Sirtuin 5 (SIRT5) Suppresses Tumor Growth by Regulating Mitochondrial Metabolism and Synaptic Remodeling in Gliomas.

Sirtuin 5 (SIRT5) is increasingly recognized as a key regulator of cellular metabolism, which is commonly dysregulated in cancer cells, resulting in enhanced proliferation and tumor progression. To investigate the clinicopathologic implications of SIRT5 dysregulation in glioblastoma, we performed comprehensive analyses of transcriptomic data and functional verifications using in vitro and in vivo glioblastoma models. We found that higher SIRT5 expression levels were associated with a favorable prognosis in glioma patients. Knockdown of SIRT5 significantly enhanced glioblastoma cell growth. Our data suggest its potential role in regulating mitochondrial metabolism in gliomas. Furthermore, SIRT5 is also significantly correlated with synaptic remodeling pathways. Our findings indicate a tumor-suppressive role for SIRT5 that extends beyond regulating cancer metabolism, by which it may function through modulating neuroplasticity. Understanding these cellular interactions provides nuanced insights into the multifaceted role of SIRT5 and the broader therapeutic implications of this for the development of novel treatment strategies.

Separation and quantification of lactate and lipid at 1.3 ppm by diffusion-weighted magnetic resonance spectroscopy.

PURPOSE: To separate the spectrally overlapped lactate and lipid signals at 1.3 ppm using diffusion-weighted magnetic resonance spectroscopy (DW-MRS) based on their large diffusivity difference. METHODS: DW-MRS was applied to the gel phantoms containing lactate and lipid droplets, and to the rat brain tumors. Lactate and lipid signals and their apparent diffusion coefficients were computed from the diffusion-weighted proton spectra. Biexponential fitting and direct spectral subtraction approaches were employed and compared. RESULTS: DW-MRS could effectively separate lactate and lipid signals both in phantoms and rat brain C6 glioma by biexponential fitting. In phantoms, lactate and lipid signals highly correlated with the known lactate concentration and lipid volume fractions. In C6 glioma, both lactate and lipid signals were detected, and the lipid signal was an order of magnitude higher than lactate signal. The spectral subtraction approach using three diffusion weightings also allowed the separation of lactate and lipid signals, yielding results comparable to those by the biexponential fitting approach. CONCLUSION: DW-MRS presents a new approach to separate and quantify spectrally overlapped molecules and/or macromolecules, such as lactate and lipid, by using the diffusivity difference associated with their different sizes or mobility within tissue microstructure. Magn Reson Med 77:480-489, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Effects of progesterone vs. dexamethasone on brain oedema and inflammatory responses following experimental brain resection.

BACKGROUND: Dexamethasone (DEXA) is commonly used to reduce brain swelling during neurosurgical procedures. DEXA, however, has many side-effects that can increase the risks of post-operative complications. In contrast, progesterone (PRO) has fewer side-effects and has been found to be neuroprotective on traumatic brain injury (TBI). Whether PRO may be used as an alternative to DEXA during routine procedures has not been fully explored. OBJECT: To compare the effects of DEXA and PRO on surgical brain injury (SBI). METHODS: Seventy-five adult male Sprague Dawley rats were randomized into five groups: (1) SBI + drug vehicle (peanut oil, 1 ml kg(-1)); (2) SBI + DEXA (1 mg kg(-1)); (3) SBI + low-dose PRO (10 mg kg(-1)); (4) SBI + high-dose PRO (20 mg kg(-1)); and (5) sham SBI + drug vehicle. Magnetic resonance imaging study and assessments of brain water content (BWC), blood-brain barrier (BBB) permeability, cellular inflammatory responses and matrix metalloproteinase 9 (MMP-9) expression were conducted. RESULTS: This model consistently resulted in increased BWC and BBB disruption. PRO reduced astrocyte and microglia responses and attenuated brain oedema with preservation of BBB. A significant down-regulation of MMP-9 expression occurred in the PRO 20 group. CONCLUSIONS: PRO is as effective as DEXA in reducing brain oedema and inflammation following SBI; 10 mg kg(-1) of PRO was demonstrated to be more effective in relieving acute cellular inflammatory responses.

Biomolecular condensates: hubs of Hippo-YAP/TAZ signaling in cancer.

Biomolecular condensates, the membraneless cellular compartments formed by liquid-liquid phase separation (LLPS), represent an important mechanism for physiological and tumorigenic processes. Recent studies have advanced our understanding of how these condensates formed in the cytoplasm or nucleus regulate Hippo signaling, a central player in organogenesis and tumorigenesis. Here, we review recent findings on the dynamic formation and function of biomolecular condensates in regulating the Hippo-yes-associated protein (YAP)/transcription coactivator with PDZ-binding motif (TAZ) signaling pathway under physiological and pathological processes. We further discuss how the nuclear condensates of YAP- or TAZ-fusion oncoproteins compartmentalize crucial transcriptional co-activators and alter chromatin architecture to promote oncogenic programs. Finally, we highlight key questions regarding how these findings may pave the way for novel therapeutics to target cancer.

Acute calcitriol treatment mitigates vitamin D deficiency-associated mortality after intracerebral haemorrhage.

OBJECTIVE: Vitamin D deficiency (VDD) is emerging as a predictor of poor prognosis in various neurological conditions, where clinical outcomes are often worse in stroke patients with VDD. This study aimed to provide experimental evidence on whether and how pre-existing VDD would affect survival and neurofunctional outcomes in intracerebral haemorrhage (ICH), and to evaluate whether acute vitamin D (VD) supplementation would improve post-stroke outcomes. METHODS: Experimental ICH models were induced in mice with and without VDD. Haematoma size was measured using T2*-weighted MRI and haemoglobin concentration. Post-ICH mortality, neurofunctional outcomes and the extent of blood-brain barrier (BBB) leakage were assessed to identify their correlations with VD status. Therapeutic benefits of acute VD administration were also evaluated. RESULTS: Mice with VDD exhibited significantly higher acute mortality rates and more severe motor deficits than mice without VDD post-ICH. Marked haematoma expansion and increased Evans blue extravasation were observed in VDD mice, suggesting that VDD was associated outcomes with increased BBB disruption. Acute treatment with a loading dose of VD (calcitriol) significantly improved outcomes in VDD mice. CONCLUSION: This study provides novel insights into the pathophysiological mechanisms at play in ICH concomitant with VDD and a scientific rationale for acute treatment with VD.

Postcooling But Not Precooling Benefits Motor Recovery by Suppressing Cell Death After Surgical Spinal Cord Injury in Rats.

BACKGROUND: Surgical spinal cord injury (SSCI) is often inevitable in patients with intramedullary lesions. Although regional hypothermia (RH) has been demonstrated neuroprotective, the value of priming RH in SSCI has never been studied. Herein, the authors investigated the impact of pre- and post-RH on neurologic recovery in a clinically relevant model. METHODS: An SSCI model was established at T10. RH was conducted by focal 4oC saline perfusion; room temperature (RT) saline was used as controls. Animals were randomized into 6 groups: SHAM-RT/RH, Pre-RT/RH, and Post-RT/RH. Motor and sensory functions were evaluated using the Basso, Beattie, and Bresnahan rating scale and Plantar test 2 weeks after surgery. TUNEL assay and Fluoro-Jade C staining were conducted to examine the cell death, and the alterations of apoptotic markers including total and cleaved casepase 3, Bcl-2, and Bax, as well as the pyroptotic proteins including NLRP3, ASC, and caspase 1, were determined. RESULTS: RH perfusion successfully created an intramedullary hypothermia approximately at 24oC, while RT controls remained above 30oC. Animals receiving postinjury RH had the least cell death and the best motor performance, while pre-RH showed the most dead cells and worst hind limb movements. Immunoblotting depicted that post-RH suppressed both apoptotic and pyroptotic death as the cleaved/total caspase 3, Bcl-2/Bax ratio, and NLRP3/ASC/caspase 1 signaling were inhibited. Priming cooling, on the contrary, elevated pyroptosis and did not affect apoptosis significantly. CONCLUSIONS: Priming RH before surgical incision could not be supported as it caused excessive cell death. In contrast, instant introduction of RH is beneficial in rescuing neurologic function.

Clinical significance of CRNDE transcript variants in glioblastoma multiforme.

The long non-coding RNA CRNDE is an oncogene that promotes tumor growth in glioblastoma multiforme (GBM). At least five CRNDE transcript variants with possibly different functional roles have been described in recent studies. Here, we report our preliminary findings on the differential expressions of CRNDE transcript variants in GBM, and their prognostic significance. Our preliminary data suggest that different transcript variants of CRNDE might have different functions in GBM and should be further studied as potential biomarkers for clinical prognostication.

Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling.

Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation conferred malignant characteristics including proliferation, invasion, migration and angiogenesis in vitro, and increased tumor growth in vivo via the mitogen-activated protein kinase (MAPK) signaling pathway. Pathway analysis suggested genetic and pharmacologic inhibition of P4HB suppressed MAPK expression and its downstream targets were involved in angiogenesis and invasion. This is the first study that demonstrates the oncogenic roles of P4HB and its underlying mechanism in glioma. Since tumor invasion and Vascularisation are typical hallmarks in malignant glioma, our findings uncover a promising anti-glioma mechanism through P4HB-mediated retardation of MAPK signal transduction.

MicroRNA-210 and Endoplasmic Reticulum Chaperones in the Regulation of Chemoresistance in Glioblastoma.

Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.

Comparison between self-assembling peptide nanofiber scaffold (SAPNS) and fibrin sealant in neurosurgical hemostasis.

RADA16-I is a synthetic type I self-assembling peptide nanofiber scaffold (SAPNS) which may serve as a novel biocompatible hemostatic agent. Its application in neurosurgical hemostasis, however, has not been explored. Although RADA16-I is nontoxic and nonimmunogenic, its intrinsic acidity may potentially provoke inflammation in the surgically injured brain. We conducted an animal study to compare RADA16-I with fibrin sealant, a commonly used agent, with the hypothesis that the former would be a comparable alternative. Using a standardized surgical brain injury model, 30 Sprague-Dawley rats were randomized into three treatment groups: RADA16-I, fibrin sealant or gelatin sponge (control). Animals were sacrificed on day 3 and 42. Astrocytic and microglial infiltrations within the cerebral parenchyma adjacent to the operative site were significantly lower in the RADA16-I and fibrin sealant groups than control. RADA16-I did not cause more cellular inflammatory response despite its acidity when compared with fibrin sealant. Immunohistochemical studies showed infiltration by astrocytes and microglia into the fibrin sealant and RADA16-I grafts, suggesting their potential uses as tissue scaffolds. RADA16-I is a promising candidate for further translational and clinical studies that focus on its applications as a safe and effective hemostat, proregenerative nanofiber scaffold as well as drug and cell carrier.

Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response.

BACKGROUND: Intratumoural hypoxia is associated with chemoresistance in glioblastoma multiforme (GBM), a highly malignant brain tumour. Adaptive response to endoplasmic reticulum stress induced by temozolomide is a major obstacle in recurrent GBM. We investigated whether hyperoxia resensitizes temozolomide-resistant GBM cells to temozolomide by abrogating the hypoxia-induced, unfolded protein response (UPR)-related protective mechanisms. MATERIALS AND METHODS: We examined changes to key UPR modulators in temozolomide-sensitive and -resistant human GBM cells (D54 and U87) treated with/without temozolomide at different oxygen concentrations using western blotting, and cytotoxic benefits of overexpressing key chaperone, P4HB, in GBM cells (U87 and U251) under normoxia and hyperoxia. RESULTS: Hyperoxia, alone or synergistically with temozolomide, activated the UPR in sensitive and resistant D54 and U87 cell lines. Hyperoxia also reduced survival benefit of U87 and U251 cells with P4HB overexpression through the UPR. CONCLUSION: Hyperoxia enhanced GBM cell sensitivity to temozolomide, likely through UPR, highlighting an important treatment modality targeting chemosensitive and -resistant GBM.