Buzhong Yiqi decoction attenuates acquired myasthenia by regulating the JAK2/STAT3/AKT signaling pathway, inhibiting inflammation, and improving mitochondrial function.

Acquired myasthenia (AM), a debilitating autoimmune disease, is typically characterized by skeletal muscle fatigue and weakness. Despite advances in myasthenia gravis treatment, current approaches remain unsatisfactory and many result in unexpected side effects. Traditional Chinese medicine has shown great potential in the treatment of myasthenia gravis, including relieving myasthenic symptoms, improving patients' quality of life, and reducing Western medicine side effects. This study investigates the protective effects and mechanism of BZYQD in mice with acquired myasthenia. BZYQD alleviates the reduced grip strength and increased expression of MAFbx and MuRF-1 in mice with acquired myasthenia. It also reduces levels of pro-inflammatory factors IL-1ß, IL-6, and TNF-α in the mouse serum. In addition, BZYQD reduces ROS accumulation and the mitochondrial ROS production rate, while increasing ATP levels and mitochondrial membrane potential in mice with acquired myasthenia. Moreover, BZYQD decreases the expression of p-JAK2, p-STAT3, and p-AKT in the skeletal muscle of mice with acquired myasthenia. In summary, BZYQD reduces inflammation, enhances mitochondrial function, and regulates the JAK2/STAT3/AKT signaling pathway to treat acquired myasthenia.

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69+CD103+CD8+ tissue-resident memory T cells in autoimmune hepatitis by regulating the JAK3/STAT3/P53 signalling pathway.

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.

CircMTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3.

Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.

Kinetic Heterogeneity Improves the Specificity of Dynamic Enhanced MRI in Differentiating Benign and Malignant Breast Tumours.

RATIONALE AND OBJECTIVES: To investigate whether kinetic heterogeneity in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) improves the specificity of breast cancer (BC) diagnosis. MATERIALS AND METHODS: The DCE-MRI data of patients with benign breast tumours and BC from June 2020 to July 2022 were retrospectively evaluated. MATLAB and SPM were used to determine six major kinetic parameters: peak, enhancement volume, heterogeneity, as well as persistent, plateau, and washout proportions. Continuous variables were compared using the Student's t-test or Mann-Whitney U tests, and categorical variables were compared using the chi-square or Fisher's exact tests. Receiver operating characteristic curves were plotted. The intraclass correlation coefficient (ICC) was used to evaluate agreement between the two observers. Multivariate logistic regression analysis was conducted to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for the association between benign and malignant breast tumours. RESULTS: In total, 147 patients (mean age, 47 years old) were included in the study, 76 of whom had BC. Data analysis by the two observers showed good consistency in the peak, enhancement volume, persistent proportion, plateau proportion, washout proportion, and heterogeneity, with ICCs of 0.865, 0.988, 0.906, 0.940, 0.740, and 0.867, respectively (p < 0.001). In the DCE kinetic analysis, differences in all the six kinetic parameters were statistically significant (p < 0.05). The area under the curve for heterogeneity was 0.92 (95% CI:0.88,0.97), and the sensitivity and specificity were 0.895 and 0.845, respectively. Multivariate logistic regression analysis showed that heterogeneity was an independent predictor of BC compared to benign breast tumours (OR=2.020; 95% CI:1.316, 3.100; p = 0.001). CONCLUSION: The kinetic heterogeneity of DCE-MRI can effectively distinguish between benign and malignant breast tumours and improve the specificity of BC diagnosis.

Comparison of the Utility of PI-RADS 2.1, ADC Values, and Combined Use of Both, for the Diagnosis of Transition Zone Prostate Cancers.

OBJECTIVE: To assess the performance of apparent diffusion coefficient (ADC; values or category) alone, Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) scoring alone, and the two in combination, to diagnose transition zone prostate cancers (PCas). METHODS: This retrospective study included 222 patients who underwent multiparametric magnetic resonance imaging of the prostate between May 2020 and December 2022 and who had pathologically confirmed PCa or benign prostatic hyperplasia (BPH). Prostate Imaging Reporting and Data System version 2.1 and ADC (values or category) were used in the assessment of suspicious findings identified in the transition zone. The interobserver agreements for region-of-interest measurements were calculated by intraclass correlation coefficients. Logistic regression analyses were used to determine the performance of PI-RADS v2.1 alone and in combination with ADC (values or category) to diagnose PCa. Receiver operating characteristic curve and DeLong test were used to evaluate the diagnostic performance of the quantitative parameters. RESULTS: A total of 152 patients had BPH, and 70 patients had PCa. For BPH versus PCa, the ADC values of PCa (0.64 × 10 -3 ± 0.16 × 10 -3 mm 2 /s) were significantly lower than BPH (1.06 ± 0.18 × 10 -3 mm 2 /s; P < 0.001). The PI-RADS scores for PCa (5 [interquartile range, 5-5]) were significantly higher than BPH (2 [interquartile range, 2-3]; P < 0.001). For all patients who had PI-RADS 1-5, the combined use of ADC (values or category) together with PI-RADS v2.1 did not perform significantly better than the use of PI-RADS v2.1 alone. The receiver operating characteristic of ADC category in combination with PI-RADS v2.1 score, 0.756 (95% confidence interval, 0.646-0.846), was significantly higher than that for PI-RADS 2.1 alone, 0.631 (95% confidence interval, 0.514-0.738), in PI-RADS 3-4 lesions ( P = 0.047). CONCLUSION: The ADC category can help to improve the diagnostic performance of PI-RADS v2.1 category 3-4 lesions in diagnosing PCa.

MTA2 is one of 14 Transcription factors predicting recurrence free survival in gastric cancer and promotes cancer progression by targeting MCM5.

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Transcription factors (TFs) are essential gene expression regulators, and play critical roles in cancer development. However, the biological actions and prognostic value of TFs in GC remain unclear. In this study, we identified a risk model based on a 14-TF signature to predict recurrence-free survival in patients with GC. We further analyzed the ability of 14-TF to predict recurrence-free survival time in GC and found that a higher expression level of metastasis-associated protein 2 (MTA2) was associated with shorter overall survival and disease-free survival time in GC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promotes GC growth and metastasis. Furthermore, we identified MTA2 binding to the promoter of minichromosome maintenance deficient 5 (MCM5), thereby promoting GC progression. Overall, these findings strongly support the prognostic potential of the 14-TFs signature and suggest that targeting MTA2 may be a promising strategy to treat GC.

Application Effect of Laparoscopic Myomectomy and Comprehensive Rehabilitation Nursing on Patients with Uterine Fibroids.

Background: Uterine fibroids are most common in women aged 30-50 and are the most common benign gynecological tumors. Relevant data suggest that about 25% of patients with uterine fibroids are at childbearing age. Uterine fibroids not only cause the discomfort symptoms, and affect the pregnancy, but also have certain malignant transformation risk, thus needed to be treated positively and promptly. Aim: This study is aimed at exploring the effect of laparoscopic myomectomy and comprehensive rehabilitation nursing on patients with uterine fibroids. Methods: The clinical data of 110 cases of uterine fibroids admitted to our hospital from August 2019 to December 2021 were analyzed retrospectively, and they were divided into two groups according to postoperative rehabilitation strategies. Both groups were treated with laparoscopic myomectomy. The A group was treated with routine rehabilitation strategy, while the B group was treated with comprehensive rehabilitation nursing strategy. The differences in operation-related indicators, stress factors, inflammatory factors, nutritional indicators, knowledge mastery, occurrence of adverse symptoms and pain scores, negative emotion scores, nursing satisfaction, and simplified comfort status scale (GCQ) scores between the two groups under nursing strategies were compared. Results: The postoperative exhaust time (13.14 ± 2.03) h, bed time (9.86 ± 1.94) h, postoperative hospital stay (4.37 ± 1.31) d, and total hospital stay (6.78 ± 1.69) d in the B group were shorter than those in the A group, and the hospitalization expenses (0.74 ± 0.25) million were less than those in the A group (P < 0.05). Before operation, stress factors, inflammatory factors, and nutritional indexes were compared between the two groups (P > 0.05). On the 3rd day after operation, tumor necrosis factor-α (TNF-α), cortisol (Cor), norepinephrine (NE), and interleukin-1ß (IL-1ß) in the two groups showed a significantly upward trend compared with those before operation, and albumin and transferrin were significantly fell compared with those before operation. However, the values of stress factor and inflammatory factor in the B group were significantly lower than those in the A group, and the values after the decrease of nutritional index were significantly higher than those in the A group (P < 0.05). The pain scores at 24 h, 48 h, and 72 h after operation in the B group were significantly lower than those in the A group (P < 0.05). Negative emotions, nursing satisfaction, and GCQ scores were compared between the two groups before intervention (P > 0.05). After the intervention, the scores of Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) in the two groups were significantly lower than those before the intervention, and the scores of nursing satisfaction and GCQ were higher than those before the intervention. The values of negative emotions in the B group after the decline were significantly lower than those in the A group, while the values of nursing satisfaction and GCQ after the increase were higher than those in the A group (P < 0.05). The excellent and good rate of knowledge acquisition in the B group was 94.55% (52/55), which was significantly higher than 78.18% (43/55) in the A group (P < 0.05). The incidence of adverse symptoms in the B group was 9.09% (5/55), which was lower than 21.82% (12/55) in the A group, while the difference was not statistically significant (P > 0.05). Conclusion: Laparoscopic myomectomy combined with comprehensive rehabilitation nursing can reduce the postoperative stress state of patients with uterine fibroids, improve patient satisfaction, reduce adverse emotions, and promote rehabilitation.

Novel parameter based on lipid indicators ratio improves prognostic value of plasma lipid levels in resectable colorectal cancer patients.

BACKGROUND: At present, the value of lipid indicators in evaluating the prognosis of colorectal cancer is still relatively limited. AIM: To evaluate the value of a novel parameter for colorectal cancer (CRC) prognosis scoring based on preoperative serum lipid levels. METHODS: Four key serum lipid factors, namely, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), were detected. Two representative ratios, HDL-C-LDL-C ratio (HLR) and ApoA1-ApoB ratio (ABR) were calculated. The relationship of these parameters with the prognosis of CRC patients including progression-free survival (PFS) and overall survival (OS) was analyzed by Kaplan-Meier plot and Cox proportional hazards regression. A novel lipoprotein cholesterol-apolipoprotein (LA) score based on HLR and ABR was established and its value in prognosis evaluation for CRC patients was explored. RESULTS: Multivariate Cox proportional hazards regression analysis of PFS and OS showed that HDL-C, ApoA1, HLR, and ABR were positively associated with the prognosis of CRC patients. LA score was independently associated with a good prognosis in resectable CRC patients. Data processing of a dummy variable showed that the prognosis of patients with higher LA scores is better than that with lower LA scores. CONCLUSION: The newly established LA score might serve as a better predictor of the prognosis of resectable CRC patients.

Alpinetin Attenuates Persistent Inflammation, Immune Suppression, and Catabolism Syndrome in a Septic Mouse Model.

Patients who survive the acute phase of sepsis can progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which usually results in extended recovery periods and multiple complications. Alpinetin is a flavonoid isolated from Alpinia katsumadai Hayata that has been demonstrated to have anti-inflammatory, antibacterial, and antioxidant activities. The aim of this study was to investigate whether the administration of alpinetin could attenuate PICS in a septic mouse model. Mice were randomly divided into four groups: the (1) sham-operated group, (2) sham+alpinetin (1 mg/kg intravenously infused for once per day after sham operation), (3) cecal ligation and puncture (CLP), and (4) CLP+alpinetin (50 mg/kg intravenously infused for once per day after CLP). Eight days after sham operation or CLP surgery, mice were euthanized for subsequent examination. Alpinetin significantly improved the survival of septic mice. Also, it attenuated the CLP-induced persistent inflammation, immunosuppression, and catabolism syndrome. The level of plasma proinflammatory cytokines and apoptosis of T lymphocytes were obviously decreased by alpinetin as well. Moreover, oxidative stress in the organs was compelling lower in the alpinetin-treated CLP mice. In this clinically relevant model of sepsis, alpinetin ameliorates CLP-induced organ dysfunction and improves the likelihood of survival, possibly through suppressing the inflammatory response, oxidative stress, and apoptosis. These findings suggested that alpinetin could be a potential novel therapeutic approach to prevent sepsis-induced PICS.