The NADase CD38 is a central regulator in gouty inflammation and a novel druggable therapeutic target.

OBJECTIVES: Cellular NAD+ declines in inflammatory states associated with increased activity of the leukocyte-expressed NADase CD38. In this study, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. METHODS: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals and used the air pouch gouty inflammation model. RESULTS: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1ß and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 activity in macrophages. BMDM RNA-seq analysis of differentially expressed genes (DEGs) revealed CD38 to control multiple MSU crystal-modulated inflammation pathways. Top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-κB activation when it is overexpressed. CONCLUSIONS: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.

Endothelial APC/PAR1 distinctly regulates cytokine-induced pro-inflammatory VCAM-1 expression.

Introduction: Dysfunction of the endothelium impairs its' protective role and promotes inflammation and progression of vascular diseases. Activated Protein C (APC) elicits endothelial cytoprotective responses including barrier stabilization, anti-inflammatory and anti-apoptotic responses through the activation of the G protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR1) and is a promising therapeutic. Despite recent advancements in developing new Activated protein C variants with clinical potential, the mechanism by which APC/PAR1 promotes different cytoprotective responses remains unclear and is important to understand to advance Activated protein C and new targets as future therapeutics. Here we examined the mechanisms by which APC/PAR1 attenuates cytokine-induced pro-inflammatory vascular cell adhesion molecule (VCAM-1) expression, a key mediator of endothelial inflammatory responses. Methods: Quantitative multiplexed mass spectrometry analysis of Activated protein C treated endothelial cells, endothelial cell transcriptomics database (EndoDB) online repository queries, biochemical measurements of protein expression, quantitative real-time polymerase chain reaction (RT-qPCR) measurement of mRNA transcript abundance, pharmacological inhibitors and siRNA transfections of human cultured endothelial cells. Results: Here we report that Activated Protein C modulates phosphorylation of tumor necrosis factor (TNF)-α signaling pathway components and attenuates of TNF-α induced VCAM-1 expression independent of mRNA stability. Unexpectedly, we found a critical role for the G protein-coupled receptor co-receptor sphingosine-1 phosphate receptor-1 (S1PR1) and the G protein receptor kinase-2 (GRK2) in mediating APC/PAR1 anti-inflammatory responses in endothelial cells. Discussion: This study provides new knowledge of the mechanisms by which different APC/PAR1 cytoprotective responses are mediated through discrete ß-arrestin-2-driven signaling pathways modulated by specific G protein-coupled receptor co-receptors and GRKs.

Targeting CD38 to Suppress Osteoarthritis Development and Associated Pain After Joint Injury in Mice.

OBJECTIVE: This study was undertaken to determine the role of CD38, which can function as an enzyme to degrade NAD+ , in osteoarthritis (OA) development. METHODS: Human knee cartilage from normal donors and OA donors were examined for CD38 expression. "Gain-of-function," through overexpression of CD38 via transient transfection, and "loss-of-function," through pharmacologic inhibition of CD38, approaches were used to assess the effects of CD38 on intracellular NAD+ :NADH ratio and catabolic activity in chondrocytes. We also initiated joint injury-induced OA by surgical destabilization of the medial meniscus (DMM) in CD38 knockout mice and wild-type (WT; C57BL/6) mice and in WT male mice in the presence or absence of apigenin treatment. Cartilage degradation, synovial inflammation, subchondral bone changes, and pain behavior were evaluated after DMM surgery. We also examined expression of CD38 and the neuropeptide calcitonin gene-related peptide (CGRP) in knee sections from these mice. RESULTS: CD38 expression was up-regulated in human knee OA cartilage and in chondrocytes stimulated with the proinflammatory cytokine interleukin-1ß (IL-1ß). Overexpression of CD38 in chondrocytes resulted in reduced cellular NAD+ :NADH ratio and augmented catabolic responses to IL-1ß. These effects were reversed by pharmacologic inhibition of CD38. Cartilage degradation and synovial inflammation, associated with increased CD38 expression in cartilage and synovium, osteophyte formation and subchondral bone sclerosis, and pain-like behavior linked to increased CGRP expression in the synovium were observed in WT mice after joint injury. Such effects were significantly reduced in mice deficient in CD38 through either genetic knockout or pharmacologic inhibition. CONCLUSION: CD38 deficiency exerts OA disease-modifying effects. Inhibition of CD38 has the potential to be a novel therapeutic approach for OA treatment.

Analysis of the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas.

BACKGROUND: The purpose of this retrospective study was to investigate the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas (ASDH). METHODS: A total of 256 patients who underwent decompressive craniectomy for isolated traumatic ASDH between April 2013 and December 2020 were included. We evaluated the risk factors for intraoperative acute diffuse brain swelling using a multivariate logistic regression analysis. RESULTS: The incidence of intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH was 21.88% (56/256). Dilated pupils (OR = 24.78), subarachnoid haemorrhage (OR = 2.41), and the time from injury to surgery (OR = 0.32) were independent risk factors for intraoperative acute diffuse brain swelling, while no independent associations were observed between these risk factors and sex, age, the mechanism of injury, the Glasgow Coma Scale score, site of haematoma, thickness of haematoma, midline shift and the status of the basal cistern, although the mechanism of injury, the Glasgow Coma Scale score and the status of the basal cistern were correlated with the incidence of intraoperative acute diffuse brain swelling in the univariate analyses. CONCLUSIONS: This study identified the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH. An increased risk of intraoperative acute diffuse brain swelling occurs in patients with bilaterally dilated pupils, subarachnoid haemorrhage and a shorter time from injury to surgery. These findings should help neurosurgeons obtain information before surgery about intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH.

Comparative risk for intracranial hemorrhage related to new oral anticoagulants: A network meta-analysis.

BACKGROUND: The intracranial hemorrhage (ICH) risk of oral anticoagulants/non-vitamin K antagonist oral anticoagulants (NOACs) remains largely unknown. Patients who need oral anticoagulants such as aspirin or warfarin often suffer from obvious complications. METHODS: This network meta-analysis intended to assess the ICH risk in patients taking NOACs. The data from PubMed, the Cochrane database, and Embase were reviewed. All phase III randomized controlled trials of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), aspirin and warfarin were reviewed. RESULTS: Twenty-three trials involving 137,713 participants were included, involving 6 regimens. Warfarin had the first risk of ICH (surface under the cumulative ranking area: 0.82), followed by dabigatran, edoxaban, aspirin, apixaban, rivaroxaban, and placebo. Dabigatran had the lowest risk of all-cause mortality (surface under the cumulative ranking area: 0.63), followed by apixaban, edoxaban, warfarin, rivaroxaban, aspirin, and placebo. CONCLUSION: Warfarin significantly increased the risk of ICH in patients taking oral anticoagulants compared with 4 NOACs (dabigatran, edoxaban, apixaban, rivaroxaban) and aspirin. Apixaban is least likely to induce all-cause mortality.

The coexistence of recurrent pituitary adenoma and meningioma: case report.

The coexistence of pituitary adenoma and meningioma is very rare. Here, we present a case of recurrent non-functioning pituitary adenoma and temporal lobe meningioma in a patient without previous irradiation. A 73-year-old woman underwent a right-sided craniotomy of pituitary adenoma for visual deficits 30 years ago. She presented again with a 2-year history of lack of alertness, confusion and visual deficits. Brain magnetic resonance imaging (MRI) demonstrated a recurrent pituitary adenoma and a left temporal lobe tumour. The patient underwent a left frontotemporal craniotomy. After the surgery, the patient showed improvement in neurological symptoms. The histology of the sellar region tumour revealed that it was a pituitary adenoma, and the histology of the temporal lobe tumour demonstrated that it was a meningioma of transitional type. The coexistence of pituitary adenoma and meningioma is a very rare surgical entity, especially in a patient with recurrent pituitary adenoma. Although this co-occurrence is rare, more cases and additional studies are necessary to explain these unusual findings.

Apical-Basal Polarity Signaling Components, Lgl1 and aPKCs, Control Glutamatergic Synapse Number and Function.

Normal synapse formation is fundamental to brain function. We show here that an apical-basal polarity (A-BP) protein, Lgl1, is present in the postsynaptic density and negatively regulates glutamatergic synapse numbers by antagonizing the atypical protein kinase Cs (aPKCs). A planar cell polarity protein, Vangl2, which inhibits synapse formation, was decreased in synaptosome fractions of cultured cortical neurons from Lgl1 knockout embryos. Conditional knockout of Lgl1 in pyramidal neurons led to reduction of AMPA/NMDA ratio and impaired plasticity. Lgl1 is frequently deleted in Smith-Magenis syndrome (SMS). Lgl1 conditional knockout led to increased locomotion, impaired novel object recognition and social interaction. Lgl1+/- animals also showed increased synapse numbers, defects in open field and social interaction, as well as stereotyped repetitive behavior. Social interaction in Lgl1+/- could be rescued by NMDA antagonists. Our findings reveal a role of apical-basal polarity proteins in glutamatergic synapse development and function and also suggest a potential treatment for SMS patients with Lgl1 deletion.

Amyloid ß oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate.

Amyloid ß (Aß) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aß production. High nanomolar synthetic oligomeric Aß42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aß-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aß-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aß-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aß induces early synaptic deficits in AD.

Management of subdural effusion and hydrocephalus following decompressive craniectomy for posttraumatic cerebral infarction in a patient with traumatic brain injury: a case report.

BACKGROUND: Subdural effusion with hydrocephalus (SDEH) is a rare complication of traumatic brain injury, especially following decompressive craniectomy (DC) for posttraumatic cerebral infarction. The diagnosis and treatment are still difficult and controversial for neurosurgeons. CASE PRESENTATION: A 45-year-old man developed traumatic cerebral infarction after traumatic brain injury and underwent DC because of the mass effect of cerebral infarction. Unfortunately, the complications of traumatic subdural effusion (SDE) and hydrocephalus occurred in succession following DC. Burr-hole drainage and subdural peritoneal shunt were performed in sequence because of the mass effect of SDE, which only temporarily improved the symptoms of the patient. Cranioplasty and ventriculoperitoneal shunt were performed ultimately, after which SDE disappeared completely. However, the patient remains severely disabled, with a Glasgow Outcome Scale of 3. CONCLUSIONS: It is important for neurosurgeons to consider the presence of accompanying hydrocephalus when treating patients with SDE. Once the diagnosis of SDEH is established and the SDE has no mass effect, timely ventriculoperitoneal shunt may be needed to avoid multiple surgical procedures, which is a safe and effective surgical method to treat SDEH.

The Clinical Efficacy of Electromagnetic Navigation-Guided Hematoma Puncture Drainage in Patients with Hypertensive Basal Ganglia Hemorrhage.

OBJECTIVE: To investigate the clinical efficacy of navigation-guided minimally invasive surgery in patients with hypertensive basal ganglia hemorrhage. METHODS: A total of 64 patients with hypertensive basal ganglia hemorrhage were enrolled in this retrospective study. They were divided into a navigation group and a traditional group based on surgical approaches. The data for the 2 groups of patients were analyzed with regard for the hematoma clearance rate, duration of surgery, duration of hospitalization, Glasgow Outcome Scale score at discharge, Barthel index score at 6 months, and postoperative complication rates for rebleeding and pneumonia. RESULTS: There were no significant differences in basic characteristics between the 2 groups (P > 0.05). The hematoma clearance rate was significantly lower in the navigation group (49.18 ± 16.76%) than in the traditional group (84.29 ± 6.91%, P < 0.01). The duration of surgery and duration of hospitalization were significantly shorter in the navigation group (55.00 ± 11.89 minutes and 24.25 ± 7.1 days, respectively) than in the traditional group (156.38 ± 47.9 minutes and 32.63 ± 9.8 days, respectively; both P < 0.01). There were also significant differences between the 2 groups in Glasgow Outcome Scale scores (P = 0.006). The Barthel index scores were significantly greater in the navigation group (73.13 ± 18.76) than in the traditional group (57.63 ± 26.63, P < 0.05). There were no significant differences between the 2 groups in the complication rates (P > 0.05). CONCLUSIONS: Under certain conditions, compared with standard craniotomy and hematoma evacuation, navigation-guided hematoma puncture aspiration and catheter drainage is simple, effective, and safe as a treatment for hypertensive basal ganglia hemorrhage.

Management of Penetrating Brain Injury Caused by a Nail Gun: Three Case Reports and Literature Review.

BACKGROUND: Penetrating brain injury (PBI) caused by a nail gun is an extremely rare neurosurgical emergency that poses a challenge for neurosurgeons because of its rarity and complexity. CASE DESCRIPTION: Here we present 3 cases of PBI caused by a nail gun. In the first case, the nail entered through the right parietal bone and lodged in the right parietal lobe and basal ganglia. In the second case, the nail entered through the right occipital bone and lodged in the right occipital lobe. In the third case, the nail entered through the right parietal bone and lodged in the right frontal and parietal lobes. All patients underwent surgical removal of the nail. The first patient presented with reduced left-side strength, whereas the second and third patients were neurologically intact on presentation. CONCLUSIONS: PBI caused by a nail gun can present with differing clinical manifestations, and most cases require immediate surgery. A rational management strategy should provide a good postoperative prognosis with minimal neurologic deficits in these patients.

The Neuroprotective Effects of SIRT1 on NMDA-Induced Excitotoxicity.

Silent information regulator 1 (SIRT1), an NAD+-dependent deacetylase, is involved in the regulation of gene transcription, energy metabolism, and cellular aging and has become an important therapeutic target across a range of diseases. Recent research has demonstrated that SIRT1 possesses neuroprotective effects; however, it is unknown whether it protects neurons from NMDA-mediated neurotoxicity. In the present study, by activation of SIRT1 using resveratrol (RSV) in cultured cortical neurons or by overexpression of SIRT1 in SH-SY5Y cell, we aimed to evaluate the roles of SIRT1 in NMDA-induced excitotoxicity. Our results showed that RSV or overexpression of SIRT1 elicited inhibitory effects on NMDA-induced excitotoxicity including a decrease in cell viability, an increase in lactate dehydrogenase (LDH) release, and a decrease in the number of living cells as measured by CCK-8 assay, LDH test, and Calcein-AM and PI double staining. RSV or overexpression of SIRT1 significantly improved SIRT1 deacetylase activity in the excitotoxicity model. Further study suggests that overexpression of SIRT1 partly suppressed an NMDA-induced increase in p53 acetylation. These results indicate that SIRT1 activation by either RSV or overexpression of SIRT1 can exert neuroprotective effects partly by inhibiting p53 acetylation in NMDA-induced neurotoxicity.

Postnatal feeding with high-fat diet induces obesity and precocious puberty in C57BL/6J mouse pups: a novel model of obesity and puberty.

Childhood obesity and obesity-related metabolic complications are induced by a high-fat postnatal diet. The lack of a suitable animal model, however, remains a considerable challenge in obesity studies. In the current study, we provided high-fat diet (HFD) to dams during lactation and to pups after weaning. We also developed a novel model of C57BL/6J mouse pups with HFD-induced postnatal obesity. Results showed that feeding with HFD induces fat deposition and obesity in pups. Furthermore, HFD more potently increased the body weight (BW) of male than female pups. HFD-fed female pups were obese, underwent precocious puberty, and showed increased kisspeptin expression in the hypothalamus. However, parental obesity and precocious puberty exerted no synergistic effects on the HFD-induced postnatal weight gain and puberty onset of the pups. Interestingly, some HFD-fed litters with normal BW also exhibited precocious puberty. This finding suggested that diet composition but not BW triggers puberty onset. Our model suggests good construction validity of obesity and precocious puberty. Furthermore, our model can also be used to explore the mutual interactions between diet-induced postnatal childhood obesity and puberty.

Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons.

Astrocytes are critical in synapse development, and their dysfunction in crucial developmental stages leads to serious neurodevelopmental diseases, including seizures and epilepsy. Immune challenges not only affect brain development, but also promote seizure generation and epileptogenesis, implying immune activation is one of the key factors linking seizures and epilepsy to abnormal brain development. In this study, we report that activating astrocytes by systemic lipopolysaccharide (LPS) challenges in the second postnatal week promotes excitatory synapse development, leading to enhanced seizure susceptibility in mice. Toll-like receptor 4 (TLR4) activation in astrocytes increased astrocytic extracellular signal-related kinase 1/2 (Erk1/2) and phospho-Erk1/2 levels in a myeloid differentiation primary response protein 88 (MyD88)-dependent manner. Constitutively activating Erk1/2 in astrocytes was sufficient to enhance excitatory synaptogenesis without activating TLR4. Deleting MyD88 or suppressing Erk1/2 in astrocytes rescued LPS-induced developmental abnormalities of excitatory synapses and restored the enhanced seizure sensitivity. Thus, we provide direct evidence for a developmental role of astrocytes in shaping a predisposition to seizure generation.

Involvement of MAPK pathways in NMDA-induced apoptosis of rat cortical neurons.

NMDA-induced excitotoxicity cause severe neuronal damage including apoptosis and necrosis. The present study was aimed to evaluate the proportion of NMDA-induced apoptosis of rat cortical neurons and discover signal transduction mechanism. Caspase inhibitor and lactate dehydrogenase (LDH) assay were used to study the NMDA-induced apoptosis. To explore the involved signal pathways, the primary culture of rat cortical neurons were pretreated by the inhibitors of three MAPK pathways, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. With 2 h of NMDA treatment, cellular apoptosis was measured by caspase-3 activity, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and Annexin V staining. The results showed that: (1) Caspase-dependent apoptosis accounted for 22.49% in NMDA-induced neuronal death; (2) Pretreatment with p38 MAPK inhibitor SB203580 (10 µmol/L) significantly decreased NMDA-mediated caspase-3 activity by 30.43% (P < 0.05). However, ERK inhibitor PD98059 (20 µmol/L) or JNK inhibitor SP600125 (20 µmol/L) did not influence caspase-3 activity; (3) Pretreatment with SB203580 significantly reduced the number of NMDA-induced TUNEL-positive cells by 33.10% (P < 0.05). PD98059 (20 µmol/L) or SP600125 (20 µmol/L) did not show obvious effect; (4) Pretreatment with SB203580 (10 µmol/L) significantly reduced the number of NMDA-induced early apoptotic neurons by 55.56% (P < 0.05). Also, SP600125 (20 µmol/L) significantly decreased the amount of late apoptotic/dead cells by 67.59% (P < 0.05). There was no effect of PD98059 (20 µmol/L). These results indicate that: (1) NMDA induces neuronal apoptosis besides necrosis; (2) p38 MAPK, but not JNK and ERK, is involved in NMDA-induced neuronal apoptosis, and inhibition of the apoptotic signaling pathway contributes to neuroprotection; (3) JNK activation might contribute to NMDA-induced neuronal necrosis rather than apoptosis.

[Neuroprotective role of silent information regulator 1 in Alzheimer's disease].

Silent information regulator 1 (SIRT1), an NAD(+)-dependent deacetylase, is involved in the regulation of gene transcription, energy metabolism and cell aging. Recent studies have showed that SIRT1 possesses neuroprotective effects, however, it is not very clear how SIRT1 exerts the neuroprotection in Alzheimer's disease (AD). In this review, we summarized the neuroprotective role of SIRT1 in AD and its possible molecular mechanisms, proposing a novel strategy for preventing and treating neurodegeneration.

Effect of profound hypothermia on genomics of hippocampus following complete cerebral ischemia in rats.

OBJECTIVE: To determine differential gene expression of hippocampus in rats following complete cerebral ischemia with treatment of profound hypothermia compared to normothermia. METHODS: Six rats got 5 minutes of complete cerebral ischemia with circulatory arrest and randomly divided into two groups: normothermia ischemia group (37 +/- 0.3 degrees C, n = 3) and profound hypothermia ischemia group (18 +/- 0.5 degrees C, n = 3). Affymetrix U34A rat arrays were applied to detect the difference of gene expression profile in hippocampus between the two groups. RESULTS: Expression profiles of a total of 75 transcripts in the profound hypothermia ischemia group were statistically different from those of the normothermia ischemia group, and 33 of them were significantly up-regulated and other 42 were significantly down-regulated (p < 0.07). CONCLUSIONS: Compared with normothermia, profound hypothermia had a significant effect on the gene expression profiles following complete cerebral ischemia, which may be involved in the mechanisms of cerebral protection by profound hypothermia.