Extracellular Vesicles Derived from Glioma Stem Cells Affect Glycometabolic Reprogramming of Glioma Cells Through the miR-10b-5p/PTEN/PI3K/Akt Pathway.

OBJECTIVE: Glioma is one of the most prevalently diagnosed types of primary malignant brain tumors. Glioma stem cells (GSCs) are crucial in glioma recurrence. This study aims to elucidate the mechanism by which extracellular vehicles (EVs) derived from GSCs modulate glycometabolic reprogramming in glioma. METHODS: Xenograft mouse models and cell models of glioma were established and treated with GSC-EVs. Additionally, levels and activities of PFK1, LDHA, and FASN were assessed to evaluate the effect of GSC-EVs on glycometabolic reprogramming in glioma. Glioma cell proliferation, invasion, and migration were evaluated using MTT, EdU, Colony formation, and Transwell assays. miR-10b-5p expression was determined, with its target gene PTEN and downstream pathway PI3K/Akt evaluated. The involvement of miR-10b-5p and the PI3K/Akt pathway in the effect of GSC-EVs on glycometabolic reprogramming was tested through joint experiments. RESULTS: GSC-EVs facilitated glycometabolic reprogramming in glioma mice, along with enhancing glucose uptake, lactate level, and adenosine monophosphate-to-adenosine triphosphate ratio. Moreover, GSC-EV treatment potentiated glioma cell proliferation, invasion, and migration, reinforced cell resistance to temozolomide, and raised levels and activities of PFK1, LDHA, and FASN. miR-10b-5p was highly-expressed in GSC-EV-treated glioma cells while being carried into glioma cells by GSC-EVs. miR-10b-5p targeted PTEN and activated the PI3K/Akt pathway, hence stimulating glycometabolic reprogramming. CONCLUSION: GSC-EVs target PTEN and activate the PI3K/Akt pathway through carrying miR-10b-5p, subsequently accelerating glycometabolic reprogramming in glioma, which might provide new insights into glioma treatment.

Long noncoding RNAs as potential diagnostic biomarkers for diabetes mellitus and complications: A systematic review and meta-analysis.

AIMS: Long noncoding RNAs (lncRNAs) may be associated with the development of type 2 diabetes mellitus and its complications; however, the findings remain controversial. We aimed to synthesize the available data to assess the diagnostic utility of lncRNAs for identification of type 2 diabetes mellitus and its consequences. MATERIALS AND METHODS: We performed a systematic review and meta-analysis, searching PubMed, Embase, and Web of Science for articles published from September 11, 2015 to December 27, 2022. We evaluated human case-control or cohort studies on differential lncRNA expression in type 2 diabetes mellitus or its associated comorbidities. We excluded studies if they were non-peer reviewed or published in languages other than English. From 2387 identified studies, we included 17 (4685 participants). RESULTS: Analysis of the pooled data showed that lncRNAs had a diagnostic area under the curve (AUC) of 0.84 (95% CI: 0.80-0.87), with a sensitivity of 0.79 (95% CI: 0.74-0.83) and a specificity of 0.75 (95% CI: 0.69-0.80). LncRNAs had an AUC of 0.65 for the diagnosis of prediabetes, with 82% sensitivity and 65% specificity. CONCLUSIONS: LncRNAs may be promising diagnostic markers for type 2 diabetes mellitus and its complications.

Machine learning-based model for predicting inpatient mortality in adults with traumatic brain injury: a systematic review and meta-analysis.

Background and objective: Predicting mortality from traumatic brain injury facilitates early data-driven treatment decisions. Machine learning has predicted mortality from traumatic brain injury in a growing number of studies, and the aim of this study was to conduct a meta-analysis of machine learning models in predicting mortality from traumatic brain injury. Methods: This systematic review and meta-analysis included searches of PubMed, Web of Science and Embase from inception to June 2023, supplemented by manual searches of study references and review articles. Data were analyzed using Stata 16.0 software. This study is registered with PROSPERO (CRD2023440875). Results: A total of 14 studies were included. The studies showed significant differences in the overall sample, model type and model validation. Predictive models performed well with a pooled AUC of 0.90 (95% CI: 0.87 to 0.92). Conclusion: Overall, this study highlights the excellent predictive capabilities of machine learning models in determining mortality following traumatic brain injury. However, it is important to note that the optimal machine learning modeling approach has not yet been identified. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=440875, identifier CRD2023440875.

Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling.

The transformation of microglia to a pro-inflammatory phenotype at the site of traumatic brain injury (TBI) drives the progression of secondary neurodegeneration and irreversible neurological impairment. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to suppress this phenotype transformation, thereby reducing neuroinflammation following TBI, but the molecular mechanisms are unknown. We found that Omega-3 PUFA suppressed the expression of disintegrin metalloproteinase (ADAM17), the enzyme required to convert tumor necrosis factor-α (TNF-α) to the soluble form, thereby inhibiting the TNF-α/NF-κB pathway both in vitro and in a mouse model of TBI. Omega-3 PUFA also prevented the reactive transformation of microglia and promoted the secretion of microglial exosomes containing nerve growth factor (NGF), activating the neuroprotective NGF/TrkA pathway both in culture and TBI model mice. Moreover, Omega-3 PUFA suppressed the pro-apoptotic NGF/P75NTR pathway at the TBI site and reduced apoptotic neuronal death, brain edema, and disruption of the blood-brain barrier. Finally, Omega-3 PUFA preserved sensory and motor function as assessed by two broad-spectrum test batteries. The beneficial effects of Omega-3 PUFA were blocked by an ADAM17 promotor and by a NGF inhibitor, confirming the pathogenic function of ADAM17 and the central neuroprotective role of NGF. Collectively, these findings provide a strong experimental basis for Omega-3 PUFA as a potential clinical treatment for TBI.

ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-ß1/Smad Pathway Following Experimental Traumatic Brain Injury.

Microglia-mediated neuroinflammatory responses play important roles in secondary neurological injury after traumatic brain injury (TBI). The TGF-ß pathway participates in the regulation of M1/M2 phenotype transformation of microglia. TGF-ß can activate the Smad pathway by binding to TGF-ßRs, which is regulated by the cleavage function of A disintegrin and metalloproteinase 17 (ADAM17). However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear. Herein, we assessed the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after the inhibition of ADAM17. The formation of TGF-ßRs and TGF-ß1/TGF-ßRII complexes on microglia were detected to evaluate the effect of ADAM17 inhibition on the TGF-ß1/Smad pathway. ADAM17 was highly expressed after TBI and mainly located in the microglia. the inhibition of ADAM17 improved neurological function after TBI. The neuroprotective effect of ADAM17 inhibition was related to a shift from the M1 microglial phenotype to the M2 microglial phenotype, thus reducing TBI-induced neuroinflammation. ADAM17 inhibition increased expression of TGF-ßRs on the microglia membrane, promoted formation of TGF-ß1/TGF-ßRII complexes, and induced intranuclear translocation of Smads, which activated the TGF-ß/Smad pathway. In conclusion, our study suggested that ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-ß1/Smad pathway and influenced the neuroinflammatory response after TBI.

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage.

Mounting evidence indicates that inhibition of microglial activation and neuronal pyroptosis plays important roles in brain function recovery after subarachnoid hemorrhage (SAH). LDC7559 is a newly discovered gasdermin D (GSDMD) inhibitor. Previous studies have demonstrated that LDC7559 could inhibit microglial proliferation and pyroptosis. However, the beneficial effects of LDC7559 on SAH remain obscure. Based on this background, we investigated the potential role and the mechanism of LDC7559 on SAH-induced brain damage both in vivo and in vitro. The findings revealed that microglial activation and neuronal pyroptosis were evidently increased after SAH, which could be markedly suppressed by LDC7559 both in vivo and in vitro. Meanwhile, LDC7559 treatment reduced neuronal apoptosis and improved behavior function. Mechanistically, LDC7559 decreased the levels of GSDMD and cleaved GSDMD after SAH. In contrast, nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation by nigericin increased GSDMD-mediated pyroptosis and abated the beneficial effects of LDC7559 on SAH-induced brain damage. However, LDC7559 treatment did not significantly affect the expression of NLRP3 after SAH. Taken together, LDC7559 might suppress neuronal pyroptosis and microglial activation after SAH by inhibiting GSDMD, thereby promoting brain functional recovery.

PHLDA1 modulates microglial response and NLRP3 inflammasome signaling following experimental subarachnoid hemorrhage.

Balancing microglia M1/M2 polarization is an effective therapeutic strategy for neuroinflammation after subarachnoid hemorrhage (SAH). Pleckstrin homology-like domain family A member 1 (PHLDA1) has been demonstrated to play a crucial role in immune response. However, the function roles of PHLDA1 in neuroinflammation and microglial polarization after SAH remain unclear. In this study, SAH mouse models were assigned to treat with scramble or PHLDA1 small interfering RNAs (siRNAs). We observed that PHLDA1 was significantly increased and mainly distributed in microglia after SAH. Concomitant with PHLDA1 activation, nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome expression in microglia was also evidently enhanced after SAH. In addition, PHLDA1 siRNA treatment significantly reduced microglia-mediated neuroinflammation by inhibiting M1 microglia and promoting M2 microglia polarization. Meanwhile, PHLDA1 deficiency reduced neuronal apoptosis and improved neurological outcomes after SAH. Further investigation revealed that PHLDA1 blockade suppressed the NLRP3 inflammasome signaling after SAH. In contrast, NLRP3 inflammasome activator nigericin abated the beneficial effects of PHLDA1 deficiency against SAH by promoting microglial polarization to M1 phenotype. In all, we proposed that PHLDA1 blockade might ameliorate SAH-induced brain injury by balancing microglia M1/M2 polarization via suppression of NLRP3 inflammasome signaling. Targeting PHLDA1 might be a feasible strategy for treating SAH.

A dual aperture (mesoporous and macroporous) system loaded with cell-free fat extract to optimize bone regeneration microenvironment.

Injured bone regeneration requires a systemically and carefully orchestrated series of events involving inflammation, angiogenesis, and osteogenesis. Thus, we designed a multifunctional cell-supporting and drug-retarding dual-pore system: cell-free fat extract (Ceffe)-mesoporous silica nanoparticle (MSN)@poly(lactic-co-glycolic acid) (PLGA) (Ceffe-MSN@PLGA) to mimic the developmental spatial structure, the microenvironment of bone regeneration and integration during injured bone regeneration. In this system, a macroporous scaffold (pore size 200-250 µm) of PLGA is combined with mesoporous MSN (pore size 2-50 nm), aiming at realizing the slow release of Ceffe. Besides, PLGA and MSN are used to recruit the temporary support of cells that are able to degrade simultaneously with bone regeneration and provide space for bone tissue regeneration. And the Ceffe isolated from fresh human adipose tissue has a therapeutic effect in regulating the important functions of early inflammatory cell transformation, neovascularization and eventual osteogenic differentiation. Our results suggest that the mesoporous and macroporous Ceffe-MSN@PLGA system represents a promising strategy to better fit the regeneration of injured bone tissue.

Progress in research on the role of clinical nutrition in treating traumatic brain injury affecting the neurovascular unit.

The neurovascular unit (NVU) is composed of neurons, glial cells, and blood vessels. NVU dysfunction involves the processes of neuroinflammation, and microcirculatory disturbances, as well as neuronal injury after traumatic brain injury (TBI). Traditional anti-inflammatory drugs have limited efficacy in improving the prognosis of TBI. Thus, treatments that target NVU dysfunction may provide a breakthrough. A large number of clinical studies have shown that the nutritional status of patients with TBI was closely related to their conditions and prognoses. Nutrient complexes and complementary therapies for the treatment of TBI are therefore being implemented in many preclinical studies. Importantly, the mechanism of action for this treatment may be related to repair of NVU dysfunction by ensuring adequate omega-3 fatty acids, curcumin, resveratrol, apigenin, vitamins, and minerals. These nutritional supplements hold promise for translation to clinical therapy. In addition, dietary habits also play an important role in the rehabilitation of TBI. Poor dietary habits may worsen the pathology and prognosis of TBI. Adjusting dietary habits, especially with a ketogenic diet, may improve outcomes in patients with TBI. This article discusses the impact of clinical nutrition on NVU dysfunction after TBI, focusing on nutritional complexes and dietary habits.

Activation of Sirtuin-1 by Pinocembrin Treatment Contributes to Reduced Early Brain Injury after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) as a devastating neurological disorder is closely related to heightened oxidative insults and neuroinflammatory injury. Pinocembrin, a bioflavonoid, exhibits different biological functions, such as immunomodulatory, anti-inflammatory, antioxidative, and cerebroprotective activities. Herein, we examined the protective effects and molecular mechanisms of pinocembrin in a murine model of SAH. Using an endovascular perforation model in rats, pinocembrin significantly mitigated SAH-induced neuronal tissue damage, including inflammatory injury and free-radical insults. Meanwhile, pinocembrin improved behavior function and reduced neuronal apoptosis. We also revealed that sirtuin-1 (SIRT1) activation was significantly enhanced by pinocembrin. In addition, pinocembrin treatment evidently enhanced peroxisome proliferator-activated receptor-γ coactivator expression and suppressed ac-nuclear factor-kappa B levels. In contrast, EX-527, a selective SIRT1 inhibitor, blunted the protective effects of pinocembrin against SAH by suppressing SIRT1-mediated signaling. These results suggested that the cerebroprotective actions of pinocembrin after SAH were through SIRT1-dependent pathway, suggesting the potential application of pinocembrin for the treatment of SAH.

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway.

Subarachnoid hemorrhage (SAH) is an acute cerebral vascular disease featured by oxidative insults and neuroinflammation. Cycloastragenol (CAG), the major active component of Astragalus radix, has a wide range of biological functions. However, the potential beneficial effects and the underlying molecular mechanisms of CAG on SAH remain obscure. In the current study, the cerebroprotective effects and mechanism of CAG on SAH were evaluated both in vivo and in vitro. Our results indicated that CAG significantly suppressed SAH-triggered oxidative insults, inflammatory mediators production, microglia activation, and the neutrophil infiltration in the brain. In addition, CAG improved neurological function and ameliorated neuronal apoptosis and degeneration after SAH. In vitro results also revealed the therapeutic effects of CAG on neurons and microglia co-culture system. Mechanistically, CAG treatment upregulated sirtuin 1 (SIRT1) expression, inhibited the levels of FoxO1, nuclear factor-kappa B, and p53 acetylation, and suppressed the subsequent oxidative, inflammatory, and apoptotic pathways. In contrast, inhibiting SIRT1 by pretreatment with Ex527 abrogated the protective actions of CAG both in vivo and in vitro models of SAH. Collectively, our findings indicated that CAG could be a promising and effective drug candidate for SAH.

Metabolic disorders on cognitive dysfunction after traumatic brain injury.

Cognitive dysfunction is a common adverse consequence of traumatic brain injury (TBI). After brain injury, the brain and other organs trigger a series of complex metabolic changes, including reduced glucose metabolism, enhanced lipid peroxidation, disordered neurotransmitter secretion, and imbalanced trace element synthesis. In recent years, several research and clinical studies have demonstrated that brain metabolism directly or indirectly affects cognitive dysfunction after TBI, but the mechanisms remain unclear. Drugs that improve the symptoms of cognitive dysfunction caused by TBI are under investigation and treatments that target metabolic processes are expected to improve cognitive function in the future. This review explores the impact of metabolic disorders on cognitive dysfunction after TBI and provides new strategies for the treatment of metabolic disorders.

Rheological, Thermal, and Degradation Properties of PLA/PPG Blends.

The work presented herein focuses on simulating the compounding process via a torque rheometer, as well as the relationship between the melt viscosity and the polymer molecular weight (MW). We aim to predict the plasticization of polylactic acid (PLA) using polypropylene glycol (PPG) with different MWs. The rheological properties of the PLA/PPG composites containing PPG with different MWs were systematically studied by capillary rheometry and torque rheometry. The initial degradation of PLA/PPG composites during melt processing was monitored in real time. The results indicate that PPG can significantly reduce the melt viscosity of PLA/PPG composites, leading to obvious pseudoplastic fluid behavior. The lower the MW of PPG, the lower the viscosity of the PLA/PPG composite. The addition of PPG was favorable for the degradation of PLA during processing, and the degradation degree of the composite materials increased as the MW of PPG was decreased.