Elevated serum levels of soluble B-cell maturation antigen as a prognostic biomarker for multiple myeloma.

Serum B-cell maturation antigen (sBCMA) levels can serve as a sensitive biomarker in multiple myeloma (MM). In the research setting, sBCMA levels can be accurately detected by enzyme-linked immunosorbent assay (ELISA), but the approach has not been approved for clinical use. Here, we used a novel chemiluminescence method to assess sBCMA levels in 759 serum samples from 17 healthy donors and 443 patients with plasma cell (PC) diseases including AL amyloidosis, POEMS syndrome and MM. Serum BCMA levels were elevated 16.1-fold in patients with newly diagnosed MM compared to healthy donors and rare PC diseases patients. Specifically, the sBCMA levels in patients with progressive disease were 64.6-fold higher than those who showed partial response or above to treatment. The sBCMA level also correlated negatively with the response depth of MM patients. In newly diagnosed and relapsed MM patients, survival was significantly longer among those subjects whose sBCMA levels are below the median levels compared with those above the median value. We optimized the accuracy of the survival prediction further by integrating sBCMA level into the Second Revised International Staging System (R2-ISS). Our findings provide evidence that the novel chemiluminescence method is sensitive and practical for measuring sBCMA levels in clinical samples and confirm that sBCMA might serve as an independent prognostic biomarker for MM.

Regulation of microglial process elongation, a featured characteristic of microglial plasticity.

Microglia, a type of glia within the brain characterized by a ramified morphology, are essential for removing neuronal debris and restricting the expansion of a lesion site. Upon moderate activation, they undergo a transformation in morphology inducing beneficial responses. However, upon strong stimulation, they mediate neuronal damage via production of pro-inflammatory cytokines. The inhibition of this cascade is considered an effective strategy for neuroinflammation-associated disorder therapy. During this pathological activation microglia also undergo a shortening of process length which contributes to the pathogenesis of such disorders. Thus, microglial plasticity should be considered to have two components: one is the production of inflammatory mediators, and the other is the dynamic changes in their processes. The former role has been well-documented in previous studies, while the latter one remains largely unknown. Recently, we and others have reported that the elongation of microglial process is associated with the transformation of microglia from a pro-inflammatory to an anti-inflammatory state, suggesting that the shortening of process length would make the microglia lose their ability to restrict pathological injury, while the elongation of microglial process would help attenuate neuroinflammation. Compared with the traditional anti-neuroinflammatory strategy, stimulating elongation of microglial process not only reduces the production of pro-inflammatory cytokines, but restores the ability of microglia to scan their surrounding environments, thus rendering their homeostasis regulation more effective. In this review, we provide a discussion of the factors that regulate microglial process elongation in vitro and in vivo, aiming to further drive the understanding of microglial process plasticity.

Up-Regulation of CCT8 Related to Neuronal Apoptosis after Traumatic Brain Injury in Adult Rats.

Traumatic brain injury (TBI) initiates a series of neurochemical and signaling changes that could eventually lead to neuronal apoptosis. Recent studies indicated that mature neurons cell cycle re-enter played a crucial role in neuronal apoptosis. In this study, we identified that the chaperonin containing TCP-1, subunit 8 (CCT8), as a member of class II chaperonins, was significantly upregulated following TBI. Moreover, double immunofluorescence staining revealed that CCT8 was co-expressed with neuronal nuclei (NeuN). Besides, co-localization of CCT8/active caspase 3 was detected in NeuN. We also examined the expression profiles of active caspase 3 whose changes were correlated with the expression of CCT8. All our findings suggested that CCT8 might be involved in the pathophysiology of brain after TBI.

The expression changes of vacuolar protein sorting 4B (VPS4B) following middle cerebral artery occlusion (MCAO) in adult rats brain hippocampus.

Vacuolar protein sorting 4 (VPS4), is a member of ATPases associated with diverse cellular activities protein family. VPS4 is composed of VPS4A and VPS4B, VPS4B plays an important role in the lysosomal degradation pathway, intracellular protein trafficking, virus budding and abscission of cytokinesis. However, information regarding its distribution and possible function in the central nervous system is limited. Therefore, we performed a middle cerebral artery occlusion (MCAO) in adult rats and detected the dynamic changes of VPS4B in hippocampus CA1 subregion. We found that the VPS4B expression was increased strongly after MCAO and reached the peak after 3 days. VPS4B mainly located in the cytoplasm of neurons, but not astrocytes and microglia. Moreover, there was a concomitant up-regulation of active caspase-3. In vitro studies indicated that the up-regulation of VPS4B may be involved in oxygen-glucose deprivation-induced PC12 cell death. And knock-down of VPS4B in cultured differentiated PC12 cells by siRNA showed that VPS4B promoted the expression of active caspase-3. Collectively, all these results and MTT assay suggested that the up-regulation of VPS4B played an important role in the pathophysiology after MCAO, and further research is needed to have a good understanding of its function and mechanism.

Hippocampal volume and resting-state functional connectivity on magnetic resonance imaging in patients with Parkinson and depression.

Background: Recent structural and functional imaging studies of depression in Parkinson disease (DPD) have failed to reveal the relevant mechanism, and relatively few studies have been conducted on limbic systems such as the hippocampus. This study thus aimed to gain new insights into the pathogenesis of DPD by detecting the changes in the hippocampal structure and the resting-state functional connectivity (FC) of patients with DPD. Methods: This study included 30 patients with DPD (DPD group), 30 patients with nondepressed Parkinson disease (NDPD; NDPD group), and 30 normal controls (NCs; NC group) with no significant age or gender differences with the DPD group. The Hamilton Depression Rating Scale (HAMD) and three-dimensional T1-weighted imaging and blood oxygen level-dependent imaging data of all patients were collected. The hippocampal volumes were measured using MATLAB software (MathWorks). The correlation between hippocampal volume and the HAMD score in the DPD group was analyzed with Pearson correlation coefficient. The bilateral hippocampi were used as the regions of interest and as the seed points for FC. FC analysis was performed between the preprocessed functional data of the whole brain and the two seed points with Data Processing Assistant for Resting-State and Statistical Parametric Mapping 8 software, respectively. The correlation between FC and HAMD scores in the patients with DPD was determined using partial correlation analysis. Results: Compared with those in the NC group and the NDPD group, the bilateral hippocampal volumes in the DPD group were significantly decreased (P<0.05). There was a negative correlation between the bilateral hippocampal volume and the HAMD score in the DPD group (P<0.05). Compared with that of the NDPD group, the FC of the right hippocampus with the right occipital lobe and left precuneus was reduced in the DPD group. In the DPD group, the FC values of the right hippocampus, right occipital lobe, and left anterior cuneiform lobe were negatively correlated with HAMD scores. Conclusions: The volume of bilateral hippocampi in patients with DPD is significantly decreased and negatively correlated with the severity of depressive disorder. The weakened FC of the right hippocampus to the right occipital lobe and the left precuneus may play an important role in the neurological basis of DPD.

A five-year follow-up clinical study of the B cell maturation antigen chimeric antigen receptor-T cell therapy HDS269B in patients with relapsed or refractory multiple myeloma.

PURPOSE: This study aimed to report the five-year clinical outcomes of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in relapsed/refractory multiple myeloma (RRMM) patients, including those with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3-4), and to identify factors influencing long-term outcomes. METHODS: Forty-nine RRMM patients enrolled from 2016 to 2020 received HDS269B (9×106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months (95% confidence interval [CI], 5.01-13.99) and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0-2 had marked longer survival, with a median PFS of 11.0 months and median OS of 41.8 months. Early minimal residual disease negativity, and higher and persistent CAR-T cell expansion and absence of extramedullary disease were associated with better survival outcomes. No new CAR-T cell therapy associated toxicities were observed. Importantly, ECOG 0-2, prior therapy lines <4, and CAR-T cell persistence at ≥6 months were independently associated with longer OS. CONCLUSIONS: HDS269B is effective and safe, especially for patients with ECOG 0-2. Early CAR-T cell intervention may improve prognosis in patients with RRMM.

Granulocyte-macrophage colony-stimulating factor-triggered innate immune tolerance against chronic stress-induced behavioral abnormalities in mice.

Pre-stimulation of the innate immune is considered a potential strategy to prevent chronic stress-induced behavioral abnormalities in animals. In this study, we investigated whether granulocyte-macrophage colony-stimulating factor (GM-CSF), an immunostimulant used in the clinic to treat diseases of the hematopoietic system, can prevent chronic stress-induced behavioral abnormalities in mice. Our results showed that a single intraperitoneal injection of GM-CSF (100 µg/kg) one day before stress exposure prevented the depression- and anxiety-like behaviors induced by chronic social defeat stress (CSDS) in mice, including preventing the CSDS-induced increase in the immobility time in the tail suspension test and forced swimming test and decrease in the time spent in the interaction zone in the social interaction test, as well as preventing the CSDS-induced decrease in the time spent (i) in open arms in the elevated plus maze test, (ii) on the illuminated side in the light-dark test, and (iii) in the central region of the open field test. The single GM-CSF preinjection (100 µg/kg) also prevented the CSDS-induced increase in the expression levels of interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) mRNA in the hippocampus and medial prefrontal cortex of the mice. Further analysis showed that the preventive effect of GM-CSF on CSDS-induced depression- and anxiety-like behaviors and neuroinflammatory responses was abolished by pretreatment with minocycline (an innate immune inhibitor). These results indicate that a single low dose of GM-CSF before injection could be a potential way to prevent behavioral abnormalities induced by chronic stress in mice.

Identification of the expression of farnesoid X receptor in astrocytes.

Recently, we have identified a functional expression of farnesoid X receptor (FXR) in neurons in vitro and in vivo. However, whether the FXR is expressed in astrocytes remains unclear. In the present study, we addressed this issue by using an array of experimental methods such as immunofluorescence and western blot. Results showed that the FXR mRNA and protein were expressed in mouse brain primary cultured astrocytes. In mouse primary cultured astrocytes in vitro the FXR was predominantly localized in the nucleus with an obvious punctuate distribution property. Unlike its expressional characteristic in cultured astrocytes, the FXR was not detected in astrocytes in the mouse hippocampus and prefrontal cortex, suggesting that the FXR is not expressed in astrocytes at conditions in vivo. Functional studies in vitro showed that activation of the FXR in primary cultured astrocytes by chenodeoxycholic acid or GW4064 induced a marked increase in expression levels of small heterodimer partner mRNA and protein. Taken together, these findings show a differential expression of FXR in astrocytes at conditions in vitro but not in vivo, and in mouse primary cultured astrocytes the FXR can be activated by its ligands.

A comprehensive understanding about the pharmacological effect of diallyl disulfide other than its anti-carcinogenic activities.

Diallyl disulfide (DADS), an oil-soluble sulfur compound that is responsible for the biological effects of garlic, displays numerous biological activities, among which its anti-cancer activities are the most famous ones. In recent years, the pharmacological effects of DADS other than its anti-carcinogenic activities have attracted numerous attentions. For example, it has been reported that DADS can prevent the microglia-mediated neuroinflammatory response and depression-like behaviors in mice. In the cardiovascular system, DADS administration was found to ameliorate the isoproterenol- or streptozotocin-induced cardiac dysfunction via the activation of the nuclear factor E2-related factor 2 (Nrf2) and insulin-like growth factor (IGF)-phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling. DADS administration can also produce neuroprotective effects in animal models of Alzheimer's disease and protect the heart, endothelium, liver, lung, and kidney against cellular or tissue damages induced by various toxic factors, such as the oxidized-low density lipoprotein (ox-LDL), carbon tetrachloride (CCl4), ethanol, acetaminophen, Cis-Diammine Dichloroplatinum (CisPt), and gentamicin. The major mechanisms of action of DADS in disease prevention and/or treatment include inhibition of inflammation, oxidative stress, and cellular apoptosis. Mechanisms, including the activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase A (PKA), and cyclic adenosine monophosphate-response element binding protein (CREB) and the inhibition of histone deacetylases (HDACs), can also mediate the cellular protective effects of DADS in different tissues and organs. In this review, we summarize and discuss the pharmacological effects of DADS other than its anti-carcinogenic activities, aiming to reveal more possibilities for DADS in disease prevention and/or treatment.

Acute Diallyl Disulfide Administration Prevents and Reveres Lipopolysaccharide-Induced Depression-Like Behaviors in Mice via Regulating Neuroinflammation and Oxido-Nitrosative Stress.

Neuroinflammation and oxidative stress play critical roles in pathogenesis of depression. Diallyl disulfide (DADS), an active compound in garlic oil, has been shown to exhibit obvious anti-inflammatory and anti-oxidative activities. Preliminary evidence indicates that depression is associated with high levels of pro-inflammatory cytokines and oxidative markers, suggesting that inhibition of neuroinflammatory response and oxidative stress may be beneficial for depression interruption. Here, we investigated the antidepressant effect of DADS as well as it mechanisms in a depression-like model induced by lipopolysaccharide (LPS). Similarly to imipramine (10 mg/kg), a clinical antidepressant, DADS (40 or 80 mg/kg), which was administered 1 h before LPS treatment (pre-LPS) or 1.5 h and 23.5 h after LPS treatment (post-LPS), prevented and reversed LPS (100 µg/kg)-induced increase in immobility time in the tail suspension test (TST) and forced swim test (FST) in mice. Mechanistic studies revealed that DADS pre-treatment or post-treatment at the dose of 40 and 80 mg/kg prevented and reversed (i) LPS-induced increases in interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) levels in the hippocampus and prefrontal cortex, (ii) LPS-induced increases in contents of malondialdehyde (MDA), a parameter reflecting high levels of oxidative stress, and (iii) LPS-induced decreases in contents of GSH, a marker reflecting weakened anti-oxidative ability, in the hippocampus and prefrontal cortex in mice. These results indicate that DADS is comparable to imipramine in effectively ameliorating LPS-induced depression-like behaviors in mice, providing a potential value for DADS in prevention and/or therapy of depression.

A prophylactic effect of macrophage-colony stimulating factor on chronic stress-induced depression-like behaviors in mice.

Innate immune activation has been shown to reduce the severity of nervous system disorders such as brain ischemia and traumatic brain damage. Macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, is an enhancer of the innate immune response. In the present study, we evaluated the effect of M-CSF preconditioning on chronic social defeat stress (CSDS)-induced depression-like behaviors in mice. Results showed that a single M-CSF injection 1 day before stress exposure at the dose of 100 and 500 µg/kg, or a single M-CSF injection (100 µg/kg) 1 or 5 days but not 10 days before stress exposure prevented CSDS-induced depression-like behaviors in mice. Further analysis showed that a second M-CSF injection 10 days after the first M-CSF injection and a 2 × or 4 × M-CSF injections 10 days before stress exposure also prevented CSDS-induced depression-like behaviors. Molecular studies revealed that a single M-CSF injection prior to stress exposure skewed the neuroinflammatory responses in the brain in CSDS-exposed mice towards an anti-inflammatory phenotype. These behavioral and molecular actions of M-CSF were correlated with innate immune stimulation, as pre-inhibiting the innate immune activation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of M-CSF on CSDS-induced depression-like behaviors and neuroinflammatory responses. These results provide evidence to show that innate immune activation by M-CSF pretreatment may prevent chronic stress-induced depression-like behaviors via preventing the development of neuroinflammatory response in the brain, which may help to develop novel strategies for the prevention of depression.

A review for the pharmacological effect of lycopene in central nervous system disorders.

Lycopene is an aliphatic hydrocarbon carotenoid extracted from plants like tomatoes, papayas, and watermelons. Previous studies have shown that lycopene can exert prophylactic and/or therapeutic effects in different disorders, such as heart failure and neoplasm via anti-oxidative, anti-inflammatory, and anti-proliferative activities. In the central nervous system (CNS), lycopene also has prophylactic and/or therapeutic effects in different type of disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), cerebral ischemia, epilepsy, and depression. Lycopene also improves cognition and memory ability of rodents in different pathological conditions, such as diabetes, colchicine exposure, high-fat diet (HFD), and aging. Further, lycopene can prevent neuro-toxicities induced by monosodium glutamate (MSG), trimethyltin (TMT), methylmercury (MeHg), tert-butyl hydroperoxide (t-BHP), and cadmium (Cd). In some special conditions such as ethanol addiction and haloperidol-induced orofacial dyskinesia, lycopene administration displays special therapeutic effects. Mechanisms including inhibition of oxidative stress and neuroinflammation, inhibition of neuronal apoptosis, and restoration of mitochondrial function have been shown to mediate the neuroprotective effects of lycopene. Other mechanisms, such as inhibition of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), activation of the nuclear factor erythroid 2-related factor (Nrf2) and brain-derived neurotrophic factor (BDNF) signaling, and restoration of intracellular Ca2+ homeostasis, may be also involved in the neuroprotective effect of lycopene. In hope of get a clear impression about the role of lycopene in the CNS, we summarize and discuss the pharmacological effects of lycopene as well as its possible mechanisms in CNS disorder prevention and/or therapy.

Effects of sulforaphane in the central nervous system.

Sulforaphane (SFN) is an active component extracted from vegetables like cauliflower and broccoli. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is a common mechanism for the anti-oxidative and anti-inflammatory activity of some herb-derived compounds, such as icariin and berberine. However, due to its peculiar ability in Nrf2 activation, SFN is recognized as an activator of Nrf2 and recommended as a supplementation for prevention and/or treatment of disorders like neoplasm and heart failure. In the central nervous system (CNS), the prophylactic and/or therapeutic effects of SFN have been revealed in recent years. For example, it has been reported to prevent the progression of Alzheimer's disease, Parkinson's disease, cerebral ischemia, Huntington's disease, multiple sclerosis, epilepsy, and psychiatric disorders via promotion of neurogenesis or inhibition of oxidative stress and neuroinflammation. SFN is also implicated in reversing cognition, learning, and memory impairment in rodents induced by scopolamine, lipopolysaccharide, okadaic acid, and diabetes. In models of neurotoxicity, SFN has been shown to suppress neurotoxicity induced by a wide range of toxic factors, such as hydrogen peroxide, prion protein, hyperammonemia, and methamphetamine. To date, no consolidated source of knowledge about the pharmacological effects of SFN in the CNS has been presented in the literature. In this review, we summarize and discuss the pharmacological effects of SFN as well as their possible mechanisms in prevention and/or therapy of disorders afflicting the CNS, aiming to get a further insight into how SFN affects the pathophysiological process of CNS disorders.

An outline for the pharmacological effect of icariin in the nervous system.

Icariin is a major active component of the traditional herb Epimedium, also known as Horny Goat Weed. It has been extensively studied throughout the past several years and is known to exert anti-oxidative, anti-neuroinflammatory, and anti-apoptotic effects. It is now being considered as a potential therapeutic agent for a wide variety of disorders, ranging from neoplasm to cardiovascular disease. More recent studies have shown that icariin exhibits potential preventive and/or therapeutic effects in the nervous system. For example, icariin can prevent the production of amyloid ß (1-42) and inhibit the expression of amyloid precursor protein (APP) and ß-site APP cleaving enzyme 1 (BACE-1) in animal models of Alzheimer's disease (AD). Icariin has been shown to mitigate pro-inflammatory responses of microglia in culture and in animal models of cerebral ischemia, depression, Parkinson's disease (PD), and multiple sclerosis (MS). Icariin also prevents the neurotoxicity induced by hydrogen peroxide (H2O2), endoplasmic reticulum (ER) stress, ibotenic acid, and homocysteine. In addition, icariin is implicated in facilitating learning and memory in both normal aging animals and disease models. To date, we still have no consolidated source of knowledge about the pharmacological effects of icariin in the nervous system, though its roles in other tissues have been reviewed in recent years. Here, we summarize the pharmacological development of icariin as well as its possible mechanisms in prevention and/or therapy of disorders afflicting the nervous system in hope of expanding the knowledge about the preventive and/or therapeutic effect of icariin in brain disorders.

Identification of a microglial activation-dependent antidepressant effect of amphotericin B liposome.

Chronic stress-induced decline in microglia in the hippocampus is a newly hypothesized mechanism of depression, and reversal of this decline by microglial activators has been shown to suppress depression-like behaviors in mice. This suggests that activation of immune cells in the hippocampus may be a potential strategy for depression therapy. Since amphotericin B, an anti-fungal medication, is known to activate macrophages and microglia, we investigated whether conventional amphotericin B or its liposomal form displays antidepressant activity. Our results showed that both amphotericin B and its liposomal form at various doses induced obvious depression-like behaviors in naïve mice, likely owing to increased serum interleukin-6 (IL-6) and IL-1ß levels. However, under stressed conditions, amphotericin B liposome, but not amphotericin B itself, reversed chronic unpredictable stress (CUS)-induced increase in immobility time in the tail suspension test and forced swim test as well as CUS-induced decrease in sucrose intake in the sucrose preference test and the time spent in the center region of the open field test in a dose-dependent manner. Immunofluorescence analysis showed that amphotericin B liposome reversed the CUS-induced decline in dentate gyrus (DG) microglia, and inhibition or ablation of microglia in the hippocampus by minocycline (40 mg/kg) or PLX3397 pre-treatment (290 mg/kg) abrogated the antidepressant effect of the amphotericin B liposome in CUS-treated mice. These results not only identify a novel pharmacological effect of amphotericin B liposome, but further support the notion that microglial activation in the hippocampus is a potential strategy for depression therapy.

SMIP004: A compound with antidepressant-like activities in mouse models.

This study was designed to examine the potency of SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), to exert antidepressant-like properties in mouse models following acute or chronic administration to C57BL6/J mice. To this end, the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT) were utilized and the antidepressant-like activity of SMIP004 at different concentrations or time points in mice with or without chronic unpredictable stress (CUS) treatment were evaluated. Results showed that in the time- and dose-dependent experiment the antidepressant-like activity of SMIP004 in naïve mice occurred at day 11 and at the dosage of 2 and 4 mg/kg. SMIP004 (2 mg/kg) also produces antidepressant-like activities in naïve mice after three times in a 24-h administration scheme (24, 5, and 1 h before the test) but not after acute treatment (1 h before the test). Combined SMIP004-fluoxetine administration was found to induce coordinated antidepressant-like effects in naïve mice in the TST and FST. These results seem to be specific because the mice in different experimental groups showed no increased locomotor activity in the open field test. Further, long-term SMIP004 treatment at the dosage of 2 but not 1 mg/kg reversed CUS-induced increase in immobility time in the TST and FST as well as CUS-induced decrease in sucrose preference in the SPT, suggesting that SMIP004 can produce antidepressant-like activities at stressed conditions. These results show that SMIP004 displays obvious antidepressant-like activities in all conducted tests, and suggest that SMIP004 might be a novel antidepressant.

Genetic regulatory network analysis reveals that low density lipoprotein receptor-related protein 11 is involved in stress responses in mice.

To study whether Lrp11 is involved in stress response and find its expression regulatory network, the model of stress has been built using C57BL/6J (B6) and DBA/2 (D2) mice. Western blotting, qPCR and immunohistochemistry were used to investigate the expression variation of Lrp11 in amygdala tissue after exposure to stress. We found the quantity of Lrp11 was more obvious in stress models than that in normal mice (P<0.05) which suggests Lrp11 might participate in the process of stress response. The expression of Lrp11 is controlled by a cis-acting quantitative trait locus (cis-eQTL). We identified four genes that are regulated by Lrp11 and the expression of 66 genes highly correlated with Lrp11, seven of which have previously been implicated in stress pathways. To evaluate the relationship between Lrp11 and its downstream genes or network members, we transfected HEK 293T cells and SH-SY5Y cells with Lrp11 siRNA leading to down-regulation of Lrp11mRNA and were able to confirm a significant influence of Lrp11 depletion on the expression of Xpnpep1, Maneal, Pgap1 and Uprt. These validated downstream targets and members of Lrp11 gene network provide new insight into the biological role of Lrp11 and may be an important risk factor in the development of stress.

The expression of CAP1 after traumatic brain injury and its role in astrocyte proliferation.

Adenylate cyclase-associated protein 1 (CAP1), a member of cyclase-associated proteins involved in the regulation of actin filaments, was recently reported to play a role in the pathology of sciatic nerves injury. However, the distribution and function of CAP1 in the central nervous system (CNS) remain unclear. To investigate whether CAP1 is involved in CNS injury and repair, we used an acute traumatic brain injury (TBI) model in adult rats. Western blot analysis and immunohistochemistry showed a significant upregulation of CAP1 in ipsilateral peritrauma cortex compared with the contralateral and sham-operated ones. Double immunofluorescence staining showed that CAP1 was co-expressed with glial fibrillary acidic protein (GFAP). In addition, we detected that Ki-67 had colocalization with GFAP and CAP1 after TBI. In vitro, during the process of lipopolysaccharide (LPS)-induced primary astrocyte proliferation, we observed enhanced expression of CAP1. Specially, CAP1-specific siRNA-transfected primary astrocytes show significantly decreased ability for proliferation. Together, all these data indicated that the change of CAP1 protein expression was associated with astrocyte proliferation after the trauma of the central nervous system (CNS).