Effects of Brain-Derived Neurotrophic Factor on Local Inflammation in Experimental Stroke of Rat

This study was aimed to investigate whether brain-derived neurotrophic factor (BDNF) can modulate local cerebral inflammation in ischemic stroke. Rats were subjected to ischemia by occluding the right middle cerebral artery (MCAO) for 2 hours. Rats were randomized as control, BDNF, and antibody groups. The local inflammation was evaluated on cellular, cytokine, and transcription factor levels with immunofluorescence, enzyme-linked immunosorbent assay, real-time qPCR, and electrophoretic mobility shift assay, respectively. Exogenous BDNF significantly improved motor-sensory, sensorimotor function, and vestibulomotor function, while BDNF did not decrease the infarct volume. Exogenous BDNF increased the number of both activated and phagocytotic microglia in brain. BDNF upregulated interleukin10 and its mRNA expression, while downregulated tumor necrosis factor α and its mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B. BDNF antibody, which blocked the activity of endogenous BDNF, showed the opposite effect of exogenous BDNF. Our data indicated that BDNF may modulate local inflammation in ischemic brain tissues on the cellular, cytokine, and transcription factor levels

Evolutionary dynamics of rabies viruses highlights the importance of China rabies transmission in Asia

AbstractRabies in Asia is emerging as a serious public health issue. To explore the possible origin, phylogenetic relationships, and evolutionary dynamics of Asian Rabies viruses (RABV), we examined 200 complete nucleoprotein (N) gene sequences from RABV isolates in the region. Phylogeny supported the classification of Asian RABVs into five distinct clusters in lyssavirus genotype 1. Our geospatial and temporal analyses demonstrated that China appears to be the prime source of Asian RABVs. Understanding of rabies transmission and associated human activities, such as dog translocation, can help rabies control and elimination in Asia through collaborative efforts or programs

Developing testicular organoids for assessing reproductive toxicity of antidepression drugs

Evaluating the reproductive toxicity of antidepressants is particularly important for those depressed male patients of childbearing age and crucial for the rational use of drugs in clini

Developing rat testicular organoid models for assessing the reproductive toxicity of antidepression drugs in vitro

With the increasing incidence of depression worldwide, antidepressant medications are commonly used in males of reproductive age for long-term treatment of depression, as well as other disorders. Antidepressants are known to be associated with sexual side effects, such as decreased libido and impotence. Their effects on semen parameters and other markers of male fertility have been less thoroughly described, such as sperm motility and fertilization ability. Therefore, it is critical to determine the potential toxic effects of antidepressants on reproductive organs. A recent study systemically determined the effect of different drugs on the telomere-related DNA damage response of germ cells. In addition, another study showed that mirtazapine has less toxic effects than amitriptyline and other drugs. However, these studies used germ cell lines to determine the phenotype, which limits their potential translational value in toxicity studies in humans. Given the widespread and often long-term use of antidepressant medications, there is an urgent need for further data regarding their impact on semen quality and subsequent male fertility

Role of the Subunits Interactions in the Conformational Transitions in Adult Human Hemoglobin: an Explicit Solvent Molecular Dynamics Study

Hemoglobin exhibits allosteric structural changes upon ligand binding due to the dynamic interactions between the ligand binding sites, the amino acids residues and some other solutes present under physiological conditions. In the present study, the dynamical and quaternary structural changes occurring in two unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures of adult human hemoglobin were investigated with molecular dynamics. It is shown that, in the sub-microsecond time scale, there is no marked difference in the global dynamics of the amino acids residues in both the oxy- and the deoxy- forms of the individual structures. In addition, the R, R2 are relatively stable and do not present quaternary conformational changes within the time scale of our simulations while the T structure is dynamically more flexible and exhibited the T\rightarrow R quaternary conformational transition, which is propagated by the relative rotation of the residues at the {\alpha}1{\beta}2 and {\alpha}2{\beta}1 interface.Comment: Reprinted (adapted) with permission from J. Phys. Chem. B DOI:10.1021/jp3022908. Copyright (2012) American Chemical Societ

A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation

Globozoospermia (OMIM: 102530) is a rare type of teratozoospermia ( A; p.R1224Q) in the patient. This variant significantly reduced the protein expression of SSFA2. Immunofluorescence staining showed posi- tive SSFA2 expression in the acrosome of human sperm. Liquid chromatography–mass spectrometry/mass spectrom- etry (LC–MS/MS) and Coimmunoprecipitation (Co-IP) analyses identified that GSTM3 and Actin interact with SSFA2. Further investigation revealed that for the patient, regular intracytoplasmic sperm injection (ICSI) treatment had a poor prognosis. However, Artificial oocyte activation (AOA) by a calcium ionophore (A23187) after ICSI successfully rescued the oocyte activation failure for the patient with the SSFA2 variant, and the couple achieved a live birth. This study revealed that SSFA2 plays an important role in acrosome formation, and the homozygous c.3671G > A loss-of-function variant in SSFA2 caused globozoospermia. SSFA2 may represent a new gene in the genetic diagnosis of globozoospermia, especially the successful outcome of AOA-ICSI treatment for couples, which has potential value for clinicians in their treatment regimen selections

The effect of socioeconomic status on three-year mortality after first-ever ischemic stroke in Nanjing, China

BACKGROUND: Low socioeconomic status (SES) is associated with increased mortality after stroke in developed countries. This study was performed to determine whether a similar association also exists in China. METHODS: A total of 806 patients with first-ever ischemic stroke were enrolled in our study. From August 1999 to August 2005, the three-year all-cause mortality following the stroke was determined. Level of education, occupation, taxable income and housing space were used as indicators for SES. Stepwise univariate and multivariate COX proportional hazards models were used to study the association between the SES measures and the three-year mortality. RESULTS: Our analyses confirmed that occupation, taxable income and housing space were significantly associated with three-year mortality after first-ever stroke. Manual workers had a significant hazard ratio of 5.44 (95% CI 2.75 to 10.77) for death within three years when compared with non-manual workers. Those in the zero income group had a significant hazard ratio of 5.35 (95% CI 2.95 to 9.70) and those in the intermediate income group 2.10 (95% CI 1.24 to 3.58) when compared with those in the highest income group. Those in two of the three groups with the smallest housing space also had significant hazard ratios of 2.06 (95% CI 1.16 to 3.65) and 1.68 (95% CI 1.12 to 2.52) when compared with those in group with the largest housing space. These hazard ratios remained largely unchanged after multivariate adjustment for age, gender, baseline cardiovascular disease risk factors, and stroke severity. The analyses did not confirm an association with educational level. CONCLUSION: Lower SES has a negative impact on the outcome of first-ever stroke in Nanjing, China. This confirms the need to improve preventive and secondary care for stroke among low SES groups

Validation of NINDS-CSN neuropsychological battery for vascular cognitive impairment in Chinese stroke patients

BACKGROUND: The NINDS-Canadian Stroke Network (NINDS-CSN) recommended a neuropsychological battery of three protocols to diagnose vascular cognitive impairment (VCI), however, due to culture and language differences, the battery cannot be directly used in China. Validation of the battery in mandarin Chinese is lacking. Our study investigated the reliability and validity of the adapted Chinese versions of the battery in stroke patients with high probability of VCI. METHODS: Fifty mild stroke patients (median of National Institute of Health Stroke Scale [NIHSS] score, 2) and 50 stroke-free normal controls were recruited. All subjects’ demographics, clinical history, and stroke severity were recorded. The NINDS-CSN neuropsychological protocols were adapted into the Chinese versions. External validity, defined as the ability of the protocol summary scores to differentiate stroke patients from controls, was determined using the area under the curve (AUC) of the receiver operating characteristics curve. We also evaluated internal consistency and intra-rater reliability. RESULTS: Stroke patients performed significantly poorer than controls on all three protocols (F statistics between 24.9 and 31.4, P < 0.001). External validity evaluated by AUCs was 0.88 (95% confidence interval [CI], 0.81-0.95), 0.88 (95% CI, 0.81-0.94), and 0.86 (95% CI, 0.79-0.94) for the 60-min, 30-min and 5-min protocols, respectively. Cronbach’s alpha of the cognitive tests was 0.87 for all subjects. Intra-rater reliability was acceptable with intraclass correlation coefficients 0.90, 0.83 and 0.75 for the 60-min, 30-min and 5-min protocols, respectively. CONCLUSIONS: The adapted Chinese versions of three NINDS-CSN neuropsychological protocols were valid and reliable for assessing VCI in Chinese patients with mild stroke

Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone

<p>Abstract</p> <p>Background</p> <p>The effect of neurotrophic factors in enhancing stroke-induced neurogenesis in the adult subventricular zone (SVZ) is limited by their poor blood-brain barrier (BBB) permeability.</p> <p>Intranasal administration is a noninvasive and valid method for delivery of neuropeptides into the brain, to bypass the BBB. We investigated the effect of treatment with intranasal transforming growth factor-β1 (TGF-β1) on neurogenesis in the adult mouse SVZ following focal ischemia. The modified Neurological Severity Scores (NSS) test was used to evaluate neurological function, and infarct volumes were determined from hematoxylin-stained sections. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling was performed at 7 days after middle cerebral artery occlusion (MCAO). Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) and neuron- or glia-specific markers for identifying neurogenesis in the SVZ at 7, 14, 21, 28 days after MCAO.</p> <p>Results</p> <p>Intranasal treatment of TGF-β1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-β1 treated mice had significantly less TUNEL-positive cells in the ipsilateral striatum than that in control groups. The number of BrdU-incorporated cells in the SVZ and striatum was significantly increased in the TGF-β1 treated group compared with control animals at each time point. In addition, numbers of BrdU- labeled cells coexpressed with the migrating neuroblast marker doublecortin (DCX) and the mature neuronal marker neuronal nuclei (NeuN) were significantly increased after intranasal delivery of TGF-β1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP).</p> <p>Conclusion</p> <p>Intranasal administration of TGF-β1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-β1 may have therapeutic potential for cerebrovascular disorders.</p

Tumor macroenvironment and metabolism

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%–20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient’s outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described