Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.

Glioblastoma (GBM) cells require large amounts of iron for tumor growth and progression, which makes these cells vulnerable to destruction via ferroptosis induction. Mitochondria are critical for iron metabolism and ferroptosis. Sirtuin-3 (SIRT3) is a deacetylase found in mitochondria that regulates mitochondrial quality and function. This study aimed to characterize SIRT3 expression and activity in GBM and investigate the potential therapeutic effects of targeting SIRT3 while also inducing ferroptosis in these cells. We first found that SIRT3 expression was higher in GBM tissues than in normal brain tissues and that SIRT3 protein expression was upregulated during RAS-selective lethal 3 (RSL3)-induced GBM cell ferroptosis. We then observed that inhibition of SIRT3 expression and activity in GBM cells sensitized GBM cells to RSL3-induced ferroptosis both in vitro and in vivo. Mechanistically, SIRT3 inhibition led to ferrous iron and ROS accumulation in the mitochondria, which triggered mitophagy. RNA-Sequencing analysis revealed that upon SIRT3 knockdown in GBM cells, the mitophagy pathway was upregulated and SLC7A11, a critical antagonist of ferroptosis via cellular import of cystine for glutathione (GSH) synthesis, was downregulated. Forced expression of SLC7A11 in GBM cells with SIRT3 knockdown restored cellular cystine uptake and consequently the cellular GSH level, thereby partially rescuing cell viability upon RSL3 treatment. Furthermore, in GBM cells, SIRT3 regulated SLC7A11 transcription through ATF4. Overall, our study results elucidated novel mechanisms underlying the ability of SIRT3 to protect GBM from ferroptosis and provided insight into a potential combinatorial approach of targeting SIRT3 and inducing ferroptosis for GBM treatment.

An effective antimicrobial strategy of colistin combined with the Chinese herbal medicine shikonin against colistin-resistant Escherichia coli.

IMPORTANCE: Infections caused by multidrug-resistant Escherichia coli (MDR E. coli) have become a major global healthcare problem due to the lack of effective antibiotics today. The emergence of colistin-resistant E. coli strains makes the situation even worse. Therefore, new antimicrobial strategies are urgently needed to combat colistin-resistant E. coli. Combining traditional antibiotics with non-antibacterial drugs has proved to be an effective approach of combating MDR bacteria. This study investigated the combination of colistin and shikonin, a Chinese herbal medicine, against colistin-resistant E. coli. This combination showed good synergistic antibacterial both in vivo and in vitro experiments. Under the background of daily increasing colistin resistance in E. coli, this research points to an effective antimicrobial strategy of using colistin and shikonin in combination against colistin-resistant E. coli.

Efficacy and safety of human-derived neural stem cell in patients with ischaemic stroke: study protocol for a randomised controlled trial.

INTRODUCTION: Stroke is the most common cause of neurological disability in adults worldwide. Neural stem cell (NSC) transplantation has shown promising results as a treatment for stroke in animal experiments. The pilot investigation of stem cells in stroke phase 1 and phase 2 trials showed that transplantation of the highest dose (20 million cells) was well tolerated. Preliminary clinical benefits have also been observed. However, the trials were open-label and had a small sample size. Furthermore, human NSCs (hNSCs) were intracerebrally implanted, and some serious adverse events were considered to be related to the surgical procedure. Therefore, we plan to conduct a double-blinded, randomised controlled trial to test the safety and efficacy of intranasal injection of hNSCs. METHODS AND ANALYSIS: This single-centre, randomised, double-blinded, parallel-controlled trial will be conducted in China. Sixty patients with ischaemic stroke who met the qualification criteria will be randomly divided into two groups: the NSCs and control groups. All participants will receive intranasal administration of hNSCs or placebo for 4 consecutive weeks. Patients will be followed up at baseline and at 4, 12, 24 and 48 weeks after intervention. The primary outcome is the National Institutes of Health Stroke Scale score (4, 12, 24 weeks after intervention). Secondary outcomes include the modified Rankin scale, Barthel index, Mini-Mental State Examination score (4, 12, 24 weeks after intervention) and cranial MRI changes (24 and 48 weeks after intervention). All adverse events will be recorded during the study period. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Ren Ji Hospital (2018-009). All subjects will provide informed consent. The results will be accessible in peer-reviewed publications and will be presented at academic conferences. TRIAL REGISTRATION: ChiCTR1900022741; Chinese Clinical Trial Registry.

Telitacicept following plasma exchange in the treatment of subjects with recurrent neuromyelitis optica spectrum disorders: A single-center, single-arm, open-label study.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD), mainly mediated by B cells and AQP4 antibody, has a high rate of recurrence. Telitacicept is a novel drug specifically targeting the upstream signaling for the activation of B cell with its following production of autoimmune antibodies. Thus, it may be a promising approach. Our study preliminarily explored the potential safety and effectiveness of Telitacicept following plasma exchange in the treatment of recurrent NMOSD. METHODS: This was a single-center, single-arm, open-label study enrolling eight patients with recurrent NMOSD in China. All patients received plasma exchange three times, followed by Telitacicept 240 mg every week for 46 times. The primary endpoint was the time of first recurrence after enrollment. Secondary end points included: changes in Expanded Disability Status Scale score, Optic Spinal Impairment Scale score, Hauser Ambulation Index, number of lesions on MRI, retinal nerve fiber layer thickness measured by optical coherence tomography, latency and amplitude of visual evoked potential, titer of AQP4 antibody, and immune parameters of blood. Safety was also assessed. The study was registered with Chictr.org.cn (ChiCTR1800019427). RESULTS: Eight eligible patients were enrolled. Relapse occurred in two patients (25%) and five patients (63%) remained relapse free after 48 weeks of treatment. The time to first recurrence was prolonged and the number of recurrences was reduced (p < 0.001, power of test = 1). One patient withdrew from the study due to low neutrophil count. No serious adverse events occurred. CONCLUSIONS: In this small, uncontrolled study, Telitacicept following plasma exchange has the potential to be a safe treatment for patients with recurrent NMOSD. It may prolong the recurrence interval and reduces the annual count of recurrences. A multicenter randomized controlled study with a larger sample is thus feasible and needed to further assess its safety and efficacy.

Telitacicept Following Plasma Exchange in the Treatment of Subjects With Recurrent NMOSD: Study Protocol for a Single-Center, Single-Arm, Open-Label Study.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease that recurrently relapses and leads to severe disability. The available choices for disease prevention are few or intolerable. Previous studies suggested that telitacicept may provide a promising therapeutic strategy for autoimmune diseases involving B cells. Therefore, this study aims to assess the effectiveness and safety of telitacicept for recurrent NMOSD. Methods: We will perform a single-arm, single-center, open-label, specialist study with a total enrollment of eight participants. The treatment regimen includes plasma exchange three times and subcutaneous injection of telitacicept for 46 cycles, with a total period of 48 weeks. The primary endpoint is the time to first recurrence after enrollment. Secondary endpoints are Expanded Disability Status Scale (EDSS) score, Opticospinal Impairment Scale (OSIS) score, Hauser Ambulation Index, number of lesions on MRI, and changes in visual evoked potential (VEP), optical coherence tomography (OCT) and immunologic status. All adverse events after medication will be documented and investigated. Discussion: This study will explore the safety and effectiveness of telitacicept following plasma exchange regarding the time to recurrence in neuromyelitis optica spectrum disorder (NMOSD) for the first time. Clinical Trial Registration: Chictr.org.cn, identifier ChiCTR1800019427.

ß1-adrenoceptor-stimulated lactate production in cultured astrocytes is predominantly glycogen-independent.

Noradrenaline (NA) promotes breakdown of the glucose-polymer, glycogen, and hence enhances glycolytic production of lactate in astrocytes. Here, in cultured rat cerebrocortical astrocytes, we examined the contributions of different adrenoceptor subtypes to NA-modulated glucose metabolism, and the relationship of NA-induced glycogenolysis to lactate production. Stimulation of astrocytic glucose metabolism by NA was mediated predominantly via ß1-adrenoceptors and cAMP. Constitutive ß 1-adrenoceptor activity - in the absence of exogenous NA - contributed to the basal rate of glycogen turnover. Although mRNAs encoding both ß 1- and ß 2-adrenoceptors were detected in these astrocytes, ß 2-adrenoceptors contributed little to NA-induced modulation of glucose metabolism. Activation of α2- and α 1-adrenoceptors in these cells decreased cAMP and increased cytosolic Ca2+, respectively, but did not modulate NA-induced glycogenolysis: α 2-adrenoceptors because glycogenolysis was induced maximally by NA concentrations that only began to inhibit cAMP production; and α 1-adrenoceptors possibly because of desensitisation and depletion of Ca2+ stores. Under basal conditions, astrocytes converted glucose to extracellular lactate in near stoichiometric manner. When glucose-starved astrocytes were given fresh glucose-containing medium, lactate accumulation displayed a brief lag period before attaining a steady-state rate. During this lag period NA, acting at ß 1-adrenoceptors, increased the rate of lactate accumulation both in the absence and presence of an inhibitor of glycogen turnover. At the steady-state, the rate of glucose incorporation into accumulated glycogen was ~ 5% of that into lactate, but NA enhanced lactate output by 20-50%: this further indicates that NA, via ß 1-adrenoceptors and cAMP, can enhance astrocytic lactate production independently of its effect on glycogen turnover.

APOE ε4 Allele Is Associated with Elevated Levels of CSF VILIP-1 in Preclinical Alzheimer's Disease.

OBJECTIVES: Cerebrospinal fluid (CSF) visinin-like protein 1 (VILIP-1) has been suggested as a biomarker for neuron injury, which has been shown to have a important diagnostic value in symptomatic Alzheimer's disease (AD). The study purpose is investigating potential effects of apolipoprotein E (APOE) ε4 on CSF VILIP-1 levels among the preclinical AD. METHODS: A total of 110 subjects (including 43 APOE ε4 carriers and 67 ε4 non-carriers) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in the present study. RESULTS: The results showed that VILIP-1 concentrations in the CSF were statistically significantly increased in APOE ε4 carriers in comparison with non-carriers. Increased CSF VILIP-1 level was positively associated with the concentrations of both CSF-tau and P-tau levels. CONCLUSIONS: Our findings suggested that APOE ε4 might affect CSF VILIP-1 level in preclinical AD, indicating an important role of APOE ε4 in neuron injury leading to AD.

Predictors of relapse in patients with medication overuse headache in Shanghai: A retrospective study with a 6-month follow-up.

Medication overuse headache (MOH) has a high relapse rate and disease heterogeneity. This study aimed to determine the predictors of MOH relapse in patients through a 6-month follow-up in Shanghai. In this retrospective study, patients diagnosed with MOH from June 2016 to June 2017 were recruited and followed up for 6 months after withdrawal treatment in Renji Hospital in Shanghai. Patients' information was obtained using headache questionnaires. Follow-up was conducted via telephone interview. Patients were divided into relapse group and no-relapse group according to the outcomes after 6 months. This study enrolled 124 outpatients with MOH at baseline. 102 patients completed the follow up and were analysis finally. Demographics and clinical characteristics were compared between the relapse (n = 39, 38.24%) and no-relapse (n = 63, 61.76%) group. Binary logistic regression analysis was performed, and two variables emerged as significant predictors of relapse before withdrawal; the headache frequency (day/month) was higher in the relapse group than in the no-relapse group [odds ratio (OR) 1.107, p = 0.008]. Furthermore, patients administered analgesics of ≥ 2 units per headache day had a higher risk of relapse [odds ratio (OR) 2.791, p = 0.038]. Headache frequency and analgesics units per headache day before withdrawal may be independent predictors of MOH relapse. Therefore, early identification of high-risk groups and enhancing patients' management could contribute to improving the prognosis of MOH.