Objective To investigate the protective effect and underlying mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exo) on renal ischemia-reperfusion injury (IRI). Methods hucMSC-Exos were isolated and characterized. A mouse renal IRI model was established and the animals were divided into Sham, IRI, IRI+hucMSC-Exo, IRI+hucMSC-Exo+JY-2 and Sham+JY-2 groups. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. Hematoxylin-eosin (HE) staining was used to evaluate renal histopathology. Enzyme-linked immune absorbent assay was performed to determine serum interleukin (IL)-1β and IL-18 levels. Western blotting was used to detect the expression of activating transcription factor 3 (ATF3), Toll-like receptor 4 (TLR4), nuclear factor (NF)-κB, NOD-like receptor protein 3 (NLRP3), cysteineyl aspartate specific proteinase (Caspase)-1 p20 and Gasdermin D(GSDMD). Real-time fluorescent quantitative polymerase chain reaction was employed to measure ATF3, TLR4 and NF-κB messenger RNA (mRNA). Immunohistochemistry was conducted to examine NLRP3, Caspase-1 p20 and GSDMD. An in vitro hypoxia/reoxygenation (H/R) model was established in HK-2 cells and divided into Control, H/R, H/R+hucMSC-Exo, H/R+hucMSC-Exo+JY-2 and Control+JY-2 groups. Western blotting was used to detect the expression of ATF3, TLR4 and NF-κB. Real-time fluorescent quantitative polymerase chain reaction was used to measure NLRP3, GSDMD and Caspase-1 mRNA. Results HucMSC-Exos were successfully isolated and identified. Compared with the Sham group, the IRI group exhibited elevated Scr and BUN, higher tubular injury scores, increased protein expression levels of ATF3, TLR4, NF-κB p65, NLRP3, Caspase-1 p20 and GSDMD, and raised mRNA expression levels of ATF3, TLR4, NF-κB. Compared with the IRI group, the IRI+hucMSC-Exo group showed decreased Scr and BUN, lower tubular injury scores, up-regulated ATF3 protein and mRNA, down-regulated TLR4, NF-κB p65, NLRP3, Caspase-1 p20 and GSDMD protein, and declined TLR4 and NF-κB mRNA. Compared with the IRI+hucMSC-Exo group, the IRI+hucMSC-Exo+JY-2 group exhibited increased Scr and BUN levels, elevated renal tubular injury scores, decreased ATF3 protein expression levels, elevated protein expression levels of TLR4, NF-κB p65, NLRP3, Caspase-1 p20, and GSDMD, decreased ATF3 mRNA expression levels, and elevated mRNA expression levels of TLR4 and NF-κB. (all P < 0.05). Compared with the Control group, the expression levels of ATF3, TLR4 and NF-κB p65 proteins were increased in the H/R group, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were increased. Compared with the H/R group, the expression level of ATF3 protein was increased, the expression levels of TLR4 and NF-κB p65 proteins were decreased, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were decreased in the H/R+hucMSC-Exo group. Compared with the H/R+hucMSC-Exo group, the expression level of ATF3 protein was decreased, the expression levels of TLR4 and NF-κB p65 proteins were increased, and the expression levels of NLRP3, Caspase-1 and GSDMD mRNA were increased in the H/R+hucMSC-Exo+JY-2 group (all P < 0.05). Conclusions HucMSC-Exos alleviate renal IRI by up-regulating ATF3, thereby negatively regulating the TLR4/NF-κB signaling pathway and subsequently inhibiting pyroptosis.

BACKGROUND:Acupuncture at Xinshu(BL 15)can significantly improve cardiac function and protect myocardial cells in acute myocardial ischemia,but the effect and mechanism of thread embedding treatment at Xinshu(BL 15)on cardiac function in acute myocardial ischemia are yet unclear.Nuclear factor κB activation often appears as an intranuclear translocation of the P65 isoform,and activation of the nuclear factor κB signaling pathway is marked by elevated P65 levels.OBJECTIVE:To explore the effects of thread embedding pretreatment at Xinshu(BL 15)on cardiac function and the expression levels of interleukin-10,tumor necrosis factor-α,P65 genes and proteins in rats with acute myocardial ischemia.METHODS:Thirty-two male Sprague-Dawley rats were randomly divided into a blank group,a model group,a Xinshu(BL 15)acupoint group,and a non-meridian/non-acupoint group using a random number table method,with eight rats in each group.Rat models of acute myocardial ischemia were established in the latter three groups.The Xinshu(BL 15)acupoint group had thread embedding at Xinshu(BL 15)for 14 days,followed by subcutaneous injection of isoproterenol hydrochloride into the back to establish an acute myocardial ischemia rat model.The non-meridian/non-acupoint group had local thread embedding for 14 days,and the rest procedures were the same as above.In the model group,Xinshu(BL 15)was only marked,and the rest procedures were the same as above.In the blank group,Xinshu(BL 15)was only marked,and then an equal amount of physiological saline was injected subcutaneously into the back.After 24 hours of modeling,electrocardiogram and cardiac ultrasound were performed.Abdominal aorta blood was extracted for detection of serum creatine kinase and creatine kinase isoenzyme levels using enzyme-linked immunosorbent assay.Subsequently,the rats were euthanized and samples were collected.Hematoxylin-eosin and TUNEL staining were used to observe the pathological changes of myocardial tissue and the apoptosis of myocardial cells.Real-time fluorescence quantitative PCR(RT-qPCR)and western blot were used to detect the mRNA and protein expression of tumor necrosis factor-α,interleukin-10,and P65 in myocardial tissue respectively.RESULTS AND CONCLUSION:(1)Electrocardiogram:Compared with the blank group,the model group,non-meridian/non-acupoint group,and Xinshu(BL 15)acupoint group had significantly elevated ST segment in lead Ⅱ of the electrocardiogram.(2)Cardiac ultrasound:Compared with the model group,the Left ventricular end-systolic dimension in the Xinshu(BL 15)acupoint group were significantly reduced(P＜0.05),while left ventricular ejection fraction and left ventricular fractional shortening rate were significantly increased(P＜0.05).(4)Serum creatine kinase and creatine kinase isoenzyme:Compared with the model group,the Xinshu(BL 15)acupoint group showed a significant decrease in serum creatine kinase and creatine kinase isoenzyme levels(P＜0.05).(4)Hematoxylin-eosin staining:Compared with the model group,the arrangement of myocardial fibers in the Xinshu(BL 15)acupoint group was basically neat,with less edema and a small amount of inflammatory cell infiltration.(5)TUNEL staining:Compared with the model group,the fluorescence intensity of myocardial cell apoptosis in the Xinshu(BL 15)acupoint group was significantly reduced,and its apoptosis rate was significantly reduced(P＜0.05).(6)RT-qPCR and western blot:Compared with the model group,the myocardial tissue interleukin-10 level in the Xinshu(BL 15)acupoint group was significantly increased(P＜0.05),while tumor necrosis factor-α and P65 levels were significantly decreased(P＜0.05).These findings indicate that thread embedding pretreatment at Xinshu(BL 15)can improve cardiac function in rats with acute myocardial ischemia,and its mechanism of action may be related to the inhibition of the activation of the nuclear factor-κB signaling pathway.

BACKGROUND:Acupuncture at Xinshu(BL 15)can significantly improve cardiac function and protect myocardial cells in acute myocardial ischemia,but the effect and mechanism of thread embedding treatment at Xinshu(BL 15)on cardiac function in acute myocardial ischemia are yet unclear.Nuclear factor κB activation often appears as an intranuclear translocation of the P65 isoform,and activation of the nuclear factor κB signaling pathway is marked by elevated P65 levels.OBJECTIVE:To explore the effects of thread embedding pretreatment at Xinshu(BL 15)on cardiac function and the expression levels of interleukin-10,tumor necrosis factor-α,P65 genes and proteins in rats with acute myocardial ischemia.METHODS:Thirty-two male Sprague-Dawley rats were randomly divided into a blank group,a model group,a Xinshu(BL 15)acupoint group,and a non-meridian/non-acupoint group using a random number table method,with eight rats in each group.Rat models of acute myocardial ischemia were established in the latter three groups.The Xinshu(BL 15)acupoint group had thread embedding at Xinshu(BL 15)for 14 days,followed by subcutaneous injection of isoproterenol hydrochloride into the back to establish an acute myocardial ischemia rat model.The non-meridian/non-acupoint group had local thread embedding for 14 days,and the rest procedures were the same as above.In the model group,Xinshu(BL 15)was only marked,and the rest procedures were the same as above.In the blank group,Xinshu(BL 15)was only marked,and then an equal amount of physiological saline was injected subcutaneously into the back.After 24 hours of modeling,electrocardiogram and cardiac ultrasound were performed.Abdominal aorta blood was extracted for detection of serum creatine kinase and creatine kinase isoenzyme levels using enzyme-linked immunosorbent assay.Subsequently,the rats were euthanized and samples were collected.Hematoxylin-eosin and TUNEL staining were used to observe the pathological changes of myocardial tissue and the apoptosis of myocardial cells.Real-time fluorescence quantitative PCR(RT-qPCR)and western blot were used to detect the mRNA and protein expression of tumor necrosis factor-α,interleukin-10,and P65 in myocardial tissue respectively.RESULTS AND CONCLUSION:(1)Electrocardiogram:Compared with the blank group,the model group,non-meridian/non-acupoint group,and Xinshu(BL 15)acupoint group had significantly elevated ST segment in lead Ⅱ of the electrocardiogram.(2)Cardiac ultrasound:Compared with the model group,the Left ventricular end-systolic dimension in the Xinshu(BL 15)acupoint group were significantly reduced(P＜0.05),while left ventricular ejection fraction and left ventricular fractional shortening rate were significantly increased(P＜0.05).(4)Serum creatine kinase and creatine kinase isoenzyme:Compared with the model group,the Xinshu(BL 15)acupoint group showed a significant decrease in serum creatine kinase and creatine kinase isoenzyme levels(P＜0.05).(4)Hematoxylin-eosin staining:Compared with the model group,the arrangement of myocardial fibers in the Xinshu(BL 15)acupoint group was basically neat,with less edema and a small amount of inflammatory cell infiltration.(5)TUNEL staining:Compared with the model group,the fluorescence intensity of myocardial cell apoptosis in the Xinshu(BL 15)acupoint group was significantly reduced,and its apoptosis rate was significantly reduced(P＜0.05).(6)RT-qPCR and western blot:Compared with the model group,the myocardial tissue interleukin-10 level in the Xinshu(BL 15)acupoint group was significantly increased(P＜0.05),while tumor necrosis factor-α and P65 levels were significantly decreased(P＜0.05).These findings indicate that thread embedding pretreatment at Xinshu(BL 15)can improve cardiac function in rats with acute myocardial ischemia,and its mechanism of action may be related to the inhibition of the activation of the nuclear factor-κB signaling pathway.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, characterized by poor prognosis due to its high proliferative and invasive potential. Tumor metabolic reprogramming, particularly involving glucose metabolism, is essential for tumor survival. This study investigates the role of the Hippo pathway effector transcriptional co-activator with PDZ-binding motif (TAZ) in regulating gluconeogenesis and promoting tumorigenesis in HCC. Methods: TAZ expression in HCC was analyzed using The Cancer Genome Atlas data and validated in clinical samples and cell lines. TAZ was overexpressed or silenced in HCC cell lines to evaluate its effects on cell proliferation, apoptosis, migration, and invasion. The expression and prognostic relevance of the gluconeogenesis-related genes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) were examined, along with their correlation with TAZ expression. Tumor growth was assessed in nude mice. Interactions between TAZ and the glucocorticoid receptor (GR) were investigated using co-immunoprecipitation, immunofluorescence, and chromatin immunoprecipitation assays. Results: TAZ was significantly upregulated in HCC tissues and cell lines. TAZ overexpression enhanced proliferation, reduced apoptosis, and promoted migration and invasion. In contrast, PCK1 and G6PC were downregulated in HCC and showed a negative correlation with TAZ expression. Conclusion TAZ modulates gluconeogenesis and accelerates tumor growth, whereas its knockdown attenuates tumor progression. TAZ interacts with GR, suppressing its transcriptional activity on gluconeogenic gene promoters.

Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.
Methicillin-Resistant Staphylococcus aureus/genetics* ; Anti-Bacterial Agents/chemistry* ; Naphthoquinones/administration & dosage* ; Animals ; Microbial Sensitivity Tests ; Mice ; Humans ; Staphylococcal Infections/microbiology* ; Molecular Structure

Objective To analyze the proportion and clinicopathological characteristics of HER2-positive breast cancer patients with BRCA1/2 pathogenic variants, and their response to neoadjuvant anti-HER2 targeted therapy. Methods The clinicopathological data of 531 breast cancer patients with germline BRCA1/2 pathogenic variants (201 with BRCA1 variants and 330 with BRCA2 variants) were analyzed. Results Among the 201 BRCA1 and 330 BRCA2 variants, 17 (8.5%) and 42 (12.7%) HER2-positive breast cancer cases were identified, respectively, accounting for 11.1% of all BRCA1/2-mutated breast cancers. Compared with BRCA1/2-mutated HR-positive/HER2-negative patients, HER2-positive patients did not present any significant differences in clinicopathological features; however, compared with triple-negative breast cancer patients, HER2-positive patients had a later onset age and lower tumor grade. Among the 17 patients who received neoadjuvant anti-HER2 targeted therapy, 10 cases achieved pCR (58.8%), whereas 7 cases did not (41.2%). Conclusion HER2-positive breast cancer accounts for more than 10% of BRCA1/2-mutated patients. Approximately 40% of these patients fail to achieve pCR after neoadjuvant targeted therapy. This phenomenon highlights the possibility of combining anti-HER2 targeted agents with poly (adenosine diphosphate-ribose) polymerase inhibitors.

Objective:To explore the application value of radiomics, deep learning, and their combined models in predicting the efficacy of radioiodine adjuvant therapy in patients with papillary thyroid cancer (PTC).Methods:A retrospective analysis was conducted on the clinical and imaging data of 131 PTC patients (38 males, 93 females; age 41(33, 48) years) who received first 131I treatment at the Affiliated Hospital of Guilin Medical University from January 2018 to March 2023. Patients were randomly divided into a training set ( n=105) and a test set ( n=26) at the ratio of 8∶2. Multivariate logistic regression analysis was used to screen clinical features to determine independent predictors affecting the efficacy of 131I therapy. Radiomics and deep learning features were extracted from the enhanced CT scans and were combined by using the extremely randomized trees (ExtraTrees) algorithm to construct radiomics, deep learning, and combined models. The predictive abilities of the models were evaluated by AUC, and the Delong test was applied to compare the difference between AUCs. Results:Higher pre-ablation stimulated thyroglobulin (ps-Tg) levels (odds ratio( OR)=1.060, 95% CI: 1.025-1.095, P=0.004) and bilateral lesions ( OR=5.085, 95% CI: 1.452-17.814, P=0.033) were independent predictors of the efficacy of 131I therapy in intermediate to high-risk PTC patients. In the training set, the radiomics model (AUC=0.853) and combined model (AUC=0.880) significantly outperformed the deep learning model (AUC=0.711; Z values: 2.48, 3.09, P values: 0.013, 0.002), while there was no statistically significant difference between the radiomics and combined models ( Z=0.51, P=0.610). In the test set, AUCs of the radiomics, deep learning, and combined models were 0.746, 0.624, and 0.876, respectively, and the AUC of the combined model was higher than that of the radiomics model or deep learning model ( Z values: 2.05, 1.99, P values: 0.040, 0.047). Conclusion:The combined model demonstrates superior performance over the standalone radiomics model and deep learning model in predicting the efficacy of 131I treatment in PTC patients.

Objective:To compare the antitumor effects of FLASH irradiation(FLASH-RT) and conventional irradiation (CONV-RT) in murine breast cancer models, alongside analyzing metabolites and metabolic pathways impacted by each treatment.Methods:Female BALB/c mice bearing breast cancer tumors were randomly assigned to three groups: FLASH-RT(625 Gy/s, 23.64 Gy), CONV-RT(0.54 Gy/s, 21.33 Gy), and Sham-RT(0 Gy/s), with single irradiation. Tumor volumes were monitored over two weeks, after which mice were euthanized, and tumor samples were collected for metabolomic analysis.Results:Statistical analysis indicated no significant difference in body weight changes between mice receiving FLASH and conventional irradiation ( P>0.05). However, compared with the sham-irradiation group, both FLASH-RT ( P<0.05) and CONV-RT ( P<0.05) resulted in statistically significant differences in tumor volume changes, demonstrating effective tumor growth suppression by both radiotherapy regimens. Metabolomic analysis revealed that FLASH-RT significantly downregulated levels of the unsaturated fatty acid oleic acid (VIP=1.867, FC=0.091) and the lipid metabolite cardiolipin (VIP=1.373, FC=0.419), while upregulating the saturated fatty acid palmitic acid(VIP=1.592, FC=3.234 3)and the lipid metabolite phosphatidylcholine(VIP=2.784, FC=4.116). Differential metabolites were predominantly enriched in lipid metabolism and amino acid metabolism pathways, suggesting energy metabolic reprogramming and membrane structural remodeling in the tumor model. Pathway enrichment analysis demonstrated significant perturbation in the glycerophospholipid metabolism pathway (KEGG pathway P<0.01), with its associated metabolite phosphatidylcholine (VIP=2.784) showing a marked increase, reaching 4.12-fold higher levels compared to the CONV-RT group..This metabolic dysregulation may reflect altered tumor cell membrane fluidity or aberrant signal transduction. Conclusions:Both FLASH-RT and CONV-RT effectively inhibit tumor growth in murine breast cancer models, with FLASH-RT exhibiting distinct immunomodulatory metabolic characteristics, and the FLASH-RT shows the clinical potential in breast cancer therapy.

Epidermal growth factor receptor inhibitor (EGFRI) -related paronychia is a condition clearly related to EGFRI therapy, characterized by periungual erythema, edema, purulent exudates, periungual or subungual granulomatous lesions, and sometimes accompanied by thinning, fragility or even splitting and seperation of nail plates. Inhibition of epidermal function, inflammation and secondary infections, as well as angiogenesis are the core processes in the occurrence and development of EGFRI-related paronychia. This review summarizes epidemiology, pathogenesis, clinical manifestations, prevention and treatment of EGFRI-related paronychia.

In order to understand the epidemic situation of European porcine reproductive and re-spiratory syndrome virus 1(PRRSV1)in Henan Province,molecular epidemiological investigation and virus identification were conducted on clinical specimens from some large-scale pig farms in Henan Province.RT-PCR detection and sequencing were carried out using specific primers for PRRSVI ORF5 gene.As a result,eight PRRSV1 positive samples were detected with six ORF5 gene sequences and one full gene sequence obtained.A strain of PRRSVI named as HENZMD-10 was successfully isolated using PAM cells.Based on the genetic variation analysis,the six ORF5 genes obtained were all PRRSVI.The isolated strains have relatively large ORF5 gene genetic vari-ation,belonging to different branches on the genetic evolution tree.Among them,HENJZ-11,HENJY-7,and HENJY-8 were relatively close in genetic evolution and belonged to the same branch.The genome length of HENZMD-10 isolate was 15 071 bp.Alignment analysis showed that HENZMD-10 strain shared an 89.1％of nucleotide sequence with the LV strain;62.1％and 61.5％with PRRSV2 ATCC-VR2332 strain and the American NADC30 strain,respectively.The nucleotide similarity of HENZMD-10 strain with the domestic JXA1 strain was 61.6％.The phylo-genetic analysis using complete genome sequence showed that HENZMD-10 strain was relatively close to the domestic isolated PRRSV1 NVDC-NM1-2011,LNEU12 and FJEU13 strains.The suc-cessful isolation of one PRRSV1 strain in Henan Province provides the basis for understanding the epidemic dynamics and prevention and control of PRRSV1 in China.