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Background: The gut microbiota (GM) has been implicated in neurological disorders, but the relationship with hydrocephalus, especially the underlying mechanistic pathways, is unclear. Using Mendelian randomization (MR), we aim to discover the mediating role of inflammatory factors in the relationship between GM and hydrocephalus. Methods: After removing confounders, univariable and multivariable MR analyses were performed using summary statistics to assess the causal relationships between GM, inflammatory factors (IL-17A and IL-27), and types of hydrocephalus. Meta-analyses were used to reconcile the differences in MR results between different hydrocephalus sources. Finally, mediator MR analyses were applied to determine the mediating effect of inflammatory factors. Various sensitivity analysis methods were employed to ensure the reliability and stability of the results. Results: After correction for P-values, Firmicutes (phylum) (OR, 0.34; 95%CI, 0.17-0.69; P = 2.71E-03, P FDR = 2.44E-02) significantly reduced the risk of obstructive hydrocephalus. The remaining 18 different taxa of GM had potential causal relationships for different types of hydrocephalus. In addition, Firmicutes (phylum) decreased the risk of obstructive hydrocephalus by increasing levels of IL-17A (mediating effect = 21.01%), while Eubacterium ruminantium group (genus) increased the risk of normal-pressure hydrocephalus by decreasing levels of IL-27 (mediating effect = 7.48%). Conclusion: We reveal the connection between GM, inflammatory factors (IL-17A and IL-27), and hydrocephalus, which lays the foundation for unraveling the mechanism between GM and hydrocephalus.
Subject(s)
Gastrointestinal Microbiome , Hydrocephalus , Interleukin-17 , Mendelian Randomization Analysis , Humans , Gastrointestinal Microbiome/immunology , Hydrocephalus/microbiology , Hydrocephalus/etiology , Hydrocephalus/immunology , Inflammation/microbiology , Interleukin-17/genetics , Interleukin-27/geneticsABSTRACT
Background: Hemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects. Methods: We assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders. Results: We finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40-0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08-0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02-4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09-0.77, PMVMR = 0.015) with significant causal relation to HS. Conclusion: We demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.
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Protothecosis, an infrequent human infection, is caused by achlorophyllic algae belonging to the genus Prototheca, particularly Prototheca wickerhamii. The skin stands as the most commonly affected organ. This report documents a case involving an 82-year-old male with Protothecosis. Histopathological analysis revealed granulomatous inflammation in the dermis, exhibiting necrotic features and hosting numerous non-budding spherical organisms. These organisms were positively stained using methenamine silver and periodic acid-Schiff stains, confirming identification as P. wickerhamii after validation through tissue culture and sequencing procedures. Initially, the patient received oral itraconazole at a dosage of 200 mg daily, accompanied by topical 1% naftifine-0.25% ketoconazole cream for a duration of 4 weeks, resulting in significant improvement. Subsequently, due to gastrointestinal discomfort presumably linked to itraconazole, terbinafine was administered. Over a span of 3 months, the patient received oral terbinafine at a dosage of 250 mg/day alongside the application of topical 1% naftifine-0.25% ketoconazole cream, leading to complete healing of the skin lesion, leaving behind a fibrotic scar.
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OBJECTIVE: Seizures are one of the complications that can occur after cranioplasty (CP). In some regions, titanium mesh remains the material of choice for CP. However, risk factors for seizures after titanium CP have been less studied. The purpose of this study was to identify potential risk factors for early seizures (≤7 days) and late seizures (>8 days) after titanium CP in a single institution. METHODS: A retrospective review was conducted of 241 consecutive patients who received titanium CP at the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2020. Univariate and multivariable logistic regression analyses were performed to determine the independent risk factors for new-onset seizures after titanium CP. RESULTS: Fifteen patients (6.22%) experienced early post-CP seizures, and late post-CP seizures were observed in 81 patients (33.61%). A flaccid concave cranial defect (P = 0.042) was associated with early post-CP seizures, whereas hypertension (P < 0.001) was the only significant predictor for late seizures after titanium CP. CONCLUSIONS: Seizure is a common complication after titanium CP, especially in patients who do not receive prophylactic antiepileptic drugs before the procedure. Risk factors for new-onset seizures at different periods after titanium CP were found to be different. In addition, radiologic factors before titanium CP may play a role in early new-onset seizures after titanium CP and should not be ignored.
Subject(s)
Decompressive Craniectomy , Titanium , Humans , Titanium/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Decompressive Craniectomy/adverse effects , Seizures/epidemiology , Seizures/etiology , Seizures/prevention & control , Risk Factors , Skull/surgery , Retrospective StudiesABSTRACT
Adult-onset xanthogranuloma (AOX) is one of the four rare syndromes collectively referred to as adult xanthogranulomatous disease (AXD). It primarily occurs in the orbit and ocular adnexa and displays distinctive histopathological features, characterized by the infiltration of non-Langerhans-derived foam-like histiocytes and Touton giant cells. The presence of diffuse yellow plaques on the eyelids serves as a highly indicative feature. In this report, we present a compelling case of bilateral periorbital AOX. Initially, the patient received a diagnosis of necrotizing xanthogranuloma (NBX) and underwent treatment with dapsone, which yielded a poor response. Subsequently, through repeated biopsy, immunoprotein electrophoresis, and high-throughput sequencing, the diagnosis was revised to AOX. Subsequently, the patient's treatment was modified to include oral hormone therapy, and no further progression of the periorbital plaque was observed. Notably, the patient's sister was diagnosed with xanthelasma palpebrarum (XP), suggesting a potential genetic association between AOX and XP. Unfortunately, the sister declined further histologic examination and genetic sequencing of her skin lesions, impeding the acquisition of additional evidence regarding the genetic link between these two disorders. Despite the divergent pathological features, pathogenesis, and clinical presentation of AOX and xanthelasma palbrarum, clinicians should remain cognizant of the plausible genetic correlation between these two conditions and pursue further investigations when feasible.
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BACKGROUND: Structural abnormalities in the brain of patients with atopic dermatitis (AD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of AD on brain structure. METHODS: This study utilized summary statistics from genome-wide association studies (GWASs) to investigate a collection of cerebral structural measures, encompassing cortical thickness (CT), cortical surface area (CA), and subcortical volumes in T1 images. A comprehensive GWAS meta-analysis identified a total of 20 independent single nucleotide polymorphisms linked to AD, surpassing the genome-wide significance threshold (p < 5 × 10â»8). MR estimates were aggregated through the application of the inverse variance weighted method. Additional complementary analyses (i.e., MR-Egger and weighted median approaches) were conducted to further assess the robustness of the obtained results. Sensitivity analysis and multivariate MR (MVMR) while adjusting for brain structural changes risk factors (i.e., depression and anxiety) were performed to assess the reliability and stability of observed causality. RESULTS: Genetically determined AD exhibited a causal link with reduced caudate volumes (IVW-MR: ß = -0.186, p = 0.001, p-corrected = 0.009). Furthermore, we identified potential causal associations between AD and reduced CT in the cingulate region (posterior cingulate, IVW-MR: ß = -0.065, p = 0.018, p-corrected = 0.551; isthmus cingulate, IVW-MR: ß = -0.086, p = 0.003, p-corrected = 0.188), as well as abnormal cortical surface area (CA) in the supramarginal (IVW-MR: ß = -0.047, p = 0.044, p-corrected = 0.714) and isthmus cingulate (IVW-MR: ß = 0.053, p = 0.018, p-corrected = 0.714). Additional supplementary analyses yielded consistent outcomes. There was no evidence of horizontal pleiotropy. MVMR analysis showed that the causal effects of AD on abnormal brain structure remained significant while adjusting for depression and anxiety. CONCLUSION: This MR study provided suggestive evidence that decreased caudate nucleus, posterior cingulate cortex, isthmus cingulate cortex and supramarginal gyrus are suggestively associated with higher AD risk. Future investigation into the brain regions is recommended, which helps to clarify the underlying mechanisms and point to new therapies against AD.
Subject(s)
Dermatitis, Atopic , Humans , Dermatitis, Atopic/diagnostic imaging , Dermatitis, Atopic/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Reproducibility of Results , Brain/diagnostic imagingABSTRACT
Purpose Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. Methods In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. Results We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. Conclusion Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy (AU)
Subject(s)
Humans , Glioma/drug therapy , Ivermectin/analogs & derivatives , Ivermectin/pharmacology , Apoptosis/drug effects , Reactive Oxygen Species/metabolismABSTRACT
Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. Psoriasis patients often require long-term treatment. Shanyaotianua decoction (STT), a typical traditional Chinese medicine prescription, positively affects psoriasis, although its molecular targets remain unknown. To elucidate its molecular mechanisms, a combination of network pharmacology, bioinformatics analysis, and drug similarity comparisons were employed. Participants were separated into 3 groups: non-lesional (NL), lesions after medication (LM), and psoriasis lesion groups (LS). Based on the Gene Ontology/kyoto encyclopedia of genes and genomes enrichment analyses, the key targets were mainly enriched for biological processes (immuno-inflammatory responses, leukocyte differentiation, lipid metabolic disorders, and viral infection) with the relevant pathways (Janus kinase/signal transducers and activators of transcription and adipocytokine signaling and T-helper 17 cell differentiation), thus identifying the possible action mechanism of STT against psoriasis. Target prediction for 18 STT compounds that matched the screening criteria was performed. Then, the STT compounds were intersected with the differentially expressed genes of the psoriatic process, and 5 proteins were potential targets for STT. Based on the open-source toolkit RDKit and DrugBank database, and through molecular docking and drug similarity comparisons, spinasterol, diosgenin, and 24-Methylcholest-5-enyl-3belta-O-glucopyranoside_qt may be potential drugs for psoriasis.
Subject(s)
Dermatitis , Psoriasis , Humans , Network Pharmacology , Molecular Docking Simulation , Psoriasis/drug therapy , Computational BiologyABSTRACT
[This corrects the article DOI: 10.7150/jca.46697.].
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PURPOSE: Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. METHODS: In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. RESULTS: We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. CONCLUSION: Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.
Subject(s)
Apoptosis , Glioma , Humans , Reactive Oxygen Species/metabolism , Ivermectin/pharmacology , Glioma/drug therapyABSTRACT
Background: Recent studies have suggested that the composition of gut microbiota (GM) may change after intracerebral hemorrhage. However, the causal inference of GM and hemorrhagic stroke is unknown. Mendelian Randomization (MR) is an effective research method that removes confounding factors and investigates the causal relationship between exposure and outcome. This study intends to explore the causal relationship between GM and hemorrhagic stroke with the help of MR. Methods: Univariable and multivariable MR analyses were performed using summary statistics of the GM (n = 18,340) in the MiBioGen consortium vs. the FinnGen consortium R9 summary statistics (intracerebral hemorrhage, subarachnoid hemorrhage, and nontraumatic intracranial hemorrhage). Causal associations between gut microbiota and hemorrhagic stroke were analyzed using inverse variance weighted, MR-Egger regression, weighted median, weighted mode, simple mode, and MR-PRESSO. Cochran's Q statistic, MR-Egger regression, and leave-one-out analysis were used to test for multiplicity and heterogeneity of instrumental variables. Separate reverse MR analyses were performed for microbiota found to be causally associated with hemorrhagic stroke in the forward MR analysis. Also, multivariate MR analyses were conducted after incorporating common confounders. Results: Based on the results of univariable and multivariate MR analyses, Actinobacteria (phylum) (OR, 0.80; 95%CI, 0.66-0.97; p = 0.025) had a protective effect against hemorrhagic stroke, while Rikenellaceae RC9 gut group (genus) (OR, 0.81; 95%CI, 0.67-0.99; p = 0.039) had a potential protective effect. Furthermore, Dorea (genus) (OR, 1.77; 95%CI, 1.27-2.46; p = 0.001), Eisenbergiella (genus) (OR, 1.24; 95%CI, 1.05-1.48; p = 0.013) and Lachnospiraceae UCG008 (genus) (OR, 1.28; 95%CI, 1.01-1.62; p = 0.041) acted as potential risk factors for hemorrhagic stroke. The abundance of Dorea (genus) (ß, 0.05; 95%CI, 0.002 ~ 0.101; p = 0.041) may increase, and that of Eisenbergiella (genus) (ß, -0.072; 95%CI, -0.137 ~ -0.007; p = 0.030) decreased after hemorrhagic stroke according to the results of reverse MR analysis. No significant pleiotropy or heterogeneity was detected in any of the MR analyses. Conclusion: There is a significant causal relationship between GM and hemorrhagic stroke. The prevention, monitoring, and treatment of hemorrhagic stroke through GM represent a promising avenue and contribute to a deeper understanding of the mechanisms underlying hemorrhagic stroke.
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As one of the prevalent posttranscriptional modifications of RNA, N7-methylguanosine (m7G) plays essential roles in RNA processing, metabolism, and function, mainly regulated by the methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) complex. Emerging evidence suggests that the METTL1/WDR4 complex promoted or inhibited the processes of many tumors, including head and neck, lung, liver, colon, bladder cancer, and teratoma, dependent on close m7G methylation modification of tRNA or microRNA (miRNA). Therefore, METTL1 and m7G modification can be used as biomarkers or potential intervention targets, providing new possibilities for early diagnosis and treatment of tumors. This review will mainly focus on the mechanisms of METTL1/WDR4 via m7G in tumorigenesis and the corresponding detection methods.
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OBJECTIVE: As a chronic complication of aneurysmal subarachnoid hemorrhage(aSAH), Shunt dependent hydrocephalus (SDHC) often leads to severe neurological deficits. At present, risk factors of SDHC after aSAH are being refined. So this study aims to investigate independent risk factors and develop a novel score to identify early the patients who require a permanent shunt. METHOD: Five hundred twenty-four patients treated in the first affiliated hospital of Harbin medical university from March 2019 to March 2021 were analyzed. We collected clinical and radiographic data of patients within 72 h after the ictus. The relevant factors were firstly analyzed by univariate analysis, and the significant factors (p < 0.05) were included in the multivariate logistic regression analysis to obtain the independent risk factors with statistical differences. The MAI score was established based on the contribution of different independent risk factors to the outcome. the new score was validated in another cohort (97 patients with aSAH from April and June 2021). RESULT: We enrolled 524 aneurysm patients and 41(7.82%) patients who underwent ventriculoperitoneal shunt (VPS) after aneurysm treatment. Based on univariate and multivariate analysis, Acute Hydrocephalus (OR 6.498,:95% confidence interval (CI) 1.98-21.33, p = 0.002), Intraventricular hemorrhage (OR 3.55,:95%CI 1.189-10.599, p = 0.023) and Modified Fisher score ≥ 3 (OR 5.846, 95%CI 2.649-12.900, p = 0.001) were independent risk factors. The novel score was assigned according to the contribution of different independent risk factors to the results. The MAI score: Modified Fisher grade ≥ 3 (1 point), Acute Hydrocephalus (1 point), Intraventricular hemorrhage (1 point). In the receiver operating characteristic curve analysis, the area under the curve (AUC) for the MAI score is 0.773 (p < 0.0001, 95%CI 0.686-0.861). Patients scoring 2-3 MAI points showed a 10-fold higher risk for shunt dependency than patients scoring 0-1 MAI points (p < 0.001). We performed internal validation of the MAI scoring system. The scoring system reliably predicted SDHC after aSAH. The AUC of the internal validation was 0.950 (p ï¼ 0.002, 95%CI 0.863-1.000). CONCLUSION: We develop a novel score based on univariate and multivariate analysis. The effectiveness of the MAI score has been confirmed in this study, which can more accurately predict SDHC after aASH and can be widely used in clinical practice. Prospective studies are needed for validation in the future.
Subject(s)
Hydrocephalus , Subarachnoid Hemorrhage , Humans , Hydrocephalus/diagnostic imaging , Hydrocephalus/etiology , Hydrocephalus/surgery , Prospective Studies , Retrospective Studies , Risk Factors , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/surgery , Ventriculoperitoneal Shunt/adverse effectsABSTRACT
Glioblastoma (GBM) is one of the most widespread and lethal types of cancer. However, there are currently no drugs or therapeutic strategies that can completely cure GBM. Doramectin (DRM) has a broad range of activities against endoparasites and ectoparasites, and is extensively used in livestock. In the present study, the effect of DRM on the induction of autophagy in U87 and C6 GBM and glioma cell lines, as well as the mechanism of autophagy, were examined. First, transmission electron microscopy, plasmid transfection and western blot analysis demonstrated that DRM could induce autophagy in U87 and C6 cells in vitro. Next, MTT and colony formation assays revealed that DRMinduced autophagy prevented U87 and C6 cell viability and colony formation ratio. In addition, DRMinduced autophagy promoted U87 and C6 cell apoptosis, as indicated by DAPI analysis and flow cytometry. Furthermore, transcriptome analysis demonstrated that DRM modulated a number of genes and pathways involved in autophagy. In a nude mouse xenograft model, immunohistochemical staining and the TUNEL assay demonstrated that the effect of DRM on the tumor was consistent with that in vivo. These data indicated that DRM induced autophagy mainly by blocking the PI3K/AKT/mTOR signaling pathway in GBM cells. DRMinduced autophagy promoted the inhibition of GBM cell proliferation and apoptosis in vitro and in vivo. The present study suggested that DRM may be an effective drug for the treatment of GBM.
Subject(s)
Glioblastoma/drug therapy , Ivermectin/analogs & derivatives , Animals , Autophagy/drug effects , Autophagy/genetics , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Survival/genetics , Disease Models, Animal , Humans , Ivermectin/metabolism , Ivermectin/pharmacology , Rats/metabolismABSTRACT
AIM: To investigate the safety of combined cranioplasty (CP) and ventriculoperitoneal shunt (VPS) placement. Furthermore, we investigated whether the sequence of these procedures affects the postoperative complication rates associated with staged CP and VPS placement. MATERIAL AND METHODS: We retrospectively investigated patients who developed communicating hydrocephalus after decompressive craniectomy and subsequently underwent VPS placement and CP at the hospital at which this study was performed between January 2009 and December 2019. Patients were categorized into group 1 (simultaneous CP and VPS placement) and group 2 (CP and VPS placement performed separately). Group 2 was subcategorized into subgroup 2a (CP performed before VPS placement) and subgroup 2b (VPS placement performed before CP). The Student?s t and Chi square tests were used to analyze intergroup differences. RESULTS: This study included 86 patients; 22 in group 1 and 64 in group 2 (24 patients in subgroup 2a and 40 patients in subgroup 2b). No statistically significant difference was observed in the overall complication rates between groups 1 and 2 (36.4% vs. 28.1%, P=0.591). However, the incidence of infections was significantly higher in group 1 than in group 2 (22.7% vs. 4.7%, P=0.024). Subgroup analysis showed that the overall complication rate was signi?cantly lower in subgroup 2a than in subgroup 2b (12.5% vs. 37.5%, P=0.031). CONCLUSION: Simultaneous CP and VPS placement is associated with a high incidence of infections. Moreover, compared with initial CP, initial VPS placement is associated with a significantly higher risk of overall complications in patients who undergo a staged procedure.
Subject(s)
Decompressive Craniectomy , Hydrocephalus , Decompressive Craniectomy/adverse effects , Decompressive Craniectomy/methods , Humans , Hydrocephalus/etiology , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Retrospective Studies , Skull/surgery , Ventriculoperitoneal Shunt/adverse effects , Ventriculoperitoneal Shunt/methodsABSTRACT
Moxidectin (MOX), a broad-spectrum antiparasitic drug, has been characterized as a potential anti-glioma agent. The main objective of this study was to explore autophagy induced by MOX in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, the effects of autophagy on apoptosis in glioma cells were tested. Autophagy was measured by transmission electron microscopy (TEM), immunofluorescence, western blot and immunohistochemistry. Cell viability was detected with MTT and colony formation assay. The apoptosis rate was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Additonally, autophagy inhibition was achieved by using 3-Methyladenine (3-MA) and chloroquine (CQ). U251-derived xenografts were established for examination of MOX-induced autophagy on glioma in vivo. Firstly, our research found that MOX stimulated autophagy of glioma cells in a dose-dependent manner. Secondly, we found that MOX induced autophagy by inhibiting the AKT/mTOR signalling pathway. Thirdly, inhibition of autophagy could reduce apoptosis in MOX-treated glioma cells. Finally, MOX induced autophagy, and autophagy increased the apoptosis effect of MOX on U251 in vivo. In conclusion, our data provide evidence that MOX can induce autophagy in glioma cells, and autophagy could increase MOX-induced apoptosis through inhibiting the AKT/mTOR signalling pathway. These findings provided a new prospect for the application of MOX and a novel targeted therapy for the treatment of gliomas.
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Glioma is one of the most common types of primary brain tumors. Ivermectin (IVM), a broad-spectrum antiparasitic drug, has been identified as a novel anticancer agent due to its inhibitory effects on the proliferation of glioma cells in vitro and in vivo. However, the ability of IVM to induce autophagy and its role in glioma cell death remains unclear. The main objective of the present study was to explore autophagy induced by IVM in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, we examined the effects of autophagy on apoptosis in glioma cells. In the present study, transmission electron microscopy (TEM), immunofluorescence, Western blot and immunohistochemistry were used to evaluate autophagy activated by IVM. Cell viability was measured by 3-(4,5-dimethylthiazol2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay. The apoptosis rate was detected by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Meanwhile, autophagy inhibition was achieved by using chloroquine (CQ). U251-derived xenografts were established for examination of IVM-induced autophagy on glioma in vivo. Taken together, the results of the present study showed that autophagy induced by IVM has a protective effect on cell apoptosis in vitro and in vivo. Mechanistically, IVM induced autophagy through AKT/mTOR signaling and induced energy impairment. Our findings show that IVM is a promising anticancer agent and may be a potential effective treatment for glioma cancers.
Subject(s)
Autophagic Cell Death/drug effects , Glioma , Ivermectin/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , Cell Line, Tumor , Glioma/drug therapy , Glioma/metabolism , Glioma/pathology , Humans , MiceABSTRACT
OBJECTIVE: Intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatments. And caspase-1-mediated inflammatory response happened during the progression of ICH. Therefore, we aimed to investigate the effects of caspase-1 inhibitor Ac-YVAD-cmk on ICH. MATERIALS AND METHODS: Microglia cells were isolated and activated by thrombin for 24â¯h. Then the transcript and protein expressions of NLRP3 and inflammatory factors were assessed by RT-PCR and western blotting. Moreover, Ac-YVAD-cmk was injected into the ICH model. The mNSS and brain water content were tested at 24â¯h post-ICH. Finally, the pathological changes of microglia activation following ICH were discovered by the immunohistochemical and HE staining ways. RESULTS: Ac-YVAD-cmk inhibited the activation of pro-caspase-1 and decreased brain edema, in association with decreasing activated microglia and the expression of inflammation-related factors at 24â¯h post-ICH. Consequently, Ac-YVAD-cmk reduced the release of mature IL-1ß/IL-18 in perihematoma, improved the behavioral performance, and alleviated microglia in perihematoma region in ICH rats. CONCLUSIONS: These results indicate that caspase-1 could amplify the plural inflammatory responses in the ICH. Administration of Ac-YVAD-cmk has the potential to be a novel therapeutic strategy for ICH.