ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

Background Existing studies have confirmed that fine particulate matter (PM_2.5)is one of the important factors inducing pulmonary fibrosis. Pulmonary fibrosis is the terminal stage of a major category of lung diseases characterized by the destruction of tissue structure, and eventually leading lung ventilation and ventilation dysfunction. No effective pulmonary fibrosis treatment is available yet. Objective To investigate the protective effect of salidroside on pulmonary fibrosis induced by the exposure of PM_2.5 and its molecular mechanism. Methods Seventy 7-week-old male C57BL/6 mice were randomly divided into four groups: control group (intratracheal instillation of normal saline + saline by gavage, n=25), Sal group (intratracheal instillation of normal saline + Sal 60 mg·kg⁻¹ by gavage, n=10), PM_2.5 group (intratracheal instillation of PM_2.5 5 mg·kg⁻¹ + saline by gavage, n=10), and Sal + PM_2.5 group (intratracheal instillation of PM_2.5 5 mg·kg⁻¹ +Sal 60 mg·kg⁻¹ by gavage, n=10). The mice were administered by gavage once daily, intratracheal instillation once every 3 d, and every 3 d constituted an experimental cycle. At the end of the 26-30th cycles, 3 mice in the control group and 3 mice in the PM_2.5 group were randomly sacrificed, and the lung tissues were collected for Masson staining to verify whether the pulmonary fibrosis model was successfully established. After 30 cycles, the model was successfully constructed. After 1 week of continuous observation, the mice were sacrificed, and the blood and lung tissues of the mice were collected to make lung tissue sections. Assay kits were correspondingly employed to detect oxidative stress indicators such as serum malondialdehyde (MDA) and superoxide dismutase (SOD). Western blotting was used to detect the expression of fibrosis-related proteins (Collagen-III, α-SMA), mitochondrial dynamics-related proteins (MFN1, Drp1), and mitophagy-related proteins (PINK1, Parkin, and LC3). Results Compared with the control group, the weight gain rate of the PM_2.5 group was slowed down (P<0.05), which was alleviated by the Sal intervention (P<0.05). The lung coefficient increased after the PM_2.5 exposure (P<0.05), which was alleviated by Sal intervention. Compared with the control group, the PM_2.5 group showed severe alveolar structure damage, inflammatory cell infiltration, and blue collagen deposition, and significantly increased the lung injury score, collagen volume fraction (CVF), Szapiel score, and Ashcroft score (P<0.05), as well as serum oxidative stress levels (P<0.05). The protein expression levels of Collagen-III, α-SMA, Drp1, PINK1, Parkin, and LC3 II/I were increased (P<0.05), and the expression of MFN1 was decreased (P<0.05). Compared with the PM_2.5 group, the Sal intervention alleviated lung injury, reduced inflammatory cell infiltration and collagen deposition, showing decreased lung injury score, CVF, Szapiel score, and Ashcroft score (P<0.05), and decreased serum oxidative stress levels (P<0.05); the protein expression levels of Collagen-III, α-SMA, PINK1, Parkin, and LC3 II/I were decreased (P<0.05), the expression level of Drp1 was decreased, and the expression level of MFN1 was increased. Conclusion In the process of pulmonary fibrosis induced by PM_2.5 exposure in mice, Sal may affect mitochondrial autophagy through PINK1/Parkin pathway and play a protective role. The specific mechanism needs to be further verified.

OBJECTIVES: To investigate the protective effect and underlying mechanism of Chinese herb medicine Gandou Bushen decoction (GBD) on ovarian injury in murine hepatolenticular degeneration (HLD) model. METHODS: The chemical constituents of GBD were analyzed using liquid chromatography-mass spectrometry (LC-MS). Forty female C3He-Atp7b^tx-J mice (6-week-old) were randomly divided into model, penicillamine (positive control), low-dose GBD, and high-dose GBD groups. Ten DL syngeneic female mice served as the normal control group. Body and ovarian weights were measured to calculate the ovarian coefficient. Ovarian copper content was detected by complexometric colorimetry. Histopathological and ultrastructural changes were observed by hematoxylin-eosin staining and transmission electron microscopy, respectively. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone were measured by enzyme-linked immunosorbent assay (ELISA). RNA sequencing was performed to identify differentially expressed genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A copper overload cell model was established in ovarian granulosa cells(iCell-0114a)by inducing them with copper sulfate. Cells were divided into normal control, model control, and low-, medium-, and high-dose GBD groups. The mRNA expression of FSH receptor (FSHR), steroidogenic acute regulatory protein (StAR), insulin-like growth factor-1 (IGF-1), receptor for advanced glycation end products (RAGE), and nuclear factor κB (NF-κB) was detected by quantitative reverse transcription polymerase chain reaction. The levels of TNF-α, IL-1β, and IL-6 were measured by ELISA. Superoxide dismutase (SOD) activity was measured using a WST-1 assay. Reactive oxygen species (ROS) levels were measured using DCFH-DA fluorescence, and mitochondrial membrane potential was assessed using JC-1 staining coupled with flow cytometry. Protein expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, advanced glycation end products (AGE), RAGE, and NF-κB was determined by Western blotting. RESULTS: A total of 1465 chemical components were identified in GBD. Compared with the normal control group, the model group showed decreased body weight, ovarian weight, and ovarian coefficient (all P<0.01). GBD treatment alleviated tissue copper deposition (P<0.01), improved ovarian histomorphology and ultrastructure, and increased serum levels of FSH, LH, estradiol, and progesterone (all P<0.01). RNA sequencing identified 507 differentially expressed genes. KEGG enrichment analysis indicated that the mechanism underlying GBD's protective effects primarily involved the AGE/RAGE/NF-κB signaling pathway. In copper-overloaded granulosa cells, GBD dose-dependently increased the mRNA expression of FSHR, StAR, and IGF-1, reduced the levels of TNF-α, IL-1β, and IL-6, increased SOD activity, and decreased ROS levels (all P<0.01). The medium- and high-dose GBD groups showed a lower percentage of cells with mitochondrial depolarization (both P<0.01). All GBD dose groups showed decreased expression of Bax and caspase-3 (all P<0.05), while the medium- and high-dose groups showed increased Bcl-2 expression. Furthermore, medium and high doses of GBD reduced the protein expression of AGE, RAGE, and NF-κB, and all doses downregulated the mRNA expression of RAGE and NF-κB (P<0.05 or P<0.01). CONCLUSIONS GBD ameliorates ovarian injury in HLD, and its mechanism of action is associated with the suppression of the AGE/RAGE/NF-κB signaling pathway.

[This corrects the article DOI: 10.1016/j.apsb.2019.01.013.].

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.
Humans ; Tumor Microenvironment/immunology* ; Myeloid Cells/immunology* ; Neoplasms/therapy* ; Animals

In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

Objective:To explore the cerebral cortical mechanism of intravesical electrical stimulation (IVES) on neurogenic underactive bladder (UAB).Methods:A prospective study was conducted on healthy subjects (HS) recruited in our center and patients with neurogenic UAB treated with IVES from March 2022 to June 2023 were included. HS inclusion criteria: females aged 18-60 years; the 72-hour voiding diary was normal; the urine volume was 200-400 ml, and the free urine flow rate > 20 ml/s. HS exclusion criteria: urinary and neurological related disorders; major diseases of all systems of the body; cognitive dysfunction. Inclusion criteria for UAB patients: females aged 18-60 years; neurogenic UAB due to incomplete spinal cord injury (grade D or E) with a duration of > 3 months; previous routine use of intermittent catheterization, or indication of intermittent catheterization (residual urine accounts for > 40% of functional bladder capacity). Exclusion criteria for UAB patients: decreased bladder compliance on urodynamic examination; symptomatic urinary tract infection; concomitant hydronephrosis, vesicoureteral reflux or renal insufficiency (serum creatinine greater than 1.5 times of the normal upper limit); bladder tumors; neurological related diseases; pregnant or trying to conceive; a pacemaker or defibrillator has been implanted in the body. At baseline, the 24-hour voiding diary, residual urine, voiding efficiency, first sensation of bladder filling volume and American Urological Association Symptom Index Quality of Life scores(AUA-SI-QOL)were recorded, and the resting state-functional near-infrared spectroscopy scans of the prefrontal cortex was completed in the bladder emptying state and the strong desire to void stage. The UAB group was re-evaluated after completing 20 IVES treatments. Improvement in residual urine > 50% was defined as success of IVES treatment. The differences in functional connectivity in the prefrontal lobe between the successful UAB group before and after IVES and between the successful UAB group and the HS group were compared.Results:A total of 16 HS and 18 UAB patients were included. Eleven UAB patients were successfully treated by IVES, and 7 UAB patients were failed. Compared with pre-treatment, the post-treatment residual urine volume [90.0(50.0, 120.0) ml vs. 210.0(110.0, 300.0) ml], 24-h intermittent catheterization [3.0(2.0, 4.0) times vs. 4.0(3.0, 4.0) times], first sensation of bladder filling volume [275.0(245.0, 280.0) ml vs. 295.0 (290.0, 315.0) ml] and AUA-SI-QOL score [2.0 (2.0, 3.0) vs. 4.0 (4.0, 4.0)] of the successful UAB group were significantly lower ( P<0.05), and the voiding efficiency [75.0% (69.0%, 85.0%) vs. 42.0% (35.0%, 77.0%)] was significantly higher ( P< 0.05). Before IVES, the successful UAB group compared with the HS group, internal prefrontal functional connectivity was significantly attenuated in the bladder emptying state involving 5 brain regions: bilateral dorsolateral prefrontal cortex (DLPFC), bilateral frontopolar area, and left pars triangularis. And in the strong desire to void stage significantly attenuated involving 4 brain regions: bilateral DLPFC and bilateral frontopolar area. In the successful UAB group after IVES compared with the HS group, internal prefrontal functional connectivity was significantly attenuated in the bladder emptying state involving 2 brain regions: left pars triangularis and left DLPFC. And in the strong desire to void stage involving 4 brain regions: left DLPFC, right frontopolar area, the left pars opercularis Broca's area, and the left pars triangularis. After IVES in the successful UAB group compared with pretreatment, prefrontal internal functional connectivity was significantly enhanced in the bladder emptying state involving 4 brain regions: bilateral DLPFC and bilateral frontopolar area, and in the strong desire to void stage involving 4 brain regions: bilateral DLPFC, bilateral frontopolar area. Conclusions:Significant enhancement of functional connectivity within the prefrontal lobes (bilateral DLPFC and bilateral frontopolar area) may be the cortical mechanism of IVES for neurogenic UAB.

Objective:To investigate the efficacy and safety of a wearable percutaneous tibial nerve stimulator (TTNS) for tibial neuromodulation (TNM) in the treatment of overactive bladder (OAB).Methods:This research utilizes a single-center, prospective, open clinical trial design. Patients with OAB who were treated at the urology outpatient department of Beijing Bo’ai Hospital from July 2023 to June 2024 were enrolled. All patients met the diagnostic criteria for OAB. All patients received a transcutaneous tibial nerve regulation stimulation therapy, with a frequency of 20 Hz and a pulse width of 0.2 ms. The treatment lasted for 30 minutes each session, twice daily, for a duration of 12 weeks. Follow up evaluations were conducted at weeks 4, 8, and 12 after treatment, including a 72-hour voiding diary, Overactive Bladder Symptom Score (OABSS), patient perception of bladder condition scale (PPBC-S) score, American Urological Association Symptom Index (AUA-SI) score, American Urological Association Symptom Index Quality of Life Score (AUA-SI-QOL) score, vital signs, and adverse events.Results:This study included 68 patients, with 28 males and 40 females. Their mean age was (49.6±9.0) years old, the body mass index was(23.2 ± 2.5) kg/m 2. The duration of the disease was(42.0±14.4)months. After 12 weeks of intervention, patient's daily urination frequency decreased from (18.5 ± 3.9) times to (10.3 ± 4.5) times, nocturia frequency decreased from (6.5±2.2) times to (3.9±2.0) times, daily urine leakage decreased from (796.5±140.0) ml to (534.8±135.8)ml, OABSS decreased from (12.6±2.8) to (9.8±3.8), PPBC-S decreased from (5.5±0.6) to (3.8±1.2), AUA-SI decreased from (25.5±2.2) to (16.6±3.6), and AUA-SI-QOL decreased from (5.5±0.5) to (3.7±1.1). The differences in the above indicators before and after treatment were statistically significant ( P<0.05). During the treatment process, there were no serious adverse events related to the equipment, and no neurological related adverse events such as numbness or tingling occurred. Conclusions:The application of wearable percutaneous tibial nerve stimulators in TNM can effectively alleviate OAB symptoms like frequent urination and urgency, with minimal adverse reactions, offering a new treatment option for OAB patients.

Objective To deeply analyze the problems of public hospitals in medical service satisfaction,construct a more applicable and explanatory service satisfaction evaluation model,and provide reference for the improvement path of patients'medical service satisfaction.Methods Based on the ESCI model,this paper puts forward a research hypothesis,compiles the"Medical Service Satisfaction Evaluation Scale of Public Hospitals in S City",selects S public hospitals as the research object,and evaluates medical service satisfaction from the perspective of patients.Results At present,the main problems affecting the improvement of patients'satisfaction with medical service management in public hospitals in S city are as follows:it is urgent to improve the diagnosis and treatment technology in terms of hardware quality and optimize the environmental hygiene of public hos-pitals,and it is an urgent task to shorten the waiting time for medical treatment in software quality.The score of medical service satisfaction evaluation of S public hospitals was 3.76,and the satisfaction of patients in S public hospitals with their medical serv-ices was at a moderately low level.Conclusion In view of the above problems,it is recommended to strengthen the construction of key specialties,strengthen the construction of talent team,optimize the medical process,open digital linkage services,and strengthen service management,so as to promote the improvement of patients'satisfaction with medical services.