Identification of antimicrobial peptide genes from transcriptomes in Mandarin fish (Siniperca chuatsi) and their response to infection with Aeromonas hydrophila.

Mandarin fish (Siniperca chuatsi) is a valuable freshwater fish species widely cultured in China. Its aquaculture production is challenged by bacterial septicaemia, which is one of the most common bacterial diseases. Antimicrobial peptides (AMPs) play a critical role in the innate immune system of fish, exhibiting defensive and inhibitory effects against a wide range of pathogens. This study aimed to identify the antimicrobial peptide genes in mandarin fish using transcriptomes data obtained from 17 tissue in our laboratory. Through nucleotide sequence alignment and protein structural domain analysis, 15 antimicrobial peptide genes (moronecidin, pleurocidin, lysozyme g, thymosin ß12, hepcidin, leap 2, ß-defensin, galectin 8, galectin 9, apoB, apoD, apoE, apoF, apoM, and nk-lysin) were identified, of which 9 antimicrobial peptide genes were identified for the first time. In addition, 15 AMPs were subjected to sequence characterization and protein structure analysis. After injection with Aeromonas hydrophila, the number of red blood cells, hemoglobin concentration, and platelet counts in mandarin fish showed a decreasing trend, indicating partial hemolysis. The expression change patterns of 15 AMP genes in the intestine after A. hydrophila infection were examined by using qRT-PCR. The results revealed, marked up-regulation (approximately 116.04) of the hepcidin gene, down-regulation of the piscidin family genes expression. Moreover, most AMP genes were responded in the early stages after A. hydrophila challenge. This study provides fundamental information for investigating the role of the different antimicrobial peptide genes in mandarin fish in defense against A. hydrophila infection.

Characterization of sexual size dimorphism in mandarin fish and association with igfbp-5a/b regulation.

Mandarin fish (Siniperca chuatsi) is an important cultured fish in East Asia that shows sexual size dimorphism (SSD), with females growing faster than males when reaching marketable size. However, the regulatory mechanism of SSD is not clear. To characterize SSD of mandarin fish and its association with gh/igf1/igfbp-5 expression, gonadal developmental atlas of the females and the males were described, and growth parameters and serum levels of E2 and T, as well as the relative expression levels of gh, igf1, and igfbp-5a/b mRNAs, were determined. The results showed that the logistic growth equation of body mass and total length of female and male were W(♀) = 667.57/(1 + e^(4.19 - 1.24*t)), W(♂) = 582.71/(1 + e^(4.07 - 1.27*t)), L(♀) = 31.47/(1 + e^1.95 - 1.08*t)), L(♂) = 26.20/(1 + e^(2.56 - 1.5*t)). The month of inflection points for body mass for females and males were 3.37 mph and 3.20 mph, respectively, when the body mass were 333.79 g and 291.36 g. The month of inflection points for total length growth were 1.80 mph and 1.70 mph, respectively, when the total length were 18.52 cm and 16.28 cm. At 1.5-2.0 mph, SSD was not clearly demonstrated. At 3.0 mph, the body mass of the females was significantly higher than that of the males (P < 0.05), Serum E2, brain gh, and liver igf1 expression of the females was significantly higher than that of the males (P < 0.05); T content of the males was significantly higher than that of the females (P < 0.05). At 4.0 months of age, the body mass of the females was highly significantly higher than that of the males (P < 0.01), Serum E2, brain gh, and liver igf1 expression of the females was highly significantly higher than that of the males (P < 0.05); T content of the males was significantly higher than that of the females (P < 0.05). With the continuous development of gonads, muscle and liver igfbp-5a and -5b expression generally tend to increase in females and males, while igfbp-5a showed a gradual increasing trend, and igfbp-5b expression showed a trend of decreasing and then increasing. Male igfbp-5a/b expression was significantly higher than female at the age of 3.0-4.0 months (P < 0.05). This work verified that the females had faster growth rate since 3.0 mph compared to the males, which may be related to higher E2 levels in females leading to higher igf1 level, through inhibition of igfbp-5a/b expression.

[Genetic analysis of a child with restricted cardiomyopathy and phenylketonuria and a literature review].

OBJECTIVE: To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy (RCM) and phenylketonuria (PKU), and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review. METHODS: A child with RCM in conjunct with PKU who was admitted to the Children's Hospital Affiliated to Zhengzhou University in June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject. Relevant clinical data were collected. Peripheral blood samples of the child and his parents were collected for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatic analysis. Childhood, TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform, Chinese Journal Full-text database and PubMed database, and the search period was limited to from the time of establishment till August 2022. Clinical manifestations and characteristics of the TNNI3 gene variants were summarized. RESULTS: The child, a 2-year-old-and-4-month-old male, had normal intelligence, facial features and normal hair and skin color, but his motor and physical development was delayed, in addition with edema of bilateral eyelids and lower limbs. The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene, namely c.331C>T (p.R111X) and c.940C>A (p.P341T), which were inherited from his father and mother, respectively. In addition, he has also harbored a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the TNNI3: c.508C>T (p.R170W) was classified as a pathogenic variant (PS2+PS4+PM2_Supporting+PM5), PAH: c.331C>T (p.R111X) as a pathogenic variant (PVS1+PM2_Supporting+PM3+PP4), and c.940C>A (p.P341T) as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP4). In total 30 children with RCM caused by TNNI3 gene variants were retrieved, with a male-to-female ratio of 1 : 1.55 and manifestations including heart failure, sinus rhythm, bi-atrial enlargement, ST-T wave change, ventricular restricted filling, and decreased ventricular diastolic function. In total 16 variants of the TNNI3 gene were identified, among which c.575G>A was the most common, and all cases had conformed to an autosomal dominant inheritance. CONCLUSION: Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.

Natural history and remarkable psychiatric state of late-onset amyotrophic lateral sclerosis in China.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. The proportion of late-onset ALS in China were low and may have distinct clinical and genetic manifestations. We aimed to investigate the natural history and remarkable psychiatric state of ALS with age at onset over 60 years in China. MATERIALS AND METHODS: We collected all ALS cases from 2017 to 2020 in our center and focused on late-onset ALS patients particularly, by analyzing the clinical data, including the ALS onset and disease progression. Anxiety, depression, cognitive function, and sleep quality were assessed to reflect the psychiatric state. RESULTS: A total of 193 late-onset ALS patients were included in this study. The median age at onset of late-onset ALS was 65 years with the quartile from 62 to 68 years. When compared with 446 non-late-onset ALS, late-onset ALS showed distinct clinical presentation, with lower ALS Functional Rating Scale-Revised at diagnosis and faster rate of progression. Remarkably, late-onset ALS were suffering from worse psychiatric state, including serious anxiety and depression, as well as worse cognitive function with sleep quality. The abnormal psychiatric state was more pronounced in female patients of late-onset. CONCLUSIONS: In the current study, ALS patients with late-onset showed unique clinical features. Severe psychiatric conditions and faster progression in the early stage of the disease of late-onset ALS indicated the need for more social and psychiatric support in this population.

Purkinje cell (PC) antibody positivity in a patient with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.

PURPOSE: This case report is the first to describe the detection of antibodies against inositol 1,4,5-trisphosphate receptor 1 (ITPR1, I3PR) in a patient diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. ITPR1 is known as one of the Purkinje cell antibodies present in autoimmune cerebellar ataxia (ACA). Here, we described the association between autoimmune GFAP astrocytopathy and autoimmune cerebellar disease (ACD). MATERIALS AND METHODS: Demographic features, clinical characteristics, cerebrospinal fluid (CSF) parameters and neuroimaging findings were collected from this patient. Specifically, antibodies against GFAP and other proteins associated with neurological disorders were measured by immunofluorescence staining in both serum and CSF samples. RESULTS: A 52-year-old woman was diagnosed with autoimmune inflammatory meningoencephalitis. She presented with cognitive dysfunction, psychiatric/behavioral abnormalities and serious insomnia with subacute onset. Brain magnetic resonance imaging (MRI) showed bilateral hyperintensity in the semioval centers on axial images and perivascular linear enhancement oriented radially to the ventricles on sagittal images. GFAP-IgG, oligoclonal bands (OBs), N-methyl-D-aspartate receptor (NMDAR)-IgG and ITPR1-IgG co-existed in her CSF. She responded well to immunoglobulin and steroid treatments. CONCLUSION: Here, we describe the case of a patient with autoimmune GFAP astrocytopathy whose CSF was positive for ITPR1-IgG; however, she did not show typical ataxia manifestations or cerebellar lesions on her MRI scan. This suggests that ITPR1-IgG is not pathogenic, and the positivity of this antibody in CSF is probably associated with the presence of autoimmune inflammation.

Effect of Information-Motivation-Behavioral Model Based on Protection Motivation Theory on the Psychological Resilience and Quality of Life of Patients with Type 2 DM.

Diabetes mellitus (DM) is one of the remarkable disease challenges in the twenty-first century and poses threat to patients' physical health. Given the difficulty of treatment and the high possibility of relapse, patients often have mental illness. A total of 117 patients with type 2 DM were randomly divided into two groups for a 2-month intervention. The intervention group underwent an Information-Motivation-Behavioral skills (IMB) intervention program based on protection motivation theory, and traditional intervention was applied to the control group. No significant difference is found between the intervention and control groups before the intervention (P > 0.05). However, after the intervention, the blood glucose level and depression score of the intervention group are lower than those of the control group (P < 0.05), and the psychological resilience and quality of life are significantly higher than those of the control group (P < 0.05). The blood glucose level and depression score of the intervention group decrease after the intervention (P < 0.05), and the psychological resilience and quality of life are significantly increase (P < 0.05). No significant difference is found in the blood glucose level, depression, psychological resilience, and quality of life of the control group before and after the intervention (P > 0.05). The combination of IMB intervention and protection motivation theory is important to improving the psychological resilience of patients with type 2 DM, raising their quality of life and reducing their blood glucose level.

Endoplasmic reticulum stress-induced exosomal miR-27a-3p promotes immune escape in breast cancer via regulating PD-L1 expression in macrophages.

Immune escape of breast cancer cells contributes to breast cancer pathogenesis. Tumour microenvironment stresses that disrupt protein homeostasis can produce endoplasmic reticulum (ER) stress. The miRNA-mediated translational repression of mRNAs has been extensively studied in regulating immune escape and ER stress in human cancers. In this study, we identified a novel microRNA (miR)-27a-3p and investigated its mechanistic role in promoting immune evasion. The binding affinity between miR-27a-3p and MAGI2 was predicted using bioinformatic analysis and verified by dual-luciferase reporter assay. Ectopic expression and inhibition of miR-27a-3p in breast cancer cells were achieved by transduction with mimics and inhibitors. Besides, artificial modulation of MAGI2 and PTEN was done to explore their function in ER stress and immune escape of cancer cells. Of note, exosomes were derived from cancer cells and co-cultured with macrophages for mechanistic studies. The experimental data suggested that ER stress biomarkers including GRP78, PERK, ATF6, IRE1α and PD-L1 were overexpressed in breast cancer tissues relative to paracancerous tissues. Endoplasmic reticulum stress promoted exosome secretion and elevated exosomal miR-27a-3p expression. Elevation of miR-27a-3p and PD-L1 levels in macrophages was observed in response to exosomes-overexpressing miR-27a-3p in vivo and in vitro. miR-27a-3p could target and negatively regulate MAGI2, while MAGI2 down-regulated PD-L1 by up-regulating PTEN to inactivate PI3K/AKT signalling pathway. Less CD4+ , CD8+ T cells and IL-2, and T cells apoptosis were observed in response to co-culture of macrophages and CD3+ T cells. Conjointly, exosomal miR-27a-3p promotes immune evasion by up-regulating PD-L1 via MAGI2/PTEN/PI3K axis in breast cancer.

CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in acute lung injury induced by sepsis through modulating miR-21.

Acute lung injury (ALI) induced by sepsis is characterized by an inflammatory process related to the up-regulation of inflammatory cytokines and chemokines. In the present study, we explored the role of circC3P1 in sepsis-induced ALI in vitro and in vivo. The caecal ligation and puncture (CLP)-induced sepsis model was established through CLP surgery. Forty adult male C57BL/6 mice were randomly assigned into sham, CLP, CLP + vector and CLP + circC3P1 (each n = 10). Primary murine pulmonary microvascular endothelial cells (MPVECs) were transfected with circC3P1 or empty vector 24 hours prior to LPS treatment via Lipofectamine 2000. The expressions of circC3P1, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß were evaluated after 6-h LPS treatment. Cell apoptosis was evaluated via flow cytometry. The CLP group demonstrated pulmonary morphological abnormalities, increased concentrations of TNF-α, IL-6 and IL-1ß in the lung tissue, compared with the sham group. MPVECs treated with LPS significantly elevated TNF-α, IL-6 and IL-1ß levels and increased cell apoptosis than that in the control group. The circC3P1 overexpression in sepsis-induced ALI mice attenuated pulmonary injury, inflammation and apoptosis. Besides, circC3P1 revealed anti-inflammatory and anti-apoptotic effect in MPVEC-treated LPS. CircC3P1 overexpression reduced cell apoptosis and pro-inflammatory cytokines levels via down-regulating miR-21. CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in ALI induced by sepsis through modulating miR-21, indicating that circC3P1 is a promising therapeutic biomarker for sepsis-induced ALI.

Cocaine-induced structural and functional impairments of the glymphatic pathway in mice.

The glymphatic system plays a central role in the clearance of extracellular wastes from the brain. Cocaine exposure can lead to pathologies that affect the entire brain, resulting in addictive disorders involving motivational and cognitive impairment. However, it remains unknown whether cocaine exposure impairs glymphatic function. In the present study, using a mouse model of noncontingent cocaine exposure, we evaluated glymphatic function including cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and solute clearance during repeated exposures and withdrawal. We found that cocaine treatment, both during repeated exposure and withdrawal, significantly induced widespread astrogliosis and reduced cerebral blood flow (CBF), cerebrovascular pulsatility, and aquaporin-4 (AQP4) polarity. Glymphatic function was greatly impaired in mice after cocaine treatment, as evidenced by reduced CSF influx from paravascular pathways into the brain parenchyma and decreased efflux of interstitial molecules out of the parenchyma. These findings provide evidence that cocaine exposure impairs the clearance of wastes from the brain, which may contribute to the development of neurocognitive disorders in patients with drug addictions.

Experimental alcoholism primes structural and functional impairment of the glymphatic pathway.

Alcoholism is a risk factor for the development of cognitive decline and dementia. Here we demonstrated that the glymphatic function in the brain was impaired by alcohol administration. Acute moderate alcohol administration substantially retarded and reduced the entry of subarachnoid cerebrospinal fluid (CSF) via the paravascular space into the cerebral parenchyma, thus impaired CSF-interstitial fluid (ISF) exchange and parenchymal amyloid ß (Aß) peptide clearance. The elevated release of ß-endorphin and reduced cerebrovascular pulsatility after acute alcohol administration may account for the impairment of the glymphatic function. Chronic moderate alcohol consumption led to pronounced activation of astrocytes and a widespread loss of perivascular AQP4 polarization in the brain, which results in an irreversible impairment of the glymphatic function. The results of the study suggest that impaired glymphatic functions and reduced parenchymal Aß clearance found in both acute and chronic alcohol treatment may contribute to the development of cognitive decline and dementia in alcoholism.

Omega-3 polyunsaturated fatty acids promote brain-to-blood clearance of ß-Amyloid in a mouse model with Alzheimer's disease.

Amyloid-ß (Aß) plaques is one of the typical pathological hallmark of Alzheimer disease (AD). Accumulating evidence suggests that the imbalance between Aß production and clearance leads to extracellular Aß accumulation in the brain. It is reported that the blood-brain barrier (BBB) transport plays a predominant role in Aß clearance from brain to blood. In the present study, we investigated dynamic alterations of BBB transport function in the early disease stage of AD using APPswe/PS1dE9 C57BL/6J (APP/PS1) transgenic mice. Our results showed that the expression of lipoprotein receptor-related protein 1 (LRP-1), a main efflux transporter of BBB, started to decrease at the age of 4 months old. Interestingly, supplementing with fish oil which is rich in omega-3 polyunsaturated fatty acids (PUFAs) significantly enhanced the expression level of LRP-1 and promoted Aß clearance from the bran to circulation, as revealed by reduced soluble/insoluble Aß levels and senile plaques in the brain parenchyma and a corresponding increase of Aß levels in plasma. Besides, fish oil supplement significantly inhibited the NF-κB activation, reduced the expression of interleukin-1ß and tumor necrosis factor-α, and suppressed the glial activation in APP/PS1 mice. The results of the study provide evidence that BBB transport function could be impaired at a very early disease stage, which might contribute to Aß pathological accumulation in AD, and omega-3 PUFAs intervention could be an effective strategy for the prevention of the progression of AD through promoting Aß clearance from brain-to-blood.

Muscular involvement and tendon contracture in limb-girdle muscular dystrophy 2Y: a mild adult phenotype and literature review.

BACKGROUND: Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies. CASE PRESENTATION: A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC). CONCLUSION: We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.

Fish oil treatment reduces chronic alcohol exposure induced synaptic changes.

Alcohol addiction is a chronic neuropsychiatric disorder that represents one of the most serious global public health problems. Yet, currently there still lacks an effective pharmacotherapy. Omega-3 polyunsaturated fatty acids (N-3 PUFAs) have exhibited beneficial effects in a variety of neurological disorders, particularly in reversing behavioral deficits and neurotoxicity induced by prenatal alcohol exposure and binge drinking. In the present study, we investigated if fish oil, which is rich in N-3 PUFAs, had beneficial effects on preventing relapse and alleviating withdrawal symptoms after chronic alcohol exposure. Our results demonstrated that fish oil significantly reduced the chronic alcohol exposure-induced aberrant dendritic morphologic changes of the medium-sized spiny neurons in the core and the shell of nucleus accumbens. This inhibited the expression of AMPAR2-lacking AMPARs and their accumulation on the post synaptic membranes of medium-sized spiny neurons and eventually alleviated withdrawal symptoms and alcohol dependence. Our study therefore suggests that N-3 PUFAs are promising for treating withdrawal symptoms and alcohol dependence.

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

Omega-3 polyunsaturated fatty acids promote amyloid-ß clearance from the brain through mediating the function of the glymphatic system.

Impairment of amyloid-ß (Aß) clearance leads to Aß accumulation in the brain during the development of Alzheimer's disease (AD). Strategies that can restore or improve the clearance function hold great promise in delaying or preventing the onset of AD. Here, we show that n-3 polyunsaturated fatty acids (PUFAs), by use of fat-1 transgenic mice and oral administration of fish oil, significantly promote interstitial Aß clearance from the brain and resist Aß injury. Such beneficial effects were abolished in Aqp4-knockout mice, suggesting that the AQP4-dependent glymphatic system is actively involved in the promoting the effects of n-3 PUFAs on the clearance of extracellular Aß. Imaging on clarified brain tissues clearly displayed that n-3 PUFAs markedly inhibit the activation of astrocytes and protect the AQP4 polarization in the affected brain region after Aß injection. The results of the present study prove a novel mechanism by which n-3 PUFAs exert protective roles in reducing Aß accumulation via mediating the glymphatic system function.-Ren, H., Luo, C., Feng, Y., Yao, X., Shi, Z., Liang, F., Kang, J. X., Wan, J.-B., Pei, Z., Su, H. Omega-3 polyunsaturated fatty acids promote amyloid-ß clearance from the brain through mediating the function of the glymphatic system.

Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation.

Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti-oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long-term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-α and IL-1ß, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases.

Paeonolum protects against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population aged over 65 years old. Mitochondrial defects and oxidative stress actively participate in degeneration of dopaminergic (DA) neurons in PD. Paeonolum, a main component isolated from Moutan cortex, has potent antioxidant ability. Here, we have examined the effects of paeonolum against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. METHODS: The overall viability and neurodegeneration of DA neurons was assessed in ETvmat2:green fluorescent protein (GFP) transgenic zebrafish, in which most monoaminergic neurons are labeled by GFP. Damage to PC12 cells was measured using a cell viability assay and assessment of nuclear morphology. Intracellular reactive oxygen species (ROS) and the level of total GSH were assessed. The mitochondrial cell death pathway including mitochondrial membrane potential, cytochrome C release and caspase-3 activity were also examined in PC12 cells. RESULTS: Paeonolum protected against MPP(+)-induced DA neurodegeneration and locomotor dysfunction in zebrafish in a concentration-dependent manner. Similar neuroprotection was replicated in the PC12 cellular model of MPP(+) toxicity. Paeonolum attenuated MPP(+)-induced intracellular ROS accumulation and restored the level of total GSH in PC12 cells. Furthermore, paeonolum significantly inhibited the mitochondrial cell death pathway induced by MPP(+). CONCLUSIONS: Collectively, the present study demonstrates that paeonolum protects zebrafish and PC12 cells against MPP(+)-induced neurotoxicity.

Alzheimer's disease treated with combined therapy based on nourishing marrow and reinforcing Qi.

OBJECTIVE: To study the efficacy and safety of combined Traditional Chinese Medicine (TCM) therapy based on nourishing marrow to improve intellect and reinforcing Qi to activate bloodon mild to moderate Alzheimer's disease (AD). METHODS: Sixty-six patients with AD, whose Mini-Mental State Examination (MMSE) score were from 10-24, were randomized equally into an intervention group and a control group. The control group was given Aricept (5 mg, once daily). The intervention group was further divided into Yang-Qi deficiency (n = 18) and of Yin-Qi deficiency (n = 15) subgroups. Patients in the Yang-Qi deficiency group were intravenously administered shenfu injection, 60 mL, and deproteinized calf blood injection (DCBI), 1.2 g, once daily. The Yin-Qi deficiency group was given shenmai injection, 60 mL, and DCBI, 1.2 g, once daily. Each course lasted 21 days. RESULTS: Compared with the control group and with pre-treatment in the same group, MMSE, clinical dementia rating, and activities of daily living scale scores in the intervention group were significantly improved (all P < 0.05). These metrics mildly improved in the control group compared with before treatment (P > 0.05). No adverse effects were observed in any group during treatment. CONCLUSION: We found that combined TCM therapy is effective and safe for managing mild to moderate AD.

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury.

Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model.

Marine compound catunaregin inhibits angiogenesis through the modulation of phosphorylation of akt and eNOS in vivo and in vitro.

Angiogenesis is the formation of blood vessels from pre-existing vasculature. Excessive or uncontrolled angiogenesis is a major contributor to many pathological conditions whereas inhibition of aberrant angiogenesis is beneficial to patients with pathological angiogenesis. Catunaregin is a core of novel marine compound isolated from mangrove associate. The potential anti-angiogenesis of catunaregin was investigated in human umbilical vein endothelial cells (HUVECs) and zebrafish. HUVECs were treated with different concentrations of catunaregin in the presence or absence of VEGF. The angiogenic phenotypes including cell invasion cell migration and tube formation were evaluated following catunaregin treatment in HUVECs. The possible involvement of AKT, eNOS and ERK1/2 in catunaregin-induced anti-angiogenesis was explored using Western blotting. The anti-angiogenesis of catunaregin was further tested in the zebrafish embryo neovascularization and caudal fin regeneration assays. We found that catunaregin dose-dependently inhibited angiogenesis in both HUVECs and zebrafish embryo neovascularization and zebrafish caudal fin regeneration assays. In addition, catunaregin significantly decreased the phosphorylation of Akt and eNOS, but not the phosphorylation of ERK1/2. The present work demonstrates that catunaregin exerts the anti-angiogenic activity at least in part through the regulation of the Akt and eNOS signaling pathways.