Diterpenoids from Acanthopanacis Cortex and their anti-inflammatory activity studies.

Acanthopanacis Cortex (A.-C) with a long history of more than1000 years, has been used to treat rheumatism effectively. Nineteen diterpenoids have been isolated from A.-C, including six new compounds (1-6). Among them, compounds 7, 9-11, 13, and 17 were discovered from A.-C for the first time. The structures of 1-6 were determined by analyzing their NMR data and comparing their experimental and calculated electronic circular dichroism spectra. Moreover, the single-crystal X-ray diffraction data of 1, 2, 8, and 14 were provided. The anti-inflammatory activity of 1-5 and 7-18 on neutrophil elastase, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) has been studied in vitro, and the results showed that 15 had almost no inhibitory effects on COX-1 at 200 µM but a significant activity against COX-2 with an IC50 of 0.73 ± 0.006 µΜ. It indicated that compound 15 can provide valuable information for the design of selective COX-2 inhibitors.

UHPLC-PDA-Q-TOF-MS-α-amylase-FLD activity detection system and molecular docking.

INTRODUCTION: Traditional and some scientific literature document the antidiabetic effects of the Ziziphi Spinosae Semen (ZSS). However, the bioactive compounds of ZSS responsible for the antidiabetic effects are not well known. OBJECTIVES: This study aimed to investigate the material basis of the antidiabetic effects of ZSS by inhibiting α-amylase. METHODOLOGY: An online analysis platform was established and optimized using an ultra-performance liquid chromatography-photo-diode array-quadrupole-time-of-flight-mass spectrometry-α-amylase-fluorescence detector (UHPLC-PDA-Q-TOF-MS-α-amylase-FLD) system to screen α-amylase inhibitors in ZSS rapidly. The inhibitory effect of these compounds was confirmed by molecular docking screening. and the molecular interactions between α-amylase and active compounds were evaluated, which strongly supported the experimental results. RESULTS: Seventy-eight compounds were identified in the ZSS extract, eleven of which were screened to have significant α-amylase binding activity. CONCLUSION: This study demonstrated the feasibility of using an established platform to screen for effective components in ZSS, providing a practical method for the rapid screening of potential antidiabetic active ingredients in traditional Chinese medicine.

Radiation-based immunogenic vaccine combined with a macrophage "checkpoint inhibitor" for boosting innate and adaptive immunity against metastatic colon cancers.

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors. Especially, X-ray- induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants. However, we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines, which can specifically bind with the MerTK receptor on macrophages, acting as a "checkpoint" to facilitate immune silence in the tumor microenvironment. Therefore, we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250, a macrophage MerTK "checkpoint inhibitor," for treating peritoneal carcinomatosis in colon cancer. By incorporating UNC2250 into the treatment regimen, immunosuppressive efferocytosis of macrophages, which relies on MerTK-directed recognition of phosphatidylserine on vaccines, was effectively blocked. Consequently, the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages, thereby simultaneously eliciting robust adaptive and innate immunity. This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

Age affects vascular morphology and predictiveness of anatomical landmarks for aortic zones in trauma patients: implications for resuscitative endovascular balloon occlusion of the aorta.

PURPOSE: Understanding the vascular morphology is fundamental for resuscitative endovascular balloon occlusion of the aorta. This study aimed to evaluate the effect of aging on length and diameter of aorta and iliac arteries in trauma patients, and to investigate the predictiveness of anatomical landmarks for aortic zones. METHODS: A total of 235 patients in a regional trauma center registry from September 1, 2018, to January 3, 2024, participated in the study. Reconstruction of computed tomography was applied to the torso area. The marginal diameter and length of aorta and iliac arteries were measured. Anatomical landmark distances and aortic marginal lengths were compared. RESULTS: The length and diameter of aorta and iliac arteries increased with age, and a tortuous and enlarged morphology was observed in older patients. There was a good regression between age and diameter of the aorta. Neither the jugular notch, the xiphisternal joint, nor the umbilicus could reliably represent specific margins of aortic zones. The distance between the mid-sternum and femoral artery (427 ± 25 to 442 ± 25 mm for right, and 425 ± 28 to 440 ± 26 mm for left) was predictive for zone 1 in all groups. The distance between the lower one-third junction of the xiphisternum to the umbilicus and femoral artery (232 ± 19 to 240 ± 17 mm for right, and 229 ± 20 to 237 ± 19 mm for left) was predictive for zone 3 aorta. CONCLUSION: Aging increases the length and diameter of aorta and iliac arteries, with a tortuous and enlarged morphology in geriatric populations. The mid-sternum and the lower one-third junction of the xiphisternum to the umbilicus were predictive landmarks for zone 1 and zone 3, respectively.

Knockdown of Ubiquitin-Conjugating Enzyme E2 T Abolishes the Progression of Head and Neck Squamous Cell Carcinoma by Inhibiting NF-Κb Signaling and inducing Ferroptosis.

BACKGROUND: Ubiquitin-conjugating enzyme 2T (UBE2T) has been reported to be associated with uncontrolled cell growth and tumorigenesis in multiple cancer types. However, the understanding of its regulatory role in the carcinogenesis of Head And Neck Squamous Cell Carcinoma (HNSC) is limited. METHODS: UBE2T expression in HNSC patient samples and the correlation between its expression and patients' survival rates were evaluated using The Cancer Genome Atlas (TCGA) database. Cell survival and proliferation were investigated in UM-SCC1 and UM-SCC15 cells infected with control and shUBE2T lentivirus. The xenograft mouse model was established using UM-SCC15 cells to examine HNSC tumorigenesis with or without UBE2T. Western blot, qRT-PCR, and ferroptosis assays were carried out to disclose the interaction between UBE2T and NF-κB signaling and ferroptosis. RESULTS: The increased expression of UBE2T was noted in tumor tissues of patients with HNSC, correlating with a significantly reduced overall survival time in this patient cohort. Knockdown of UBE2T inhibited HNSC tumorigenesis and tumor growth. Mechanistically, inhibition of UBE2T suppressed NF-ΚB signaling and induced ferroptosis in HNSC. CONCLUSION: Our study underscores the multifaceted role of UBE2T in HNSC, illuminating its potential as a biomarker and therapeutic target.

Assessment of the Significance and Clinical Implications of Stress Hormones in Acute Pressure Injuries Among Trauma Patients.

Objective: This study examines the dynamic changes of stress hormones, including insulin (INS), fasting blood glucose (FBG), glucagon (Glu), and cortisol (Cort), in trauma patients. By monitoring these changes and observing acute pressure injury (API) occurrences on the skin, the research analyzes the influence of stress hormones on API development in trauma patients. Methods: A prospective analysis involved 218 trauma patients admitted to a grade III-A general hospital in Wenzhou from April 2021 to June 2023. Among them, 44 cases developed API (API group), and 174 cases did not (control group). Levels of INS, Cort, Glu, and FBG were measured in both groups. Additionally, Abbreviated Injury Scale-Injury Severity Score (AIS-ISS) surveys and API severity assessments were conducted. Correlations between stress hormone levels and AIS-ISS were discussed. The predictive effects of AIS-ISS and stress hormones on API occurrence in trauma patients were analyzed using receiver operating characteristic (ROC) curves. The relationship between stress hormone levels and API severity was also observed. Results: Study's outcomes indicated distinct relationships between stress hormone levels and API occurrence in trauma patients. Specifically, INS demonstrated a negative correlation with AIS-ISS, highlighting its potential as a significant factor. Glu, Cort, and FBG revealed positive associations, emphasizing their roles in influencing API development (P < .05). The diagnostic efficacy of stress hormones in predicting API occurrence, as represented by the Area Under Curve (AUC) = 0.8100. Notably, within the API group, INS levels demonstrated a decline with worsening API. Conversely, Glu, Cort, and FBG exhibited increases in tandem with the aggravation of API symptoms (P < .05). Conclusions: This research suggests that assessing stress hormone levels in clinical settings can effectively predict API occurrence. Early testing could aid in the development of preventive or intervention measures, reducing the incidence and harm of API in trauma patients.

Comparison of diffusion ranges at different local anesthetic volumes during superior laryngeal nerve block.

OBJECTIVES: Ultrasound-guided superior laryngeal nerve (SLN) block is a practical and painless approach to avoid the hemodynamic stress response during endotracheal intubation and relieve sore throat after laryngeal surgery. The main purpose of this study was to establish an optimal dosage of local anesthetic when performing SLN block to help anesthetists balance analgesia and side effects. METHODS: Twenty fresh larynx specimens were obtained immediately after resection and then injected with 2-, 3-, 4-, or 5- mL of a lidocaine-blue dye mixture at bilateral SLN puncture sites. Superficial areas of deposited blue dye were measured. Dye leakage and surrounding dyed tissue were recorded. Another 40 patients were included in the ultrasound investigation. Distances between the internal branch of the SLN (iSLN) and adjacent structures were calculated. RESULTS: The dye spread area was greater with the administration of larger doses, especially to the visceral space. A 2- or 3-mL injection of local anesthetic was sufficient to infiltrate the SLN gap. A higher incidence of dye leaking out of the thyrohyoid membrane and anterior epiglottis space was observed; furthermore, there was substantially more dyed hyoid/thyroid cartilage with 4 and 5 mL of injected dye mixture than 2 mL. There was no significant difference between the specimen and ultrasound measurements of for length of iSLN-adjacent structures. CONCLUSIONS: In the Chinese population, 2- or 3- mL of local anesthetic is a safe dose during SLN block. A larger volume could overflow from the cavity to cause complications. The thyrohyoid membrane combined with the superior laryngeal artery is a reliable target for positioning the iSLN during ultrasound-guided regional anesthesia.

Mitochondrial-Targeted Metal-Phenolic Nanoparticles to Attenuate Intervertebral Disc Degeneration: Alleviating Oxidative Stress and Mitochondrial Dysfunction.

As intervertebral disc degeneration (IVDD) proceeds, the dysfunctional mitochondria disrupt the viability of nucleus pulposus cells, initiating the degradation of the extracellular matrix. To date, there is a lack of effective therapies targeting the mitochondria of nucleus pulposus cells. Here, we synthesized polygallic acid-manganese (PGA-Mn) nanoparticles via self-assembly polymerization of gallic acid in an aqueous medium and introduced a mitochondrial targeting peptide (TP04) onto the nanoparticles using a Schiff base linkage, resulting in PGA-Mn-TP04 nanoparticles. With a size smaller than 50 nm, PGA-Mn-TP04 possesses pH-buffering capacity, avoiding lysosomal confinement and selectively accumulating within mitochondria through electrostatic interactions. The rapid electron exchange between manganese ions and gallic acid enhances the redox capability of PGA-Mn-TP04, effectively reducing mitochondrial damage caused by mitochondrial reactive oxygen species. Moreover, PGA-Mn-TP04 restores mitochondrial function by facilitating the fusion of mitochondria and minimizing their fission, thereby sustaining the vitality of nucleus pulposus cells. In the rat IVDD model, PGA-Mn-TP04 maintained intervertebral disc height and nucleus pulposus tissue hydration. It offers a nonoperative treatment approach for IVDD and other skeletal muscle diseases resulting from mitochondrial dysfunction, presenting an alternative to traditional surgical interventions.

Ubiquitylation of RUNX3 by RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, but the early diagnosis rate is low. The RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in several cancers but its mechanism of action in LUAD is unclear. In this study, the biological activity of MEX3C was assessed in LUAD. MEX3C and RUNX3 mRNA levels in the tissues of LUAD patients were determined using reverse transcription­quantitative PCR. The involvement of MEX3C in the growth and metastasis of LUAD cells was measured by EdU assay, CCK-8, colony formation, Transwell assay, TUNEL, and flow cytometry. Expression of apoptosis and epithelial-mesenchymal transition related proteins were determined using western blotting analysis. LUAD cells transfected with si-MEX3C were administered to mice subcutaneously to monitor tumor progression and metastasis. We found that MEX3C is strongly upregulated in LUAD tissue sections, and involved in proliferation and migration. A549 and H1299 cells had significantly higher levels of MEX3C expression compared to control HBE cells. Knockdown of MEX3C dramatically decreased cell proliferation, migration, and invasion, and accelerated apoptosis. Mechanistically, we demonstrate MEX3C induces ubiquitylation and degradation of tumor suppressor RUNX3. Moreover, RUNX3 transcriptionally represses Suv39H1, as revealed by RNA pull-down and chromatin immunoprecipitation assays. The in vivo mice model demonstrated that knockdown of MEX3C reduced LUAD growth and metastasis significantly. Collectively, we reveal a novel MEX3C-RUNX3-Suv39H1 signaling axis driving LUAD pathogenesis. Targeting MEX3C may represent a promising therapeutic strategy against LUAD.

Association between oxidative balance score and frailty in chronic obstructive pulmonary disease.

Background: Oxidative stress is associated with frailty and adverse outcomes in chronic obstructive pulmonary disease (COPD). The oxidative balance score (OBS) assesses oxidative stress from diet and lifestyle, with higher OBS indicating more antioxidants than oxidants. A cross-sectional study was conducted to investigate the potential association between OBS and frailty in US adults with COPD. Methods: A total of 1201 COPD subjects from the National Health and Nutrition Examination Survey (NHANES 1999-2018) were assessed for frailty using the Frailty Index. OBS, consisting of 20 dietary and lifestyle factors, was the exposure variable. Weighted multiple logistic regression, subgroup analysis, and restricted cubic spline curves were used to assess the association between OBS and frailty. Results: Compared with the lowest OBS reference group (Q1), the adjusted odds ratios (ORs) for the highest quartile group (Q4) for OBS, dietary OBS, and lifestyle OBS were 0.41 (95% CI: 0.19-0.92), 0.37 (95% CI: 0.20-0.71), and 0.41 (95% CI: 0.24-0.71), respectively. All trend p-values were less than 0.05. Subgroup and RCS analyses revealed a negative linear association between OBS and frailty, with a significant reduction in frailty risk observed in women compared to men. Conclusions: OBS was negatively associated with frailty in COPD. The higher the OBS, the lower the risk of frailty, especially in women. Identifying at-risk populations with OBS and through antioxidant diet and lifestyle are potential ways to reduce the prevalence of frailty.

Epidemiology and Clinical Characteristics of Pediatric Sepsis in PICUs in Southwest China: A Prospective Multicenter Study.

OBJECTIVES: To describe the epidemiological characteristics of pediatric sepsis in Southwest China PICUs. DESIGN: A prospective, multicenter, and observational study. SETTING: Twelve PICUs in Southwest China. PATIENTS: The patients admitted to the PICU from April 1, 2022, to March 31, 2023. The age ranged from 28 days to 18 years. All patients met the criteria of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 31 PICUs invited to participate, 12 PICUs (capacity of 292 beds) enrolled patients in the study. During the study period, 11,238 children were admitted to the participating PICUs, 367 (3.3%) of whom met the diagnosis of severe sepsis or septic shock. The most prevalent sites of infection were the respiratory system (55%) and the digestive system (15%). The primary treatments administered to these patients included antibiotics (100%), albumin (61.3%), invasive mechanical ventilation (58.7%), glucocorticoids (55.6%), blood products (51%), gammaglobulin (51%), and vasoactive medications (46.6%). Sepsis-related mortality in the PICU was 11.2% (41/367). Nearly half of the sepsis deaths occurred within the first 3 days of PICU admission (22/41, 53.7%). The mortality rate of septic shock (32/167, 19.2%) was significantly higher than that of severe sepsis (9/200, 4.5%; p < 0.001). The outcomes of a multivariate logistic regression analysis suggested that a higher pediatric Sequential Organ Failure Assessment score, and the use of invasive mechanical ventilation and vasoactive medications were independently associated with PICU mortality in children with sepsis. CONCLUSIONS: This report updates the epidemiological data of pediatric sepsis in PICUs in Southwest China. Sepsis is still a life-threatening disease in children.

Social anxiety and loneliness among older adults: a moderated mediation model.

BACKGROUND: Few studies have clarified the mechanisms linking social anxiety and loneliness in older populations. The study aimed to explore how social network mediate the relationship between social anxiety and loneliness in older adults, with perceived social support playing a moderating role. METHODS: A total of 454 older patients completed the Social Avoidance and Distress Scale, Lubben Social Network Scale-6, Chinese version of the Short Loneliness Scale and Perceived Social Support Scale. Bootstrap and simple slope methods were used to test the moderated mediation model. RESULTS: Social anxiety had a significant positive predictive effect on loneliness and social network partially mediated this relationship. The relationship between social anxiety and social network, as well as the relationship between social network and loneliness, was moderated by perceived social support. Specifically, perceived social support buffered the effects of social anxiety on social network, but the buffering effect diminished with increasing levels of social anxiety. On the social network and loneliness pathway, the social network of older persons with higher perceived social support has a stronger prediction of loneliness. CONCLUSIONS: The study found that social anxiety can contribute to loneliness by narrowing older adults' social network. High perceived social support can buffer this process, but do not overstate its protective effects. Thus, interventions to reduce social anxiety and improve social network and social support may help prevent and alleviate loneliness in older adults.

Anatomical Variations of the Ascending Pharyngeal Artery: Implications for Endoscopic Surgery in the Parapharyngeal Space.

Objectives: The ascending pharyngeal artery (APA) travels with the parapharyngeal internal carotid artery (pICA) in the parapharyngeal space (PPS). This study aimed to investigate the anatomical variations of the APA, and to explore their implications for endoscopic surgery in the PPS. Methods: Dissection of the APA in the PPS was performed on 10 cadaveric specimens (20 sides). The relationship between APA and PPS tumors was retrospectively reviewed in 20 patients, attempting to ascertain the APA during the resection of 10 pre-styloid and 10 retro-styloid PPS tumors. Results: During the cadaveric dissections, the APA was identified at the medial, posteromedial, or bilateral aspects of the pICA in 12 (60%) and 4 (20%) sides, respectively. In the remaining 4 sides (20%), the APA branched into several subcategory arteries lying at the medial and lateral aspects of the pICA. Branches of the APA were observed in 13/20 sides (65%). Two branches were found in 9/13 sides and 3 branches in 4/13, respectively. The APA was only identifiable in 1/10 (10%) of pre-styloid tumors, a patient with basal cell adenoma. In contrast, the APA was encountered surrounding the pICA in 8/10 (80%) of patients with retro-styloid tumors, all of which were schwannomas. No inadvertent injury of the APA or the pICA occurred in this cohort. Conclusions: With identification of the ascending pharyngeal artery on preoperative magnetic resonance imaging, it may serve as an additional landmark during the endoscopic extirpation of tumors arising in the PPS.

Long Non-Coding RNA BCYRN1 Drives Cellular Processes to Promote Asthma Development.

INTRODUCTION: Asthma is a common chronic inflammatory respiratory disease worldwide. The long non-coding RNA (lncRNA) BCYRN1 has been shown to function in the inhibition of smooth muscle cell differentiation and vascular development, but its function and potential molecular mechanisms of lncRNA BCYRN1 in bronchial smooth muscle cells (BSMCs) in asthma remain unknown. METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was performed to detect the expression level of lncRNA BCYRN1 in blood and sputum of asthma patients. The effects of lncRNA BCYRN1 on the proliferation and migration of BSMCs were explored by cell counting kit-8, Transwell, colony formation, and flow cytometry analysis. Differentially expressed genes between lncRNA BCYRN1 overexpression and knockdown cells were identified using RNA-seq and verified using RT-qPCR. RESULTS: LncRNA BCYRN1 was upregulated in asthma patients. Overexpression of lncRNA BCYRN1 significantly promoted the proliferation and migration of BSMCs, inhibited cell apoptosis and affected cell cycle arrest, promoting DNA replication. These effects were reversed after lncRNA BCYRN1 inhibition. RNA-seq identified 434 common differentially expressed genes in the lncRNA BCYRN1 overexpression and knockdown groups and verified their expression levels by RT-qPCR. Gene ontology, Kyoto Encyclopedia of Genes and Genomes and Gene set enrichment analysis indicated that these genes were mainly involved in external stimulus, cell cycle, growth factor activity, cytokine interactions, and inflammatory response. CONCLUSION: The identification of the highly expressed lncRNA BCYRN1 in patients with asthma, combined with functional experiments and transcriptional data, suggests that lncRNA BCYRN1 can mediate the development of asthma and can be used as a promising diagnostic and prognostic biomarker for asthma.

[Retracted] Downregulation of ROS­FIG inhibits cell proliferation, colony­formation, cell cycle progression, migration and invasion, while inducing apoptosis in intrahepatic cholangiocarcinoma cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data shown in Fig. 9 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to International Journal of Molecular Medicine, or were under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 34: 661­668, 2014; 10.3892/ijmm.2014.1823].

Relevance of the Internal Jugular Vein for Surgery in the Upper Parapharyngeal Space.

Objective: Tumors arising from the upper parapharyngeal space (UPPS) may have intimate relationships with the internal carotid artery (ICA) and the internal jugular vein (IJV). The significance of the ICA in UPPS has been sufficiently articulated, whereas the relevance of the IJV has not been addressed. This study aimed to assess the anatomical variations of the IJV within the UPPS, and to explore its implications for surgical procedures. Methods: An endoscopic dissection of the IJV was performed on 10 cadaveric specimens. In addition, 30 patients who underwent transoral or transcervical resection of UPPS tumors were retrospectively reviewed to characterize the IJV and its relation to the tumor. Results: On the cadaveric specimens, the IJV was located at the posteromedial and posterolateral aspects of the styloid process in 13 (65%) and 7 (35%) sides, respectively. In our clinical series, the IJV was not encountered in 18 patients with pre-styloid tumors. In 12 patients harboring retro-styloid tumors, the IJV was partially (n = 5) or completely (n = 7) compressed and was displaced into the posterolateral aspect of the tumor. The IJV was injured intraoperatively in 1 patient, requiring an immediate conversion to an open transcervical corridor that allowed its exposure and ligation without difficulty. Conclusion: This study characterizes the IJV and its relationship with adjacent neurovascular structures in the UPPS, which may provide further safeguards during transoral and transcervical procedures in the UPPS.

Lignan and Phthalide Derivatives from the Rhizome of Ligusticum chuanxiong (Rhizoma chuanxiong) and Evaluation of Their anti-Xanthine Oxidase Activities.

The previous research results showed that the extracts of ethyl acetate of the rhizome of Ligusticum chuanxiong (Rhizoma chuanxiong) possessed significant antigout effects in model mice. To explore the active ingredients responsible for the effects, phytochemical studies were performed, which led to the isolation of three rare 8', 9-linked neolignans, ligusticumins A-C (1-3), together with two novel phthalide-phenylpropanoid heterodimers, ligusticumalides A-B (4 and 5). It is noteworthy that 4 possesses an unprecedented 7-styryl phthalide skeleton. The structures and absolute configurations of 1-5 were elucidated by one-dimensional (1D) and two-dimensional (2D) NMR spectroscopy and electron-capture detector (ECD) spectroscopic methods. The bioassay results showed that compounds 1, 2, 3, and 5 presented moderate inhibitory activities against xanthine oxidase (XO) and 4 possessed a significant XO inhibitory effect with an IC50 value of 93.88 µM. This is the first time to investigate the anti-XO active ingredients of R. chuanxiong, which provides valuable information for searching for new antigout agents from natural products.

Neural stem cell transplantation improves neurological function in focal cerebral ischemia through GDNF/PI3K/AKT axis.

The aim of this experiment was to analyze the ameliorating effect of neural stem cells (NSCs) on focal cerebral ischemia (FCI) through GDNF/PI3K/AKT axis, so as to provide evidence for future clinical application of NSCs. In this study, the 15 Sprague-Dawley (SD) male rats were modeled for middle cerebral artery occlusion (MCAO)-induced FCI and then grouped: NSCs group was treated with NSC transplantation, GDNF/NSCs group was transplanted with recombinant adenovirus pAdEasy-1-pAdTrackCMV-GDNF-transfedcted NSCs, and the blank group was treated with normal saline transplantation. Rats were tested by rotarod and corner turn tests at 1 week and 4 weeks after NSC transplantation, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6/8 (IL-6/8), superoxide dismutase (SOD) and malondialdehyde (MDA) were quantified. Then all rats were killed and their brain tissues were HE stained for the determination of and GDNF/PI3K/AKT axis-associated protein expression. The results of the experiment showed that: at the 1st and 4th week after transplantation, the time on the rod, number of turnings and SOD were the lowest in the blank group among the three groups, while IL-6, IL-8, TNF-α and MDA were the highest (P<0.05). Increased time on the rod, number of turnings and SOD, as well as decreased IL-6, IL-8, TNF-α and MDA were observed in NSCs and GDNF/NSCs groups after transplantation, with better performance in GDNF/NSCs group (P<0.05). Based on HE staining of brain tissue, GDNF/NSCs group had the most significant improvement in tissue injury and the highest GDNF, PI3K, AKT and p-AKT protein expression among the three groups (P<0.05). In conclusions, NSC transplantation can ameliorate neurological function in MCAO-induced FCI rats through the GDNF/PI3K/AKT axis.

TGF-ß score based on silico analysis can robustly predict prognosis and immunological characteristics in lower-grade glioma: the evidence from multicenter studies.

INTRODUCTION: Nowadays, mounting evidence shows that variations in TGF-ß signaling pathway-related components influence tumor development. Current research has patents describing the use of anti-TGF-ß antibodies and checkpoint inhibitors for the treatment of proliferative diseases. Importantly, TGF-ß signaling pathway is significant for lower-grade glioma (LGG) to evade host immunity. Loss of particular tumor antigens and shutdown of professional antigen-presenting cell activity may render the anti-tumor response ineffective in LGG patients. However, the prognostic significance of TGF-ß related genes in LGG is still unknown. METHODS: We collected RNA-seq data from the GTEx database (normal cortical tissues), the Cancer Genome Atlas database (TCGA-LGG), and the Chinese Glioma Genome Atlas database (CGGA-693 and CGGA-325) for conducting our investigation. RESULTS: In addition, previous publications were explored for the 223 regulators of the TGF-ß signaling pathway, and 30 regulators with abnormal expression in TCGA and GTEx database were identified. In order to identify hub prognostic regulators, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were used to screen from differentially expressed genes (DEGs). On the basis of 11 genes from LASSO-Cox regression analysis (NEDD8, CHRD, TGFBR1, TP53, BMP2, LRRC32, THBS2, ID1, NOG, TNF, and SERPINE1), TGF-ß score was calculated. Multiple statistical approaches verified the predictive value of the TGF-ß score for the training cohort and two external validation cohorts. Considering the importance of the TGF-ß signaling pathway in immune regulation, we evaluated the prediction of the TGF-ß score for immunological characteristics and the possible application of the immunotherapeutic response using six algorithms (TIMER, CIBERSORT, QUANTISEQ, MCP-counter, XCELL and EPIC) and three immunotherapy cohorts (GSE78820, Imvigor-210 and PRJEB23709). Notably, we compared our risk signature with the signature in ten publications in the meta-cohort (TCGA-LGG, CGGA-693 and CGGA-325), and the TGF-ß score had the best predictive efficiency (C-index =0.812). CONCLUSION: In conclusion, our findings suggest that TGF-ß signaling pathway-related signatures are prognostic biomarkers in LGG and provide a novel tool for tumor microenvironment (TME) assessment.