LSD1 inhibition by tranylcypromine hydrochloride reduces alkali burn-induced corneal neovascularization and ferroptosis by suppressing HIF-1α pathway.

Background: Corneal neovascularization (CNV) is a sight-threatening condition that necessitates epigenetic control. The role of lysine-specific demethylase 1 (LSD1) in CNV remains unclear, despite its established significance in tumor angiogenesis regulation. Methods: An alkali burn-induced CNV mouse model was used in vivo. The effects of LSD1 inhibitor tranylcypromine hydrochloride (TCP) were examined through slit lamp, histological staining, and immunofluorescence. The expression of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were assessed in corneal tissues. Oxidative stress and ferrous ion expression during CNV were determined using 4-HNE, GPX4, and FerroOrange staining. In vitro, a hypoxia-reoxygenation (H/R) model was established using human umbilical vein endothelial cells (HUVECs) to study LSD1 or hypoxia-inducible factor (HIF-1α) knockdown and lentiviral overexpression of HIF-1α. The effects on HUVECs migration, invasion, and angiogenesis were evaluated through cell scratching assay, transwell migration assay and tube formation assay. The role of ferroptosis was investigated using ROS staining, FerroOrange staining, and key ferroptosis proteins. Further, The JAK2/STAT3 pathway's involvement in CNV regulation was explored through in vivo experiments with subconjunctival injection of AG490. Results: The results showed a substantial correlation between corneal damage and LSD1 levels. In addition, HIF-1α expression was also elevated after alkali burns, and subconjunctival injection of TCP reduced corneal inflammation and neovascularization. Corneal alkali burns increased ROS levels and reduced antioxidative stress indicators, accompanied by elevated ferrous ion levels, which were reversed by TCP injection. In vitro, TCP or siRNAs inhibited H/R-induced ferroptosis and angiogenesis in HUVECs by affecting specific protein expressions and MDA, SOD, and GSH levels. HIF-1α levels, associated with ROS production, ferroptosis, and angiogenesis, increased during H/R, but were reversed by TCP or siRNA administration. HIF-1α overexpression counteracted the effects of LSD1 inhibition. Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. Discussion: These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target.

Predictive value of delta-radiomic features for prognosis of advanced non-small cell lung cancer patients undergoing immune checkpoint inhibitor therapy.

Background: No robust predictive biomarkers exist to identify non-small cell lung cancer (NSCLC) patients likely to benefit from immune checkpoint inhibitor (ICI) therapies. The aim of this study was to explore the role of delta-radiomics features in predicting the clinical outcomes of patients with advanced NSCLC who received ICI therapy. Methods: Data of 179 patients with advanced NSCLC (stages IIIB-IV) from two institutions (Database 1 =133; Database 2 =46) were retrospectively analyzed. Patients in the Database 1 were randomly assigned into training and validation dataset, with a ratio of 8:2. Patients in Database 2 were allocated into testing dataset. Features were selected from computed tomography (CT) images before and 6-8 weeks after ICI therapy. For each lesion, a total of 1,037 radiomic features were extracted. Lowly reliable [intraclass correlation coefficient (ICC) <0.8] and redundant (r>0.8) features were excluded. The delta-radiomics features were defined as the relative net change of radiomics features between two time points. Prognostic models for progression-free survival (PFS) and overall survival (OS) were established using the multivariate Cox regression based on selected delta-radiomics features. A clinical model and a pre-treatment radiomics model were established as well. Results: The median PFS (after therapy) was 7.0 [interquartile range (IQR): 3.4, 9.1] (range, 1.4-13.2) months. To predict PFS, the model established based on the five most contributing delta-radiomics features yielded Harrell's concordance index (C-index) values of 0.708, 0.688, and 0.603 in the training, validation, and testing databases, respectively. The median survival time was 12 (IQR: 8.7, 15.8) (range, 2.9-23.3) months. To predict OS, a promising prognostic performance was confirmed with the corresponding C-index values of 0.810, 0.762, and 0.697 in the three datasets based on the seven most contributing delta-radiomics features, respectively. Furthermore, compared with clinical and pre-treatment radiomics models, the delta-radiomics model had the highest area under the curve (AUC) value and the best patients' stratification ability. Conclusions: The delta-radiomics model showed a good performance in predicting therapeutic outcomes in advanced NSCLC patients undergoing ICI therapy. It provides a higher predictive value than clinical and the pre-treatment radiomics models.

Brainstem Gliomas With Isocitrate Dehydrogenase Mutation: Natural History, Clinical-Radiological Features, Management Strategy, and Long-Term Outcome.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical, radiological, pathological features, treatment options, and outcomes of isocitrate dehydrogenase (IDH)-mutant brainstem gliomas (BSG-IDHmut). METHODS: A retrospective analysis of 22 patients diagnosed with BSG-IDHmut and treated at our institution from January 2011 to January 2017 was performed. Their clinical, radiological data, and long-term outcomes were collected and analyzed. RESULTS: The median age of patients was 38.5 years, with a male predominance (63.6%). All patients had IDH1 and TP53 mutations, with noncanonical IDH mutations in 59.1% of cases, 06-methylguanine-DNA methyltransferase promoter methylation in 55.6%, and alpha-thalassemia mental retardation X-linked loss in 63.2%, respectively. Tumors were primarily located in the pontine-medullary oblongata (54.5%) and frequently involved the pontine brachium (50%). Most tumors exhibited ill-defined boundaries (68.2%), no T2-FLAIR mismatch (100%), and no contrast enhancement (86.3%). Two radiological growth patterns were also identified: focal and extensively infiltrative, which were associated with the treatment strategy when tumor recurred. Seven patients (31.8%) received surgery only and 15 (68.2%) surgery plus other therapy. The median overall survival was 124.8 months, with 1-year, 2-year, 5-year, and 10-year survival rates of 81.8%, 68.2%, 54.5%, and 13.6%, respectively. Six patients experienced tumor recurrence, and all retained their radiological growth patterns, with 2 transformed into central nervous system World Health Organization grade 4. CONCLUSION: BSG-IDHmut represents a unique subgroup of brainstem gliomas with distinctive features and more favorable prognosis compared with other brainstem gliomas. Further research is required to better understand the molecular mechanisms and optimize treatment strategies for this rare and complex disease.

Efficacy of Apagliflozin Plus Pentoxifylline in the Treatment of Early Diabetic Nephropathy and Its Effect on Serum Inflammatory Factors and Immune Function.

Objective: To explore the efficacy of dapagliflozin plus pentoxifylline in the treatment of early diabetic nephropathy and its effect on serum inflammatory factors and immune function. Methods: A total of 90 patients with early diabetic nephropathy who were admitted to Cangzhou Central Hospital from January 2019 to January 2022 were recruited and randomized (1:1) into a control group and an observation group using the random number table method. The control group was treated with dapagliflozin, and the observation group was treated with pentoxifylline plus dapagliflozin. The effectiveness of urinary α (1) microglobulin (α 1-mg) was determined by immunoturbidimetric method, and urinary ß (2) microglobulin (ß 2-mg) was determined. Urine creatinine was determined enzymatically, and the urinary microprotein albumin creatinine ratio (mAlb/Cr) was calculated. The levels of inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] were detected. Before and after treatment, 3 mL of venous blood was drawn from the two groups of patients, and serum CD4+, CD8+, and CD4+/CD8+ levels were detected. The incidence of adverse reactions between the two groups was calculated. Results: Dapagliflozin plus pentoxifylline was associated with a higher effective rate than dapagliflozin alone (96.67% vs 81.67%) (RR 0·80 [95% CI 0·61-0.98]; P = .021). Dapagliflozin plus pentoxifylline led to lower renal function parameters versus dapagliflozin alone, in favor of the observation group (RR 0.67 [95% CI 0.66-0.88]; P = .032). After treatment, the serum levels of IL-6 and TNF-α in patients treated with dapagliflozin plus pentoxifylline were lower than counterparts treated with dapagliflozin (RR 0.62 [95% CI 0.51-0.78]; P = .037). After treatment, CD4+ and CD4+/CD8+ in the two groups were increased compared with baseline parameters, and the level of CD8+ was decreased ; the increase and decrease were greater in the observation group than in the control group (RR 0.70 [95% CI 0.71-0.96]; P = .044) (RR 0.53 [95% CI 0.41-0.78]; P = .033). The two groups demonstrated similar safety profiles with no statistical difference observed in the incidence of adverse reactions between the two groups (RR 0.73 [95% CI 0.73-1.08]; P = .051). Conclusion: Dapagliflozin plus pentoxifylline might be a promising alternative in the treatment of patients with early diabetic nephropathy, it significantly mitigates the body's inflammatory response, enhances immune function, attenuates the main clinical symptoms, with a high safety profile.

Inhibiting PRMT1 protects against CoNV by regulating macrophages through the FGF2/PI3K/Akt pathway.

Corneal neovascularization (CoNV) is predominantly initiated by inflammatory processes, resulting in aberrant vascular proliferation and consequent visual impairment. Existing therapeutic interventions for CoNV demonstrate limited efficacy and potential for adverse reactions. Protein arginine methyltransferase 1 (PRMT1) is associated with the regulation of inflammation and M2 macrophage polarization. Nevertheless, the precise mechanism by which PRMT1 operates in CoNV remains uncertain. This study explored the impact of PRMT1 inhibition in a murine model of CoNV induced by alkali burn. Our findings indicated a direct relationship between PRMT1 levels and corneal damage. Moreover, our observations indicated an increase in fibroblast growth factor 2 (FGF2) expression in CoNV, which was reduced after treatment with a PRMT1 inhibitor. The inhibition of PRMT1 alleviated both corneal injury and CoNV, as evidenced by decreased corneal opacity and neovascularization. Immunofluorescence analysis and evaluation of inflammatory factor expression demonstrated that PRMT1 inhibition attenuated M2 macrophage polarization, a phenomenon that was reversed by the administration of recombinant FGF2 protein. These results were confirmed through experimentation on Human Umbilical Vein Endothelial Cells (HUVECs) and Mouse leukemia cells of monocyte macrophage cells (RAW264.7). Furthermore, it was established that FGF2 played a role in PI3K/Akt signal transduction, a critical regulatory pathway for M2 macrophage polarization. Importantly, the activity of this pathway was found to be suppressed by PRMT1 inhibitors. Mechanistically, PRMT1 was shown to promote M2 macrophage polarization, thereby contributing to CoNV, through the FGF2/PI3K/Akt pathway. Therefore, targeting PRMT1 may offer a promising therapeutic approach.

Effectiveness of exercise-based cardiac rehabilitation for patients with left ventricular assist device: A systematic review and meta-analysis.

PURPOSE: Exercise-based cardiac rehabilitation (EBCR) improves functional capacity in heart failure (HF). However, data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs) are limited. This meta-analysis aimed to evaluate the impact of EBCR on the functional ability of LVAD patients by comparing the corresponding outcome indicators between the EBCR and ST groups. METHODS: PubMed, Embase, Clinical Trials, and Cochrane Library databases were searched for studies assessing and comparing the effects of EBCR and standard therapy (ST) in patients following LVAD implantation. Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion, and a meta-analysis was performed using a fixed-effects model. The protocol was registered on INPLASY (202340073). RESULTS: In total, 12 trials involving 477 patients were identified. The mean age of the participants was 52.9 years, and 78.6% were male. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 11 months post-LVAD implantation. The median rehabilitation period ranged from 2 weeks to 18 months. EBCR was associated with improved peak oxygen uptake (VO2) in all trials. Quantitative analysis was performed in six randomized studies involving 214 patients (EBCR: n = 130, ST: n = 84). EBCR was associated with a significantly high peak VO2 (weighted mean difference [WMD] = 1.64 mL/kg/min; 95% confidence interval [CI], 0.20-3.08; p = .03). Similarly, 6-min walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD = 34.54 m; 95% CI, 12.47-56.42; p = .002) in 266 patients (EBCR, n = 140; ST, n = 126). Heterogeneity was low among the included trials. None of the included studies reported serious adverse events related to EBCR, indicating the safety of EBCR after LVAD implantation. CONCLUSION: This study demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by the improved peak VO2 and 6MWD values. Considering the small number of patients in this analysis, further research on the clinical impact of EBCR in LVAD patients is warranted.

A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management: a single-institution experience of 57 cases.

OBJECTIVE: Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decision-making and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up. METHODS: Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed. RESULTS: The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0-12.8 years); the largest tumor volume (median 31.9 cm3, IQR 17.2-42.6 cm3); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50-70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image-guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8-33 years); tumor volume (median 13.9 cm3, IQR 9.5-20.5 cm3); a good preoperative KPS score (median 80, IQR 70-80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm3, IQR 5.1-17.4 cm3 and median 11.84 cm3, IQR 5.7-18.3 cm3, respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches. CONCLUSIONS: A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.

Primary adult choroid plexus carcinomas: a single-center experience with a systematic review.

Objective: Primary adult choroid plexus carcinomas (PACPCs) are extremely rare brain tumors. The existing literature primarily comprises case reports, which limits our understanding of this uncommon disease. This study aims to describe the clinical characteristics and prognosis of PACPCs, as well as to identify optimal treatment strategies. Methods: We conducted a comprehensive analysis of clinical data from 7 patients with PACPCs who underwent surgical treatment at the Department of Neurosurgery, Beijing Tiantan Hospital, between March 2011 and March 2023. Additionally, a thorough search of the PubMed database was performed using the keywords "choroid plexus carcinoma" or "choroid plexus carcinomas" within the time frame of August 1975 to April 2023, which yielded a total of 28 identified cases. Subsequently, we evaluated risk factors for progression-free survival (PFS) and overall survival (OS) based on the pooled cases. Results: The pooled cohort, consisting of 7 cases from our institution and 28 cases from the literature, included 20 males and 15 females with a mean age of 44.3 ± 14.7 years (range: 21-73 years). Gross-total resection (GTR) and non-GTR were achieved in 22 (62.9%) and 13 (37.1%) patients, respectively. Radiotherapy and chemotherapy were administered to 29 (90.6%) and 13 (40.6%) patients, respectively. After a mean follow-up of 21.0 ± 26.7 months (range: 2-132 months), 18 patients were alive, and 11 patients had died. The multivariate Cox regression model demonstrated that non-GTR (HR 5.262, 95% CI 1.350-20.516, p=0.017) was a negative prognostic factor for OS. However, we did not find any risk factors for PFS. Conclusion: Complete surgical resection should be considered as the primary treatment approach for this rare disease. Chemotherapy and radiotherapy appear to have limited effectiveness in treating this condition. Further research with large cohorts is needed to validate our conclusions.

Whole human-brain mapping of single cortical neurons for profiling morphological diversity and stereotypy.

Quantifying neuron morphology and distribution at the whole-brain scale is essential to understand the structure and diversity of cell types. It is exceedingly challenging to reuse recent technologies of single-cell labeling and whole-brain imaging to study human brains. We propose adaptive cell tomography (ACTomography), a low-cost, high-throughput, and high-efficacy tomography approach, based on adaptive targeting of individual cells. We established a platform to inject dyes into cortical neurons in surgical tissues of 18 patients with brain tumors or other conditions and one donated fresh postmortem brain. We collected three-dimensional images of 1746 cortical neurons, of which 852 neurons were reconstructed to quantify local dendritic morphology, and mapped to standard atlases. In our data, human neurons are more diverse across brain regions than by subject age or gender. The strong stereotypy within cohorts of brain regions allows generating a statistical tensor field of neuron morphology to characterize anatomical modularity of a human brain.

Clinical characteristics and surgical outcomes of primary intracranial angiosarcomas.

OBJECTIVE: Primary intracranial angiosarcomas (PIAs) are exceedingly uncommon, with the literature predominantly comprising case reports. The clinical characteristics and prognosis of this condition remain elusive. Our objective is to describe the clinical characteristics and surgical prognosis of this rare disease while offering insights into the most effective contemporary treatment strategy. METHODS: The authors of this article incorporated a cohort of 28 cases of PIAs, consisting of 3 from our institution and 25 from previously documented literature sources. Subsequently, we conducted both Cox univariate and multivariate analyses to assess the potential risk factors influencing overall survival (OS). RESULTS: The cohort include 19 males and 9 females with a mean age of 39.6 ± 23.5 years (range: 0.03-73 years). Radiologically, 24 cases were located at supratentorial area, while only 4 cases were located at infratentorial area. 17 cases underwent gross total resection (GTR), and 11 cases underwent Non-GTR. Postoperative radiotherapy was administered to 17 cases, and postoperative chemotherapy was administered to 6 cases. After a mean follow-up time of 21.5 ± 26.4 months, 19 (67.9%) patients died. The 1-year, 2-year, 5-year OS is 55.3%, 50.7% and 24.6%, respectively. Univariate and multivariate Cox regression analysis showed that Non-GTR was the sole factor predicting a shorter OS (p = 0.004). CONCLUSION: In this study, we found that PIAs have a higher incidence in males than in females, and most cases show evidence of old hemorrhage on preoperative MRI. Through our statistical analysis, GTR plays a crucial role in for treating this rare disease. Further clinical data are needed to validate our conclusions.

Clinical features and surgical outcomes of high grade pleomorphic xanthoastrocytomas: a single-center experience with a systematic review.

Purpose: High grade pleomorphic xanthoastrocytomas (HGPXAs) are very rare and their management and prognostic outcomes remain unclear. To better understand the disease, we aimed to evaluate the risk factors for progression-free survival (PFS) and overall survival (OS), and propose a treatment protocol based on cases from our institute and cases from the literature. Methods: The authors reviewed the clinical data of 26 patients with HGPXAs who underwent surgical treatment in Department of Neurosurgery of Beijing Tiantan Hospital between August 2014 and September 2021. We also searched the PubMed database using the keywords "anaplastic" combined with "pleomorphic xanthoastrocytoma(s)" between January 1997 and October 2022. Risk factors for PFS and OS were evaluated in the pooled cases. Results: The authors' cohort included 11 males and 15 females with a mean age of 36.7 ± 20.3 years (range: 5.5-71 years). Gross-total resection (GTR) and non-GTR were achieved in 17 (65.4%) and 9 (34.6%) patients, respectively. Radiotherapy and chemotherapy were administered to 22 and 20 patients, respectively. After a mean follow-up of 20.5 ± 21.2 months (range: 0.5-78.1 months), 7 patients suffered tumor recurrence and 6 patients died with a mean OS time of 19.4 ± 10.8 months (range: 8-36 months). In the literature between January 1997 and October 2022, 56 cases of HGPXAs were identified in 29 males and 27 females with a mean age of 29.6 ± 19.6 years (range; 4-74 years). Among them, 24 (44.4%) patients achieved GTR. Radiotherapy and chemotherapy was administered to 31 (62%) patients and 23 (46%) patients, respectively. After a median follow-up of 31.4 ± 35.3 months (range: 0.75-144 months), the mortality and recurrence rates were 32.5% (13/40) and 70% (28/40), respectively. Multivariate Cox regression model demonstrated that non-GTR (HR 0.380, 95% CI 0.174-0.831, p=0.015), age≥30 (HR 2.620, 95% CI 1.183-5.804, p=0.018), no RT (HR 0.334,95% CI 0.150-0.744, p=0.007) and no CT (HR 0.422, 95% CI 0.184-0.967, p=0.042) were negative prognostic factors for PFS. Non-GTR (HR 0.126, 95% CI 0.037-0.422, p=0.001), secondary HGPXAs (HR 7.567, 95% CI 2.221-25.781, p=0.001), age≥30 (HR 3.568, 95% CI 1.190-10.694, p=0.023) and no RT (HR 0.223,95% CI 0.073-0.681, p=0.008) were risk factors for OS. Conclusion: High grade pleomorphic xanthoastrocytomas are very rare brain tumors. Children and younger adults have better clinical outcome than elderly patients. Secondary HGPXAs had worse OS than primary HGPXAs. Complete surgical excision plus RT and CT is recommended for this entity. The frequency of BRAF mutations in HGPXAs is 47.5% (19/40) in this study, however, we do not find the connections between BRAF mutations and clinical outcomes. Future studies with larger cohorts are necessary to verify our findings.

Primary intracranial histiocytic sarcomas: a report of six cases and a pooled analysis of individual patient data.

OBJECTIVE: Primary intracranial histiocytic sarcomas (PIHSs) are extremely rare with limited reported cases, making their prognostic factors and management uncertain. This study aims to describe the clinical characteristics of PIHSs and propose a treatment protocol for this entity. METHODS: Clinical data were collected from six patients diagnosed with PIHSs at Beijing Tiantan Hospital between March 2011 and October 2022. Additionally, a comprehensive search of the PubMed database was conducted using the keywords "primary intracranial" or "primary central nervous system" combined with "histiocytic sarcoma" or "histiocytic sarcomas" between 1996 and 2022, identifying 24 cases. A pooled analysis of individual patient data was performed to assess risk factors for overall survival (OS). RESULTS: The six cases included four males and two females, with a mean age of 42.2 ± 13.3 years. In total, 24 cases of PIHSs were identified from previous studies. Multivariate Cox regression analysis revealed that gross total resection (GTR) was the only factor predicting a longer OS (p = 0.027). Kaplan-Meier analysis demonstrated that GTR (p = 0.0013), solitary lesions (p = 0.0048), and radiotherapy (p = 0.0492) were associated with a longer OS. CONCLUSION: PIHSs are rare brain tumors with poor clinical prognosis. Patients with solitary lesions have a longer OS than those with multifocal lesions. Gross total resection must be the first choice. Radiotherapy may bring benefits for these patients, but chemotherapy may not be useful. Further studies involving larger cohorts are necessary to validate these findings.

LncRNA NKILA Exacerbates Alzheimer's Disease Progression by Regulating the FOXA1-Mediated Transcription of TNFAIP1.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the world, which seriously affects AD patients' life quality. Recently, long non-coding RNAs (lncRNAs) have been reported to play a key role in AD pathogenesis, however, the specific mechanism remains unclear. Herein, we aimed to investigate the role of lncRNA NKILA in AD. The learning and memory performance of rats from streptozotocin (STZ)-treated or other treated groups were tested by Morris water maze test. Relative levels of genes and proteins were measured using RT-qPCR and Western blotting. Mitochondrial membrane potential was tested by JC-1 staining. Levels of ROS, SOD, MDA, GSH-Px, and LDH were measured using corresponding commercial kits. Apoptosis was evaluated by TUNEL staining or Flow cytometry assay. RNA Immunoprecipitation (RIP), RNA pulldown, Chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were utilized to test the interaction between indicated molecules. STZ treatment caused learning and memory impairment in rats and oxidative stress damage in SH-SY5Y cells. LncRNA NKILA was found to be elevated in the hippocampal tissues of rats and SH-SY5Y cells after STZ exposure. Knockdown of lncRNA NKILA alleviated STZ-induced neuronal damage. Furthermore, lncRNA NKILA could bind to ELAVL1, which regulate the stability of FOXA1 mRNA. Moreover, TNFAIP1 transcription process was controlled by FOXA1, which targeted the promoter of TNFAIP1. In vivo results demonstrated that lncRNA NKILA accelerated STZ-induced neuronal damage and oxidative stress by FOXA1/TNFAIP1 axis. Our findings indicated that knockdown of lncRNA NKILA inhibited the neuronal damage and oxidative stress induced by STZ through the FOXA1/TNFAIP1 axis, thereby alleviating the development of AD, revealing a promising therapeutic axis for AD treatment.

Arctiin alleviates functional constipation by enhancing intestinal motility in mice.

Functional constipation (FC), a common symptom that is primarily associated with intestinal motility dysfunction, is a common problem worldwide. Arctiin (Arc) is a lignan glycoside isolated from the Chinese herbal medicine Arctium lappa L., which is a health food in China. The present study aimed to evaluate the laxative effects of Arc against FC in mice. A model of FC induced by loperamide (5 mg/kg) was established in male Institute of Cancer Research (ICR) mice. Arc was administered at a dose of 100 mg/kg as a protective agent. The faecal status, intestinal motility and histological analyses were evaluated. Furthermore, the levels of gastrointestinal motility-associated neurotransmitters, such as motilin (MTL), nitric oxide (NO), and brain-derived neurotrophic factor (BDNF) and the protective effect of Arc on interstitial cells of Cajal (ICC) were assessed. Arc treatment reversed the loperamide-induced reduction in faecal number and water content and the intestinal transit ratio in ICR mice. Histological analysis confirmed that Arc administration mitigated colonic injury. Moreover, Arc treatment increased levels of motilin and brain-derived neurotrophic factor while decreasing nitric oxide levels and ICC injury in the colon of FC mice. Arc decreased inflammation induction and aquaporin expression levels. Owing to its pro-intestinal motility property, Arc was shown to have a protective effect against FC and may thus serve as a promising therapeutic strategy for the management of FC.

Molecular Characterization and Prognosis of Lactate-Related Genes in Lung Adenocarcinoma.

OBJECTIVE: To explore the lactate-related genes (LRGs) in lung adenocarcinoma (LUAD) by various methods, construct a prognostic model, and explore the relationship between lactate subtypes and the immune tumor microenvironment (TME). METHODS: 24 LRGs were collected. The mutation landscape and the prognosis value of LRGs were explored by using The Cancer Genome Atlas (TCGA) data. Consensus clustering analysis was used for different lactate subtype identification. Based on the lactate subtypes, we explore the landscape of TME cell infiltration. A risk-score was calculated by using the LASSO-Cox analysis. A quantitative real-time PCR assay was utilized to validate the expression of characteristic genes in clinical cancer tissues and paracarinoma tissues from LUAD patients. RESULTS: Comparing the normal samples, 18 LRGs were differentially expressed in tumor samples, which revealed that the differential expression of LRGs may be related to Copy Number Variation (CNV) alterations. The two distinct lactate subtypes were defined. Compared to patients in the LRGcluster A group, LUAD patients in the LRGcluster B group achieved better survival. The prognostic model was constructed based on differentially expressed genes (DEGs) via the LASSO-Cox analysis, which showed the accuracy of predicting the prognosis of LUAD patients using the ROC curve. A high-risk score was related to a high immune score, stromal score, and tumor mutation burden (TMB). Patients had better OS with low risk compared with those with high risk. The sensitivities of different risk groups to chemotherapeutic drugs were explored. Finally, the expression of characteristic genes in clinical cancer tissues and paracarinoma tissues from LUAD patients was verified via qRT-PCR. CONCLUSIONS: The lactate subtypes were independent prognostic biomarkers in LUAD. Additionally, the difference in the lactate subtypes was an indispensable feature for the individual TME. The comprehensive evaluation of the lactate subtypes in the single tumor would help us to understand the infiltration characteristics of TME and guide immunotherapy strategies.

Luteolin ameliorates loperamide-induced functional constipation in mice.

Functional constipation (FC) is one of the most common gastrointestinal disorders characterized by hard stools and infrequent bowel movements, which is associated with dysfunction of the enteric nervous system and intestinal motility. Luteolin, a naturally occurring flavone, was reported to possess potential pharmacological activities on intestinal inflammation and nerve injury. This study aimed to explore the role of luteolin and its functional mechanism in loperamide-induced FC mice. Our results showed that luteolin treatment reversed the reduction in defecation frequency, fecal water content, and intestinal transit ratio, and the elevation in transit time of FC models. Consistently, luteolin increased the thickness of the muscular layer and lessened colonic histopathological injury induced by loperamide. Furthermore, we revealed that luteolin treatment increased the expression of neuronal protein HuC/D and the levels of intestinal motility-related biomarkers, including substance P (SP), vasoactive intestinal polypeptide (VIP), and acetylcholine (ACh), as well as interstitial cells of Cajal (ICC) biomarker KIT proto-oncogene, receptor tyrosine kinase (C-Kit), and anoctamin-1 (ANO1), implying that luteolin mediated enhancement of colonic function and contributed to the anti-intestinal dysmotility against loperamide-induced FC. Additionally, luteolin decreased the upregulation of aquaporin (AQP)-3, AQP-4, and AQP-8 in the colon of FC mice. In summary, our data showed that luteolin might be an attractive option for developing FC-relieving medications.

Effects of Emodin on Protein Expression Related to Autophagy of Interstitial Cells of Cajal in Diabetic Rats.

This work aims to investigate the effects and mechanism of emodin in treating diabetic gastroenteropathy and colonic dysmotility in STZ + HS/HF diet induced diabetic gastroenteropathy rats. Diabetic colonic dysmotility model was established by high-fat/high-glucose (HS/HF) feeding combined with streptozotocin (STZ). Emodin was divided into high, medium and low dose groups. After eight weeks of intervention, fasting blood glucose (FBG) and body weight were measured. Gastrointestinal transmission time was evaluated. Serum vasoactive intestinal peptide (VIP) and substance P (SP) were detected. Colonic protein expression of selective autophagy adaptor proteins p62 and beclin1 were detected by immunohistochemistry. Colonic protein expression of beclin1, autophagy related gene 5 (Atg5), C-kit and p62 were detected by Western blot. After treating with emodin, gastrointestinal transmission rate was improved. The expression of serum SP was increased and serum VIP was decreased. Colonic c-kit and p62 were up-regulated. The expressions of beclin1 and Atg5 were down-regulated. Emodin can improve colonic dysmotility and promote the recovery of colonic motility and intestinal defecation in diabetic rats. Its mechanism may involved with up-regulating the expression of C-kit and P62, down-regulating the expression of Beclin1 and Atg5 in colon, which are associated with colon over-autophagy of Cajal interstitial cell (ICC).

Luteolin ameliorates loperamide-induced functional constipation in mice

Functional constipation (FC) is one of the most common gastrointestinal disorders characterized by hard stools and infrequent bowel movements, which is associated with dysfunction of the enteric nervous system and intestinal motility. Luteolin, a naturally occurring flavone, was reported to possess potential pharmacological activities on intestinal inflammation and nerve injury. This study aimed to explore the role of luteolin and its functional mechanism in loperamide-induced FC mice. Our results showed that luteolin treatment reversed the reduction in defecation frequency, fecal water content, and intestinal transit ratio, and the elevation in transit time of FC models. Consistently, luteolin increased the thickness of the muscular layer and lessened colonic histopathological injury induced by loperamide. Furthermore, we revealed that luteolin treatment increased the expression of neuronal protein HuC/D and the levels of intestinal motility-related biomarkers, including substance P (SP), vasoactive intestinal polypeptide (VIP), and acetylcholine (ACh), as well as interstitial cells of Cajal (ICC) biomarker KIT proto-oncogene, receptor tyrosine kinase (C-Kit), and anoctamin-1 (ANO1), implying that luteolin mediated enhancement of colonic function and contributed to the anti-intestinal dysmotility against loperamide-induced FC. Additionally, luteolin decreased the upregulation of aquaporin (AQP)-3, AQP-4, and AQP-8 in the colon of FC mice. In summary, our data showed that luteolin might be an attractive option for developing FC-relieving medications.

Non-canonical Small GTPase RBJ Promotes NSCLC Progression Through the Canonical MEK/ERK Signaling Pathway.

BACKGROUND: Although the majority of members belonging to the small GTPase Ras superfamily have been studied in several malignancies, the function of RBJ has remained unclear, particularly in non-small cell lung cancer (NSCLC). OBJECTIVE: The research aims to determine the function of RBJ in NSCLC. METHODS: The levels of RBJ protein in tumor tissue and para-carcinoma normal tissue were ascertained via immunohistochemistry (IHC). The growth, migration, and invasion of NSCLC cells were assessed by 5- ethynyl-2-deoxyuridine (EdU) assay, colony formation, cell counting kit-8 (CCK8), transwell and wound healing assays. Furthermore, a nude mouse xenograft model was established to study the function of RBJ in tumorigenesis in vivo. RESULTS: The IHC analysis revealed that the protein levels of RBJ were notably increased in tumor tissue and positively associated with the clinical stage. In addition, the knockdown of RBJ restrained the growth, invasion, and migration of NSCLC cell lines by inhibiting the epithelial-mesenchymal transition (EMT) through the MEK/ERK signaling pathway. Accordingly, opposite results were observed when RBJ was overexpressed. In addition, the overexpression of RBJ accelerated tumor formation by A549 cells in nude mice. CONCLUSION: RBJ promoted cancer progression in NSCLC by activating EMT via the MEK/ERK signaling. Thus, RBJ could be used as a potential therapeutic against NSCLC.

L-Cysteine Alleviates Myenteric Neuron Injury Induced by Intestinal Ischemia/Reperfusion via Inhibitin the Macrophage NLRP3-IL-1ß Pathway.

Ischemia/reperfusion injury is a common pathophysiological process in the clinic. It causes various injuries, multiple organ dysfunction, and even death. There are several possible mechanisms about ischemia/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were used to establish the ischemia/reperfusion model in vivo. Peritoneal macrophages were used for ATP depletion and hypoxia/reoxygenation experiment in vitro. L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia/reperfusion led to the injury of myenteric neurons. From experiments in vitro and in vivo, we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1ß. L-cysteine increased cystathionine beta synthase and H2S produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1ß-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia/reperfusion injury.