SLC25A32 promotes malignant progression of glioblastoma by activating PI3K-AKT signaling pathway.

BACKGROUND: Solute carrier family 25 member 32 (SLC25A32) is an important member of SLC25A family and plays a role in folate transport metabolism. However, the mechanism and function of SLC25A32 in the progression of human glioblastoma (GBM) remain unclear. METHODS: In this study, folate related gene analysis was performed to explore gene expression profiles in low-grade glioma (LGG) and GBM. Western blotting, real-time quantitative PCR (qRT-PCR), and immunohistochemistry (IHC) were used to confirm the expression levels of SLC25A32 in GBM tissues and cell lines. CCK-8 assays, colony formation assays, and Edu assays were performed to assess the role of SLC25A32 on proliferation in GBM in vitro. A 3D sphere invasion assay and an ex vivo co-culture invasion model were performed to assess the effects of SLC25A32 on invasion in GBM. RESULTS: Elevated expression of SLC25A32 was observed in GBM, and high SLC25A32 expression was associated with a high glioma grade and poorer prognosis. Immunohistochemistry performed with anti-SLC25A32 on samples from an independent cohort of patients confirmed these results. Knockdown of SLC25A32 inhibited the proliferation and invasion of GBM cells, but overexpression of SLC25A32 significantly promoted cell growth and invasion. These effects were mainly due to the activation of the PI3K-AKT-mTOR signaling pathway. CONCLUSION: Our study demonstrated that SLC25A32 plays a significant role in promoting the malignant phenotype of GBM. Therefore, SLC25A32 can be used as an independent prognostic factor in patients with GBM, providing a new target for the comprehensive treatment of GBM.

Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice.

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/ß-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aß) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aß levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aß phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.

Fully neuroendoscopic resection of cerebellopontine angle tumors through a retrosigmoid approach: a retrospective single-center study.

The objective of this study is to preliminarily investigate the surgical safety, efficacy, techniques, and clinical value of fully neuroendoscopic surgery for the resection of cerebellopontine angle (CPA) tumors via a retrosigmoid approach. The clinical data of 47 cerebellopontine angle area (CPA) tumors that were treated by full neuroendoscopic surgery from June 2014 to June 2023 were retrospectively analyzed. The efficacy and advantages of the surgical techniques were evaluated based on indicators such as duration of the surgery, neuroendoscopic techniques, intraoperative integrity of nerves and blood vessels, extent of tumor resection, outcomes or postoperative symptoms, and incidence of complications. The 47 cases of cerebellopontine angle tumors include 34 cases of epidermoid cysts, 7 cases of vestibular schwannomas, and 6 cases of meningiomas. All patients underwent fully neuroendoscopic surgery. Twenty tumors were removed using the one-surgeon two-hands technique, and 27 tumors were removed using the two-surgeons four-hands technique. The anatomical integrity of the affected cranial nerves was preserved in all 47 cases. None of the patients suffered a postoperative hemorrhage, cerebrospinal fluid leak, and aseptic or septic meningitis, or died. The rate of total tumor resection was 72.3% (34/47), and the symptom improvement rate was 89.4% (42/47). All patients were followed up for 2 to 12 months, and none died nor showed any signs of tumor recurrence. By analyzing 47 fully neuroendoscopic resections of CPA tumors using the posterior sigmoid sinus approach in our center, we believe that such method allows complete, safe, and effective resection of CPA tumors and is thereby worthy of clinical promotion.

Evaluation of nausea and vomiting in the first trimester on the risk of adverse birth outcomes and the contribution of genetic polymorphisms: a pilot prospective study.

PURPOSE: To evaluate the impact of Nausea and Vomiting in Pregnancy (NVP) on the risk of Preterm Birth (PTB) and Low Birth Weight (LBW), and explore the effect of genetic polymorphisms on the severity of NVP. METHODS: A prospective study was conducted. Participants' experience of NVP prior to 12 gestational weeks were evaluated by a Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale. 11 Single Nucleotide Polymorphisms (SNPs) loci located in growth differentiation factor 15 (GDF15) and leucine-rich repeat containing 25 (LRRC25) gene of chr19p13.11 and intergenic region of chr4q12 were genotyped, which were implicated as genetic risk factors for NVP. Logistic regression models were applied to determine the effect of NVP in the first trimester on the risk of PTB and LBW, and genetic polymorphisms on the risk of NVP. RESULTS: Among 413 pregnant women, the incidence of nausea and vomiting was 85.5% (n = 353) in the first trimester, including 38.7% (n = 160) mild vomiting, 42.6% (n = 176) moderate vomiting and 4.1% (n = 17) severe vomiting. 33 were PTB, 20 were LBW. Compared with pregnant women without NVP, women with mild, moderate or severe NVP in the first trimester were not associated with the risk of PTB and LBW. Besides, the polymorphisms of 11 SNPs loci were not associated with the risk of NVP. CONCLUSIONS: Our study indicated that symptoms of nausea and vomiting in the first trimester were not significantly associated with PTB and LBW, and there were also no associations between GDF15 and LRRC25 polymorphisms and NVP.

A Novel Strategy for Rapid Fluorescence Detection of FluB and SARS-CoV-2.

Undoubtedly, SARS-CoV-2 has caused an outbreak of pneumonia that evolved into a worldwide pandemic. The confusion of early symptoms of the SARS-CoV-2 infection with other respiratory virus infections made it very difficult to block its spread, leading to the expansion of the outbreak and an unreasonable demand for medical resource allocation. The traditional immunochromatographic test strip (ICTS) can detect one analyte with one sample. Herein, this study presents a novel strategy for the simultaneous rapid detection of FluB/SARS-CoV-2, including quantum dot fluorescent microspheres (QDFM) ICTS and a supporting device. The ICTS could be applied to realize simultaneous detection of FluB and SARS-CoV-2 with one test in a short time. A device supporting FluB/SARS-CoV-2 QDFM ICTS was designed and had the characteristics of being safe, portable, low-cost, relatively stable, and easy to use, ensuring the device could replace the immunofluorescence analyzer in cases where there is no need for quantification. This device does not need to be operated by professional and technical personnel and has commercial application potential.

[The correlation between sperm DNA damage and IVF-ET clinical pregnancy outcomes in different BMI population with normal routine semen examination].

OBJECTIVE: To analyze the correlation between sperm DFI, HDS and IVF-ET pregnancy outcomes in different BMI populations with normal routine semen examination. METHODS: The clinical data of 199 cycles of IVF-ET were retrospectively analyzed. Sperm chromatin structure analysis based on flow cytometry was used to detect sperm DFI and HDS. The correlation between sperm DFI, HDS and pregnancy outcome of IVF-ET were analyzed. RESULTS: The sperm DFI was negatively correlated with IVF-ET pregnancy in overweight (24.0 kg/m2≤BMI<28.0 kg/m2) population (OR=0.935, P=0.043). In the normal BMI group (18.5 kg/m2≤BMI < 24.0 kg/m2), the clinical pregnancy outcome of IVF-ET was not significantly correlated with sperm DFI, and was negatively correlated with male age (OR=0.744, P=0.020). In the obese population (BMI ≥ 28.0 kg/m2) , there was no significant correlation between the clinical pregnancy outcome of IVF-ET and sperm DNA fragmentation index (DFI) , but a negative correlation with male BMI (OR = 0.779, P = 0.043). CONCLUSION: The male BMI affected the correlation between sperm DFI and IVF-ET pregnancy outcomes: ①Sperm DFI was only associated with IVF-ET clinical pregnancy outcome in the overweight population; ② In normal BMI and obese populations, male age and male BMI were important factors affecting IVF-ET clinical pregnancy outcome respectively; ③No correlation was found between sperm HDS and IVF-ET pregnancy outcomes.

SIRT3 attenuates coronary atherosclerosis in diabetic patients by regulating endothelial cell function.

BACKGROUND: This study aimed to explore the relationship between the Sirtuin 3 (SIRT3) gene and endothelial cell dysfunction, contributing to the progression of coronary atherosclerosis driven by hyperglycemia. METHODS: We measured serum SIRT3 levels using enzyme-linked immunosorbent assay in 95 patients with type 2 diabetes mellitus (T2DM) who underwent diagnostic coronary angiography. The patients were divided into two groups according to the presence (n = 45) or absence (n = 50) of coronary artery disease (CAD). Human aortic endothelial cells (HAECs) grown in vitro in a medium with various concentrations of glucose (5.5, 11, 16.5, 22, 27.5, 33, and 38.5 mM) for 24 h were assessed for protein expression of SIRT3, peroxisome proliferator-activated receptor alpha (PPAR-α), endothelial nitric oxide (NO) synthase (eNOS), and inducible NO synthase (iNOS) using Western blot analysis. HAECs were subjected to SIRT3 overexpression or inhibition through SIRT3 adenovirus and siRNA transfection. RESULTS: Serum SIRT3 levels were significantly lower in T2DM patients with CAD than in those without CAD (p = 0.048). The in vitro results showed that HG significantly increased SIRT3, PPAR-α, and eNOS protein expression in a concentration-dependent manner. Moreover, iNOS expression was decreased in HAECs in response to HG. Reduced PPAR-α and eNOS levels and increased iNOS levels were observed in SIRT3 silenced HAECs cells. In contrast, SIRT3 overexpression significantly improved PPAR-α and eNOS expression and suppressed iNOS expression. CONCLUSION: SIRT3 was associated with the progression of atherosclerosis in T2DM patients through upregulation of PPAR-α and eNOS and downregulation of iNOS, which are involved in endothelial dysfunction under hyperglycemic conditions.

Investigating the binding properties between antimony(V) and dissolved organic matter (DOM) under different pH conditions during the soil sorption process using fluorescence and FTIR spectroscopy.

Antimony (Sb) is listed as a priority pollutant by European Union and U.S. Environmental Protection Agency. However, reports on its environmental behavior, particularly the sorption process in soil are still limited. In this paper, Sb(V) was selected as the sorbate and the black soil as the sorbent. The initial sorption rate (k2qe,cal2) was calculated to be 0.1254 mg g-1∙min-1 and the maximum sorption amount (qm) 57.33 mg g-1. Once the dissolved organic matter (DOM) was removed from the soil, the values of k2qe,cal2 and qm went down to 0.1066 mg g-1∙min-1 and 19.01 mg g-1, respectively. These results suggested that the existence of DOM significantly influenced the mass transfer rate and sorption amount of Sb(V) in soil. In order to find out the reason why DOM exerted such an influence, the binding interaction mechanism between Sb(V) and DOM was investigated under different pH values. The protein-like and humic-like substances as well as the functional groups of CO, phenol hydroxyl, C-O, C-H, C-X and sulfur/phosphorus contributed to the formation of DOM-Sb(V)-complexes under pH of 7.0, in which the humic-like substance and the functional groups containing oxygen showed higher binding affinity for Sb(V) than protein-like substance and other functional groups, respectively. The protein-like substance and some functional groups disappeared under pH of 4.0 and 10.0. Alkaline condition resulted in a bigger impact on reducing the number of functional groups than acid condition. It can be concluded that the strongest binding interaction occurred at pH of 7.0 then followed by 4.0 and 10.0. This paper might be helpful to further studying the environmental behavior of Sb(V) in soil.

Key Role of Lanthanum Oxychloride: Promotional Effects of Lanthanum in NiLaOy /NaCl for Hydrogen Production from Ethyl Acetate and Water.

The hydrogen economy is accelerating technological evolutions toward highly efficient hydrogen production. In this work, the catalytic performance of NiO/NaCl for hydrogen production via autothermal reforming of ethyl acetate and water is further improved through lanthanum modification, and the resulted 3%-NiLaOy /NaCl catalyst achieves as high as 93% H2 selectivity and long-term stability at 600 °C. The promoting effect is caused by the strong interactions between lanthanum and NiO/NaCl, by which LaNiO3 and a novel LaOCl phase are formed. The key role of LaOCl in promoting low-temperature hydrogen production is highlighted, while effects of LaNiO3 are well known. The LaOCl (010) facet possesses high adsorption capacity toward co-chemisorbing ethyl acetate and water. LaOCl strongly interacts with ethyl acetate and H2 O in the form of hydrogen bonding and coordination effect. The interactions induce tensions inside ethyl acetate and H2 O, activate the molecules, and hence decrease the energy barrier for reaction. In situ Fourier transform infrared spectroscopy (FTIR) reveals that LaOCl along with NaCl enhances the adsorption ability of NiO/NaCl. Moreover, LaOCl improves the dispersion of Ni species in NiO-LaNiO3 -LaOCl nanosheets, which possess abundant active sites. The effects together promote hydrogen evolution. Furthermore, the NiLaOy /NaCl catalyst can be easily reborn after deactivation due to the water solubility of NaCl.

SIRT3 MEDIATES THE CARDIOPROTECTIVE EFFECT OF THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST AND RESUSCITATION BY RESTORING AUTOPHAGIC FLUX VIA THE PI3K/AKT/MTOR PATHWAY.

ABSTRACT: Background : Postresuscitation cardiac dysfunction is a significant contributor to early death following cardiopulmonary resuscitation (CPR). Therapeutic hypothermia (TH) mitigates myocardial dysfunction due to cardiac arrest (CA); however, the underlying mechanism remains unclear. Sirtuin 3 (Sirt3) was found to affect autophagic activity in recent research, motivating us to investigate its role in the cardioprotective effects of TH in the treatment of CA. Methods : Sprague-Dawley rats were used to establish an in vivo CA/CPR model and treated with a selective Sirt3 inhibitor or vehicle. Survival rate, myocardial function, autophagic flux, and Sirt3 expression and activity were evaluated. H9C2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro . The cells were transfected with Sirt3-siRNA and treated with the autophagy inhibitor chloroquine or the PI3K inhibitor LY294002, and cell viability and autophagic flux were assessed. Results : Rats exhibited decreased survival and impaired cardiac function after CA/CPR, which were alleviated by TH. Mechanistically, TH restored Sirt3 expression and autophagic flux, which were impaired by CA/CPR. Sirt3 inactivation diminished the capacity of TH to restore autophagic flux and partially abolished the improvements in myocardial function and survival. An in vitro study further showed that TH-induced restoration of disrupted autophagic flux by OGD/R was attenuated by pretreatment with Sirt3-siRNA, and this attenuation was partially rescued by the inhibition of PI3K/Akt/mTOR signaling cascades. Conclusions : Sirt3 mediates the cardioprotective effect of TH by restoring autophagic flux via the PI3K/Akt/mTOR pathway. These findings suggest the potential of Sirt3 as a therapeutic target for CA.

Association between hypertensive disorders and Bell's palsy in pregnancy: protocol for a systematic review and meta-analysis.

BACKGROUND: Bell's palsy is an idiopathic peripheral nerve palsy involving the facial nerve. Pregnancy, diabetes mellitus and hypertension are the risk factors for Bell's palsy. However, the association between hypertensive disorders and Bell's palsy during pregnancy or the puerperium remains unclear. This systematic review will comprehensively summarise the literature and evaluate the association between Bell's palsy and hypertensive disorders during pregnancy or the puerperium. METHODS AND ANALYSIS: Systematic searches of PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials will be undertaken using prespecified search strategies. Observational studies (cross-sectional studies, cohort studies, case reports and series case reports) written in English that investigate the association between hypertensive disorders of late pregnancy and Bell's palsy during pregnancy or the puerperium will be included. Different authors will independently conduct the eligible study selection, perform data extraction and appraise the quality of included studies. Subgroup analysis will be carried out based on the age of pregnant women (≤35 years old, >35 years old), parity (primipara, multipara) and fetus number (singleton or multiple-gestation pregnancy). ETHICS AND DISSEMINATION: This review will be based on published literature, and thus there is no requirement for ethics approval. The results of this study will aid in the knowledge of the relationship between Bell's palsy during pregnancy or the puerperium and hypertensive disorders of late pregnancy. The results of this systematic review will be shared through publication in a peer-reviewed journal with good visibility for the field of obstetrics and presentations at academic conferences. PROSPERO REGISTRATION NUMBER: CRD42023422902.

Air-Liquid Interface Microfluidic Monitoring Sensor Platform for Studying Autophagy Regulation after PM2.5 Exposure.

Undoubtedly, a deep understanding of PM2.5-induced tumor metastasis at the molecular level can contribute to improving the therapeutic effects of related diseases. However, the underlying molecular mechanism of fine particle exposure through long noncoding RNA (lncRNA) regulation in autophagy and, ultimately, lung cancer (LC) metastasis remains elusive; on the other hand, the related monitoring sensor platform used to investigate autophagy and cell migration is lacking. Herein, this study performed an air-liquid interface microfluidic monitoring sensor (AIMMS) platform to analyze human bronchial epithelial cells after PM2.5 stimulation. The multiomics analysis [RNA sequencing (RNA-seq) on lncRNA and mRNA expressions separately] showed that MALAT1 was highly expressed in the PM2.5 treatment group. Furthermore, RNA-seq analysis demonstrated that autophagy-related pathways were activated. Notably, the main mRNAs associated with autophagy regulation, including ATG4D, ATG12, ATG7, and ATG3, were upregulated. Inhibition or downregulation of MALAT1 inhibited autophagy via the ATG4D/ATG12/ATG7/ATG3 pathway after PM2.5 exposure and ultimately suppressed LC metastasis. Thus, based on the AIMMS platform, we found that MALAT1 might become a promising therapeutic target. Furthermore, this low-cost AIMMS system as a fluorescence sensor integrated with the cell-monitor module could be employed to study LC migration after PM2.5 exposure. With the fluorescence cell-monitoring module, the platform could be used to observe the migration of LC cells and construct the tumor metastasis model. In the future, several fluorescence probes, including nanoprobes, could be used in the AIMMS platform to investigate many other biological processes, especially cell interaction and migration, in the fields of toxicology and pharmacology.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/ß-catenin pathway in glioblastoma.

BACKGROUND: Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance. METHODS: In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets. RESULTS: HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of ß-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo. CONCLUSIONS: Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and ß-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.

Heterostructure tailoring of carbon nanotubes grown on prismatic NiCo clusters for high-efficiency electromagnetic absorption.

The employment of electromagnetic (EM) absorbers integrating elaborate architecture, enhanced microwave absorption and multifunctional features remains a formidable challenge in practical applications including military stealth and incoming 5G electronic information era. Herein, a novel microwave absorber has been fabricated by in-situ growing carbon nanotubes (CNTs) on the prismatic nickel-cobalt (NiCo) clusters derived from Ni-Co layered double hydroxides (NiCo-LDH) via catalytic carbonization of ethyl acetate. The NiCo/CNTs composites with highly porous texture could provide sufficient open space to balance the impedance and introduce magnetic loss mechanism. Accordingly, the absorbers achieved remarkable EM absorption performance with a minimum reflection loss of -46.2 dB at 1.5 mm and broad bandwidth of 5.8 GHz owing to synergistic magnetic-dielectric effects and distinct structural merits. The NiCo/CNTs absorber manifests superior radar wave attenuation by the radar cross section simulation and density functional theory (DFT) was also performed to elucidate the potential mechanisms of the heterostructure formation and performance enhancement in the NiCo/CNTs composites. This work is expected to provide new insights or inspirations to modulate EM properties by rationally designing heterostructure for the elimination of severe EM pollution.

Integrated system for rapid enrichment and detection of airborne polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are extremely toxic environmental pollutants, which are harmful to the human body. Direct collection and analysis of airborne PAHs is essential for air quality monitoring. Herein, we demonstrated an integrated system for airborne PAHs enrichment and detection. The enrichment cube was composed of channels with threaded structures and curved channels, which had high capture efficiency. Then PAHs-carried particles could be crushed into the detection chip for testing. The whole process took about 25 min (5 min for PAHs enrichment and 20 min for PAHs test). The limit of detection was 3.3 ng/m3, which could meet the needs of daily analysis. It had the advantages of low cost, low reagent consumption, simple operation, semi-automatic operation, high sensitivity, high speed and high throughput compared with conventional techniques, showing the potential for becoming an air pollution monitoring platform.

BCL2L13 promotes mitophagy through DNM1L-mediated mitochondrial fission in glioblastoma.

There is an urgent need for novel diagnostic and therapeutic strategies for patients with Glioblastoma multiforme (GBM). Previous studies have shown that BCL2 like 13 (BCL2L13) is a member of the BCL2 family regulating cell growth and apoptosis in different types of tumors. However, the clinical significance, biological role, and potential mechanism in GBM remain unexplored. In this study, we showed that BCL2L13 expression is significantly upregulated in GBM cell lines and clinical GBM tissue samples. Mechanistically, BCL2L13 targeted DNM1L at the Ser616 site, leading to mitochondrial fission and high mitophagy flux. Functionally, these alterations significantly promoted the proliferation and invasion of GBM cells both in vitro and in vivo. Overall, our findings demonstrated that BCL2L13 plays a significant role in promoting mitophagy via DNM1L-mediated mitochondrial fission in GBM. Therefore, the regulation and biological function of BCL2L13 render it a candidate molecular target for treating GBM.

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer's disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-ß levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.

Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.