OBJECTIVE: To compare the effect of acupuncture-moxibustion on idiopathic facial palsy (IFP) at acute phase and recovery phase. METHODS: According to whether received acupuncture-moxibustion at acute phase or not, 198 IFP patients were divided into an early-phase intervention group (118 cases) and a non-early-phase intervention group (80 cases). With the propensity score matching employed, 70 cases were included in each group. On the basis of the conventional treatment of western medicine, acupuncture-moxibustion was supplemented in the two groups. In the early-phase intervention group, acupuncture-moxibustion was delivered at the acute phase (duration of illness≤7 days); in the non-early-phase intervention group, acupuncture-moxibustion was operated at the recovery phase (duration of illness>7 days). At the acute phase, warm needling was performed at Yifeng (TE17), Xiaguan (ST7), Hegu (LI4) and Zusanli (ST36) on the affected side; and at the recovery phase, electroacupuncture was delivered at Cuanzhu (BL2), Sizhukong (TE23) and Yangbai (GB14), etc. on the affected side, with the disperse-dense wave and 2 Hz/100 Hz of frequency. The intervention was operated for 30 min each time, once every two days, three treatments weekly and for 4 weeks. Before treatment, 1 week and 4 weeks of treatment, the House-Brackmann (H-B) facial nerve function grade, the score of Sunnybrook facial nerve function, and the score of facial disability index (FDI) were compared between the two groups. The clinical effect in 1 and 4 weeks of treatment and safety were evaluated. RESULTS: In 1 and 4 weeks of treatment, the H-B grade was improved when compared with that before treatment in each group (P<0.05), and in 4 weeks of treatment, H-B grade in the early-phase intervention group was superior to that of the non-early-phase intervention group (P<0.05). In 1 and 4 weeks of treatment, Sunnybrook scores and the scores of physical function of FDI were elevated in comparison with those before treatment in the two groups (P<0.05); and in 4 weeks of treatment, the elevation of these two indexes in the early-phase intervention group was greater than that of the non-early-phase intervention group (P<0.05). In 4 weeks of treatment, the scores of social function in FDI were reduced when compared with those before treatment in the two groups (P<0.05). In 4 weeks of treatment, the total effective rate (97.1%, 68/70) in the early-phase intervention group was higher than that (87.1%, 61/70) of the non-early-phase intervention group (P<0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05). CONCLUSION Acupuncture-moxibustion therapy starting at the acute phase is more beneficial to the functional recovery of the impaired facial nerve than at the recovery phase in the IFP patients.
Humans ; Female ; Male ; Acupuncture Therapy ; Moxibustion ; Adult ; Middle Aged ; Young Adult ; Acupuncture Points ; Treatment Outcome ; Facial Paralysis/therapy* ; Cohort Studies ; Aged ; Bell Palsy/therapy* ; Adolescent

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

OBJECTIVES: To investigate the therapeutic mechanism of nodakenin for Crohn's disease (CD)-like colitis in mice. METHODS: Using a colonic organoid model with lipopolysaccharide (LPS)- and ATP-induced pyroptosis, we investigated the effects of nodakenin on pyroptosis, intestinal barrier function and inflammatory response by detecting key pyroptosis-regulating factors and assessing changes in permeability and pro-inflammatory factors. In a mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced CD-like colitis, the therapeutic effect of nodakenin was evaluated by measuring changes in body weight, DAI score, colonic histopathologies, inflammation score, intestinal barrier function and intestinal epithelial cell pyroptosis. The mechanism of nodakenin protection against pyroptosis of intestinal epithelial cells was explored using network pharmacology analysis and in vivo and in vitro experiments. RESULTS: In LPS- and ATP-induced colonic organoids, treatment with nodakenin significantly inhibited the expressions of NLRP3, GSDMD-N, cleaved caspase-1 and caspase-11, improved intestinal FITC-dextran (FD4, 4000) permeability, and decreased the levels of IL-1β and IL-18. In the mouse model of TNBS-induced colitis, nodakenin treatment significantly alleviated weight loss, reduced DAI score, inflammatory cell infiltration and inflammation score, and decreased serum FD4 and I-FABP levels and bacteria translocation to the mesenteric lymph nodes, spleen and liver. The mice with nodakenin treatment had also lowered expressions of NLRP3, GSDMD-N, cleaved caspase-1 and caspase-11 in the intestinal mucosa. Network pharmacology analysis suggested that the inhibitory effect of nodakenin on colitis was associated with the PI3K/Akt pathway. In both the colonic organoid model and mouse models of colitis, nodakenin effectively inhibited the activation of the PI3K/Akt pathway, and the application of IGF-1, a PI3K/Akt pathway activator, strongly attenuated the protective effect of nodakenin against intestinal epithelial cell pyroptosis and intestinal barrier dysfunction. CONCLUSIONS Nodakenin protects intestinal barrier function and alleviates CD-like colitis in mice at least partly by inhibiting PI3K/Akt signaling to reduce intestinal epithelial cell pyroptosis.
Animals ; Pyroptosis/drug effects* ; Mice ; Trinitrobenzenesulfonic Acid ; Colitis/drug therapy* ; Epithelial Cells/drug effects* ; Intestinal Mucosa/cytology* ; Disease Models, Animal ; Coumarins/pharmacology* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Crohn Disease/drug therapy*

OBJECTIVES: To investigate the therapeutic effects of cimifugin on Crohn's disease (CD)-like colitis in mice and its possible mechanism. METHODS: Thirty adult male C57BL/6 mice were randomized equally into control group, 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced CD-like colitis model group, and cimifugin treatment (daily gavage at 12.5 mg/kg) group. The therapeutic effect of cimifugin was evaluated by observing changes in body weight, disease activity index (DAI) scores, colon length, histopathological inflammation scores, and inflammatory cytokine levels in the colonic mucosa. Intestinal barrier integrity in the mice was assessed using immunofluorescence assay and Western blotting for claudin-1 and ZO-1; T-helper (Th) cell subset ratios in the mesenteric lymph nodes were analyzed with flow cytometry. Network pharmacology, KEGG enrichment analysis and molecular docking were used to predict the targets of cimifugin and analyze the key pathways and cimifugin-MAPK protein interactions, which were validated by Western blotting in the mouse models. RESULTS: In mice with TNBS-induced colitis, cimifugin treatment significantly attenuated body weight loss and colon shortening, lowered DAI and histopathological scores, decreased IFN-γ and IL-17 levels, and increased IL-4 and IL-10 levels in the colonic mucosa. Cimifugin treatment also significantly improved TNBS-induced claudin-1 dislocation and reduction of goblet cells, upregulated claudin-1 and ZO-1 expressions, reduced Th1 and Th17 cell percentages, and increased Th2 and Treg cell percentages in the colonic mucosa of the mice. KEGG analysis suggested a possible connection between the effect of cimifugin and MAPK signaling, and molecular docking showed strong binding affinity between cimifugin and MAPK core proteins. Western blotting demonstrated significantly decreased phosphorylation levels of JNK, ERK, and p38 in the colonic mucosa of cimifugin-treated mouse models. CONCLUSIONS Cimifugin alleviates TNBS-induced CD-like colitis by repairing intestinal barrier damage and restoring Th1/Th2 and Th17/Treg balance via suppressing MAPK pathway activation.
Animals ; Mice, Inbred C57BL ; Male ; Mice ; Crohn Disease/immunology* ; Colitis/immunology* ; MAP Kinase Signaling System/drug effects* ; Trinitrobenzenesulfonic Acid ; T-Lymphocytes, Helper-Inducer/drug effects* ; Intestinal Mucosa ; Disease Models, Animal

OBJECTIVES: To investigate the subcellular localization and biological functions of transmembrane protein 240 (TMEM240). METHODS: NCBI BLAST and TMHMM bioinformatics software were used for protein sequence analysis and prediction of transmembrane domain of TMEM240. Brain tissues from male C57BL/6 mice (18-20 days old) were examined for distribution of TMEM240 using in situ hybridization, and qPCR and Western blotting were used to detect TMEM240 expression in different mouse tissues and in cortical neurons at different time points (n=3). In the in vitro experiment, HepG2 and Neuro-2a cells were transfected with plasmids for overexpression of TMEM240, and subcellular localization of TMEM240 was analyzed using cell imaging. In primary cultures of cortical neurons isolated from C57BL/6 mice, TMEM240 expression and its biological functions were investigated using qPCR, Western blotting, and immunofluorescence staining. RESULTS: Human and mouse TMEM240 proteins share a 97.69% similarity in the protein sequences, and both are transmembrane proteins with two transmembrane domains. TMEM240 mRNA and protein were highly expressed in mouse brain tissues and cortical neurons. In isolated mouse cortical neurons, TMEM240 expression reached the peak level after primary culture for 9 days and distributed in scattered spots within the cells. In HepG2 cells, TMEM240 was characterized as intracellular membrane structures and showed 80% colocalization with peroxisomes. In Neuro-2a cells, TMEM240 overexpression caused significant enhancement of the expressions of Rho GDP dissociation inhibitor β (ARHGDIB) at both the mRNA and protein levels. CONCLUSIONS TMEM240 is a novel intracellular subcellular structure specifically expressed in neurons with significant potential for targeted cellular function regulation.
Animals ; Humans ; Mice ; Peroxisomes/metabolism* ; Membrane Proteins/genetics* ; Mice, Inbred C57BL ; Neurons/metabolism* ; Male ; rho-Specific Guanine Nucleotide Dissociation Inhibitors ; Hep G2 Cells ; Brain/metabolism*

OBJECTIVES: To investigate the effect of ecliptasaponin A (ESA) for alleviating dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mice and the underlying mechanism. METHODS: Twenty-four male C57BL/6 mice (8-10 weeks old) were equally randomized into control group, DSS-induced IBD model group, and DSS+ESA (50 mg/kg) treatment group. Disease activity index (DAI), colon length and spleen index of the mice were measured, and intestinal pathology was examined with HE staining. The expressions of inflammatory mediators (TNF-α, IL-6, and iNOS) in the colon mucosa were detected using ELISA and RT-qPCR, and intestinal barrier integrity was assessed using AB-PAS staining and by detecting ZO-1 and claudin-1 expressions using immunofluorescence staining and Western blotting. In cultured RAW264.7 macrophages, the effects of treatment with 50 μmol/L ESA, alone or in combination with 20 μmol/L RO8191 (a JAK2/STAT3 pathway activator), on M1 polarization of the cells induced by LPS and IFN-γ stimulation and expressions of JAK2/STAT3 pathway proteins were analyzed using flow cytometry and Western blotting. RESULTS: In the mouse models of DSS-induced IBD, ESA treatment significantly alleviated body weight loss and colon shortening, reduced DAI, spleen index and histological scores, and ameliorated inflammatory cell infiltration in the colon tissue. ESA treatment also suppressed TNF‑α, IL-6 and iNOS expressions, protected the goblet cells and the integrity of the mucus and mechanical barriers, and upregulated the expressions of ZO-1 and claudin-1. ESA treatment obviously decreased CD86⁺ M1 polarization in the mesenteric lymph nodes of IBD mice and in LPS and IFN-γ-induced RAW264.7 cells, and significantly reduced p-JAK2 and p-STAT3 expressions in both the mouse models and RAW264.7 cells. Treatment with RO8191 caused reactivation of JAK2/STAT3 and strongly attenuated the inhibitory effect of ESA on CD86⁺ polarization in RAW264.7 cells. CONCLUSIONS ESA alleviates DSS-induced colitis in mice by suppressing JAK2/STAT3-mediated M1 macrophage polarization and mitigating inflammation-driven intestinal barrier damage.
Animals ; Mice ; Janus Kinase 2/metabolism* ; STAT3 Transcription Factor/metabolism* ; Mice, Inbred C57BL ; Male ; Dextran Sulfate ; Macrophages/cytology* ; Colitis/metabolism* ; Saponins/pharmacology* ; Signal Transduction/drug effects* ; RAW 264.7 Cells ; Triterpenes/pharmacology* ; Interleukin-6/metabolism*

Objective:To investigate the risk of falls in patients with Parkinson's disease and establish and validate a prediction model.Methods:We selected 372 patients with Parkinson's disease at Sichuan Nanchong Mental Health Centre from January 2022 to Septem-ber 2023.The patients were divided in a 7:3 ratio into model group(260 cases)and validation group(112 cases).According to previ-ous literature and suspected factors found in clinical practice,we collected general information(sex,age,etc.)and disease-related factors(the duration of Parkinson's disease,the type of medications taken,etc.)that may be associated with falls in patients with Parkinson's disease.In the model group,between patients with and those without falls within 1 year as reported by the patients or their family members,potential predictors for falls were determined through comparison of general information and disease-related factors,least absolute shrinkage and selection operator(LASSO)regression,and multivariable logistic regression.Based on the significant factors,a nomogram model was established and validated.Results:In the model group,81(31.15%)of the 260 patients experienced falls.According to the LASSO regression and multivariable logistic regression results,alcohol consumption,the type of medications,the score of the Unified Parkinson's Disease Rating Scale part Ⅲ(UPDRS-Ⅲ),the Berg Balance Scale score,the presence of arthritis,and the presence of osteoporosis were independent factors influenc-ing falls in patients with Parkinson's disease.The area under curve(AUC)of the receiver operator characteristic curve(ROC)for pre-dicting the risk of falls in patients with Parkinson's disease was 0.896(95%CI=0.856-0.935)in the model group and 0.883(95%CI=0.840-0.926)in the validation group.The calibration curve analysis results showed that the prediction curves of the model and valida-tion groups closely fitted the standard curves.The decision curve analysis results indicated that when the probability threshold for pre-dicting the fall risk in Parkinson's disease using the nomogram was 0.10-0.90,the net benefit rate of the patients was greater than 0.Conclusion:The risk of falls in patients with Parkinson's disease are mainly influenced by factors such as alcohol consumption and the type of medications.The nomogram model established in this study can be used to predict the fall risk in patients with Parkinson's disease.

Objective:To observe the effect of astragalus polysaccharides on liver injury in mice with viral hepatitis,and to investigate whether it can regulate the expression of nucleotide-binding oligomerization domain 1(NOD1)/receptor-interacting protein 2(RIP2)/nuclear factor-κB(NF-κB)immune inflammation mediated by signaling pathway plays a protective role in liver.Methods:Sixty female C3H/HeJ mice were divided into modeling group(50 mice)and normal group(10 mice)using a random number table.The mouse model of viral hepatitis was established by intraperitoneal injection of mouse hepatitis virus type 3(MHV-3)in the modeling group.After the successful modeling was confirmed,the surviving mice were divided into thymus peptide group(10 μg),astragalus polysaccharide low,medium and high dose groups(100,200,400 mg/kg astragalus polysaccharide lyophilized in 1 ml/100 g body weight saline)and model group by random number table.Model group and normal group were given the same amount of normal saline intraperitoneal injection,each group was given once a day for 1 month.Results:The model was confirmed by HE staining of liver tis-sue and detection of viral plaque.Compared with the normal group,the liver index,serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL)and tumor necrosis factor-α(TNF-α),IL-1β and IL-8,viral plaques in liver tissue,NOD1,RIP2 and NF-κB p65 expressions and p-NF-κB p65 level in the model group increased(P<0.05),and the liver tissue showed severe pathological changes.Compared with the model group,the liver indexes,serum ALT,AST,TBIL and TNF-α,IL-1β and IL-8,viral plaques in liver tissue,NOD1,RIP2 and NF-κB p65 expressions and p-NF-κB p65 level in the thymosin group and astragalus polysaccharide each 3-dose groups decreased(P<0.05),and the pathological changes of liver tissue were alleviated.The effect of astragalus polysaccharide was dose-dependent,and there were no significant differences in these indexes between thymosin group and astragalus polysaccharide medium dose group(P>0.05).Conclusion:Astragalus polysaccharides can improve the liver function of mice with viral hepatitis,reduce the inflammatory response and pathological changes of liver tissue,reduce the level of virus,specu-late and inhibit NOD1/RIP2/NF-κB pathway and down-regulate NOD1,RIP2 and NF-κB p65 expressions,inhibit p-NF-κB p65 level,and high dose of astragalus polysaccharide has the best effect,which is better than thymosin-α1.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

OBJECTIVE: To explore the effects of veno-venous extra corporeal carbon dioxide removal (V-V ECCO₂R) on local mechanical power and gas distribution in the lungs of patients with mild to moderate acute respiratory distress syndrome (ARDS) receiving non-invasive ventilation. METHODS: Retrospective research methods were conducted. Sixty patients with mild to moderate ARDS complicated with renal insufficiency who were transferred to the respiratory intensive care unit (RICU) through the 96195 platform critical care transport green channel from January 2018 to January 2020 at the collaborative hospitals of Henan Provincial People's Hospital were enrolled. According to different treatment methods, they were divided into a conventional treatment group and an ECCO₂R group, with 30 patients in each group. Both groups received standard treatments including primary disease treatment, airway management, and non-invasive ventilation. The conventional treatment group received bedside continuous renal replacement therapy (CRRT), and the ECCO₂R group received V-V ECCO₂R treatment. General information of patient such as gender, age, cause of disease, and acute physiology and chronic health evaluation II (APACHE II) were recorded; arterial blood gas analysis was performed before treatment and at 12 hours and 24 hours during treatment, recording arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂), and oxygenation index (PaO₂/FiO₂). Respiratory mechanics parameters [tidal volume, respiratory rate, maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP)] were recorded, and the rapid shallow breathing index (RSBI) was calculated; electrical impedance tomography (EIT) was used to measure regional of interest (ROI) values in different lung areas at 12 hours and 24 hours of treatment, and the pulmonary mechanical energy was calculated. RESULTS: The arterial blood gas analysis indicators, respiratory mechanics parameters, and pulmonary mechanical energy of patients in the conventional treatment group and ECCO₂R group improved significantly after 24 hours of treatment compared to 12 hours of treatment (all P < 0.05). The levels of PaCO₂, RSBI, total mechanical power, and non-dependent zone mechanical power in the ECCO₂R group were significantly lower than those in the conventional treatment group at both 12 hours and 24 hours during the treatment [PaCO₂ (mmHg, 1 mmHg ≈ 0.133 kPa): 44.03±2.96 vs. 49.96±2.50 at 12 hours, 41.65±3.21 vs. 48.53±2.33 at 24 hours; RSBI (times×min^-1×L^-1): 88.67±4.05 vs. 92.35±4.03 at 12 hours, 77.66±4.64 vs. 90.98±4.21 at 24 hours; total mechanical power (mJ): 10.40±1.15 vs. 12.93±1.68 at 12 hours, 11.13±1.18 vs. 14.05±1.69 at 24 hours; non-dependent zone mechanical power (mJ): 7.15±0.84 vs. 7.98±0.75 at 12 hours, 7.77±0.93 vs. 9.13±1.10 at 24 hours], and MEP and MIP in the ECCO₂R group were significantly higher than those in the conventional treatment group at both 12 hours and 24 hours during the treatment [MEP (cmH₂O, 1 cmH₂O ≈ 0.098 kPa): 89.88±5.04 vs. 86.09±5.57 at 12 hours, 96.57±2.59 vs. 88.66±2.98 at 24 hours; MIP (cmH₂O): 47.64±2.82 vs. 41.93±2.44 at 12 hours, 60.11±6.53 vs. 43.63±2.80 at 24 hours], the differences were statistically significant (all P < 0.05). CONCLUSIONS V-V ECCO₂R combined with non-invasive ventilation can effectively reduce the regional tidal volume, mechanical power, and respiratory rate in the non-gravitational dependent zones of patients with mild to moderate ARDS, and improve respiratory distress and oxygenation status.
Humans ; Respiratory Distress Syndrome/physiopathology* ; Retrospective Studies ; Carbon Dioxide ; Blood Gas Analysis ; Lung/physiopathology* ; Intensive Care Units ; Male ; Female ; Noninvasive Ventilation/methods* ; Continuous Renal Replacement Therapy/methods* ; APACHE ; Middle Aged