensions should be applied with caution,taking into account the characteristics and individual differences of the evaluated population,types of proxies,and measurement tools used.