Neural network disturbance in the medial prefrontal cortex might contribute to cognitive impairments induced by neuroinflammation

Neuroinflammation plays a key role in the progression of many neurodegenerative diseases, yet the underlying mechanism remains largely unexplored. Using an animal model of neuroinflammation induced by repeated lipopolysaccharide (LPS) injections, we found selectively reduced expression of parvalbumin (PV) but not somatostatin (SST) in the medial prefrontal cortex (mPFC). The reduced PV expression resulted in decreased intensities of vesicular GABA transporter and PV buttons, suggesting disinhibition in the mPFC. These further induced abnormal mPFC neural activities and consequently contributed to cognitive impairments. In addition, gamma oscillations supported by PV interneuron function were positively associated with time spent with the novel object in the novel object recognition test. Notably, down-regulation of neuroinflammation by microglia inhibitor minocycline or boosting gamma oscillations by dopamine 4 receptor agonist RO-10-5824 improved cognitive performance. In conclusion, our study proposes neural network disturbance as a likely mechanistic linker between neuroinflammation and cognitive impairments in neurodegeneration and possibly other psychiatric disorders.     

A retrospective analysis of GSE84010: Cell adhesion molecules might contribute to bevacizumab resistance in glioblastoma

Bevacizumab (BEV) is an anti-angiogenesis antibody which has shown favorable therapeutic effects on some solid tumors. However, many clinical trials showed that BEV could only improve PFS instead of OS in glioblastoma (GBM) patients. However, some studies indicate that specific molecular subtypes of GBM could still benefit from combination treatment of BEV and Stupp protocol. Through the subgroup analysis of GSE84010 dataset, we found the neural and proneural subgroup can benefit from the administration of BEV in terms of OS, which is statistically significant. The further KEGG pathway enrichment analysis showed cell adhesion molecules (CAMs) pathway was enriched, and the expression of ITGAM has a predictive value for prognosis. These findings can provide some hints for future administration of BEV in newly diagnosed GBM patients.     

Neural microvascular pericytes contribute to human adult neurogenesis

Consistent adult neurogenic activity in humans is observed in specific niches within the central nervous system. However, the notion of an adult neurogenic niche is challenged by accumulating evidence for ectopic neurogenic activity in other cerebral locations. Herein we interface precision of ultrastructural resolution and anatomical simplicity of accessible human dental pulp neurogenic zone to address this conflict. We disclose a basal level of adult neurogenic activity characterized by glial invasion of terminal microvasculature followed by release of individual platelet-derived growth factor receptor-β mural pericytes and subsequent reprogramming into NeuN⁺ local interneurons. Concomitant angiogenesis, a signature of adult neurogenic niches, accelerates the rate of neurogenesis by amplifying release and proliferation of the mural pericyte population by ≈10-fold. Subsequent in vitro and in vivo experiments confirmed gliogenic and neurogenic capacities of human neural pericytes. Findings foreshadow the bimodal nature of the glio-vascular assembly where pericytes, under instruction from glial cells, can stabilize the quiescent microvasculature or enrich local neuronal microcircuits upon differentiation.     

Temporal and spatial alterations in GPi neuronal encoding might contribute to slow down movement in Parkinsonian monkeys

Although widely investigated, the exact relationship between changes in basal ganglia neuronal activity and parkinsonian symptoms has not yet been deciphered. It has been proposed that bradykinesia (motor slowness) is related either to a modification of the activity of the globus pallidus internalis (GPi), the main output structure, or to a loss of spatial selectivity of the extrapyramidal motor system. Here we investigate the relationship between movement initiation and GPi activity in parkinsonian non-human primates. We compare neuronal encoding of movement in the normal and pathological conditions. After dopamine depletion, we observe an increased number of neurons responding to movement, with a less specific somato-sensory receptive field and a disruption of the selection mechanism. Moreover, the temporal order of the response of GPi neurons in parkinsonian animals is reversed. Indeed, whereas muscle activity and movement are delayed in parkinsonian animals, GPi neuronal responses to movement occur earlier and are prolonged, compared with normal conditions. Parkinsonian bradykinesia could thus result from an impairment of both temporal and spatial specificity of the GPi response to movement.     

Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer's disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD.     

Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery

Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest–activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n = 43) provided actigraphic data on rest–activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/T_H1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest–activity rhythms had higher Factor 1 scores (R² = .160, p = .038). Patients with elevated CAR also had higher Factor 1 scores (R² = .293, p = .020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression.     

Topological reorganization of brain network might contribute to the resilience of cognitive functioning in mildly disabled relapsing remitting multiple sclerosis

Multiple sclerosis (MS) is an inflammatory and demyelinating disease which leads to impairment in several functional systems including cognition. Alteration of brain networks is linked to disability and its progression. However, results are mostly cross-sectional and yet contradictory as putative adaptive and maladaptive mechanisms were found. Here, we aimed to explore longitudinal reorganization of brain networks over 2-years by combining diffusion tensor imaging (DTI), resting-state functional MRI (fMRI), magnetoencephalography (MEG), and a comprehensive neuropsychological-battery. In 37 relapsing-remitting MS (RRMS) and 39 healthy-controls, cognition remained stable over-time. We reconstructed network models based on the three modalities and analyzed connectivity in relation to the hierarchical topology and functional subnetworks. Network models were compared across modalities and in their association with cognition using linear-mixed-effect-regression models. Loss of hub connectivity and global reduction was observed on a structural level over-years (p < .010), which was similar for functional MEG-networks but not for fMRI-networks. Structural hub connectivity increased in controls (p = .044), suggesting a physiological mechanism of healthy aging. Despite a general loss in structural connectivity in RRMS, hub connectivity was preserved (p = .002) over-time in default-mode-network (DMN). MEG-networks were similar to DTI and weakly correlated with fMRI in MS (p < .050). Lower structural (β between .23–.33) and both lower (β between .40–.59) and higher functional connectivity (β = −.54) in DMN was associated with poorer performance in attention and memory in RRMS (p < .001). MEG-networks involved no association with cognition. Here, cognitive stability despite ongoing neurodegeneration might indicate a resilience mechanism of DMN hubs mimicking a physiological reorganization observed in healthy aging.     

Pathways involved in human conscious vision contribute to obstacle-avoidance behaviour

Human patients with visual field defects following damage to their primary visual cortex (V1) will often misperceive the midpoint of a horizontal line. They tend to shift the midpoint away from the real position towards their blind field. In patients with unilateral neglect, where midpoint shifts can also be observed, these perceptual errors do not lead to errors in an obstacle-avoidance task, which also requires the ability to find the midpoint between two obstacles. This dissociation in neglect patients was taken as evidence that obstacle-avoidance performance is guided by visual information from the dorsal visual stream. Recently it was shown that a patient with hemianopia could avoid an obstacle presented in his blind field. This suggests that obstacle-avoidance behaviour can be guided by subconscious vision alone involving a direct route from extrageniculate structures in the brain to dorsal stream areas. To investigate whether obstacle avoidance relies only on this subconscious route or also uses information from pathways involved in conscious vision, we examined the effect of the hemianopic shift on obstacle-avoidance behaviour. This shift is found in tasks where a conscious visual judgement is required and presumably arises in pathways underlying conscious vision (V1 and ventral stream areas). We compared the performance of six patients with left hemianopia with the performance of six patients with right hemianopia. We found a clear bias in both groups, which also affected obstacle-avoidance performance. It is thus concluded that obstacle avoidance does not bypass the system for conscious vision completely.     

Factors that contribute to the immmunogenicity of therapeutic recombinant human proteins

Use of recombinant human proteins has revolutionized medicine by providing over 200 highly purified hormones and proteins that effectively treat many inherited and acquired peptide hormone and protein deficiencies. With the exception of therapeutic monoclonal antibodies, these biological medicines are synthesized by cultured cells using DNA sequences that would yield proteins with identical amino acid sequences as endogenous human proteins. Therefore, there was the broad expectation that recombinant human biological medicines would be non-immunogenic in patients capable of synthesizing even sub-optimal levels of these therapeutic proteins to which they are innately tolerant. However, the widespread clinical use of recombinant human proteins has demonstrated that nearly all of them are immunogenic. This observation suggests that factors additional to differences in amino acid sequences of endogenous and biotherapeutic proteins contribute to the immunogenicity of therapeutic proteins. The main aim of this review is to summarize some of the factors that are known to contribute to the immunogenicity of recombinant therapeutic proteins.     

Urinary melatonin levels in human breast cancer patients

Summary Urinary melatonin levels were measured in 10 postmenopausal Indian women suffering from advanced stages of breast cancer and in 9 well-matched women with non-endocrine complaints, mostly uterovaginal prolapse.Urines of each patient were collected over a period of 2–3 days in four 4-hourly intervals from 6 a.m. to 10 p.m. and one 8-hourly interval from 10 p.m. to 6 a.m.Part of this work was presented at the second colloquium of the European Pineal Study Group, Gießen, July 1–5, 1981.This work was carried out by us as scholars of the Society of Servants of God, India, under the Cancer Research programme of the Society. Throughout this study we received guidance and directions from Dr. Dinshah K. Mehta, who is the Chairman of the Society of Servants of God and the All India Nature Cure Foundation Trust, founded by Mahatma Gandhi. Dr. D. K. Mehta, among other things, is the Founder of modern Naturopathy in India. He was also personal physician to Mahatma Gandhi.     

Binding of tissue plasminogen activator to cultured human fibroblasts

The binding of 125I-labeled, one-chain tissue plasminogen activator (t-PA) by WI-38 cultured human lung fibroblasts was investigated. Binding of t-PA to WI-38 monolayers was specific, saturable and temperature dependent. One and two-chain t-PAs were comparable in their ability to compete with 125I-labeled, one-chain t-PA for binding to fibroblasts, while no inhibition of binding was observed with a 500-fold molar excess of urokinase. Studies with various compounds suggest that neither the catalytic site, the fibrin binding site, nor the carbohydrate moieties on t-PA are involved in its binding to WI-38 cells. At higher temperatures, the amount of cell-bound 125I-t-PA that was removed by either incubation in binding buffer containing an excess of unlabeled t-PA, or by brief treatment with acidic buffer, was small (approximately 20%) suggesting that much of the t-PA is internalized. Electrophoretic analysis of extracts prepared from cells that had been incubated with 125I-t-PA revealed the presence of a major band of 70,000 Mr, which corresponds to intact t-PA. Our results suggest that WI-38 fibroblasts are capable of binding and internalizing t-PA, and that these processes involve a receptor site specific for t-PA.     

Anion channels contribute to the regulation of intracellular pH in human platelets

The presence of extracellular bicarbonate potentiated platelet intracellular pH rises induced by thrombin. The effect was most remarkable in sodium-depleted buffers. This effect of bicarbonate was dose-dependent and was inhibited by anion channel blockers. Bicarbonate also potentiated the pHi recovery after acid loading, but had no effect on alkali loading. It was suggested that anion exchange, most probably that of bicarbonate/chloride, contributes to the regulation of intracellular pH in human platelets.     

Cutaneous afferents from human plantar sole contribute to body posture awareness

We investigated whether the tactile information from the main supporting areas of the foot are used by the brain for perceptual purposes, namely body posture awareness and body representation in space. We applied various patterns of tactile stimulation to one or both soles of unmoving and blindfolded subjects by a 60 micro-vibrator tactile matrix set in a force platform. The perceptual effects of the stimulation were assessed through a 3D joystick handled by the subjects. All subjects reported illusory perceptions of whole-body leaning. Both orientation and amplitude of these perceptions depended on the stimulation pattern. Additional kinesthetic illusions sometimes occurred along the longitudinal axis of the body. We conclude that foot sole input contributes to the coding and the spatial representation of body posture.     

Abnormal sensitivity to cannabinoid receptor stimulation might contribute to altered gamma-aminobutyric acid transmission in the striatum of R6/2 Huntington's disease mice.

BACKGROUND: One of the earliest neurochemical alterations observed in both Huntington's disease (HD) patients and HD animal models is the dysregulation of the endocannabinoid system, an alteration that precedes the development of identifiable striatal neuropathology. How this alteration impacts striatal synaptic transmission is unknown. METHODS: We measured the effects of cannabinoid receptor stimulation on gamma-aminobutyric acid (GABA)-ergic synaptic currents recorded from striatal neurons of R6/2 HD mice in the early phase of their disease. RESULTS: The sensitivity of striatal GABA synapses to cannabinoid receptor stimulation is severely impaired in R6/2 HD mice. In particular, whereas in control animals activation of cannabinoid CB1 receptors results in a significant inhibition of both evoked and spontaneous GABA-mediated synaptic events by a presynaptic mechanism, in R6/2 mice this treatment fails to reduce GABA currents but causes, in contrast, a slight increase of spontaneous inhibitory postsynaptic currents (sIPSCs). CONCLUSIONS: Experimental HD was also associated with enhanced frequency of sIPSCs, a result consistent with the conclusion that loss of cannabinoid-mediated control of GABA transmission might contribute to hyperactivity of GABA synapses in the striatum of HD mice. Accordingly, spontaneous excitatory postsynaptic currents, which were not upregulated in R6/2 mice, were still sensitive to cannabinoid receptor stimulation.     

Chymotrypsin-like proteases contribute to human monocytic THP-1 cell as well as human microglial neurotoxicity

Activated microglia have been observed in various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis. They may exacerbate neuronal damage by secreting various toxic molecules. The list of candidate toxins includes proteases. Since it is currently not known which, if any, proteases are involved in human microglia neurotoxicity, we studied the effects of a panel of protease inhibitors on the toxicity of cell-free supernatants of stimulated human microglia and THP-1 monocytic cells to human SH-SY5Y cells. Five structurally distinct inhibitors that are known to inhibit chymotrypsin-like proteases were partially protective. They included chymostatin, AEBSF (Pefabloc SC), alpha1-antichymotrypsin, bromoenol lactone, and 3,4-dichloroisocoumarin. The data suggest that certain protease inhibitors could inhibit microglial-mediated toxicity. They might represent a novel class of drugs with benefit in diseases where overactivity of microglia contributes to the pathogenesis.     

Neuroendocrine modulation of cancer progression

Clinical and animal studies now support the notion that psychological factors such as stress, chronic depression, and lack of social support might promote tumor growth and progression. Recently, cellular and molecular studies have started to identify biological processes that could mediate such effects. This review provides a mechanistic understanding of the relationship between biological and behavioral influences in cancer and points to more comprehensive behavioral and pharmacological approaches for better patient outcomes.     

NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice

Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2′-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1β, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice.     

Increase in levels of plasminogen activator and type-1 plasminogen activator inhibitor in human breast cancer: possible roles in tumor progression and metastasis

We measured antigen levels of two kinds of plasminogen activators, tissue type plasminogen activator (t-PA) and urokinase type plasminogen activator (UK), as well as their primary inhibitor, type-1 plasminogen activator inhibitor (PAI-1) in the tissue extracts of benign and malignant breast tumors. Tumor tissues of 36 fibroadenomas and 39 breast cancers were examined. t-PA levels were not different in both groups. Malignant tumors contained the significantly higher levels of UK than benign tumors (p less than 0.001). Furthermore in breast cancer tissues, UK antigen levels of tumors with axillary lymph node involvements were significantly higher than those of tumors without lymph node involvements (p less than 0.05). PAI-1 antigen levels of breast cancer tissues were dramatically higher than those of fibroadenoma (p less than 0.001). PAI-1 levels of node positive carcinomas showed also values significantly higher than node negative ones (p less than 0.01). When we divided cancer tissues into three groups as node negative tumors, tumors with positive axillary nodes fewer than four and tumors with four or more positive nodes, PAI-1 levels increased corresponding to the progression of lymph node involvements (p less than 0.05). Immunohistochemical studies, using mouse monoclonal antibodies to human UK and PAI-1, showed that those immunoreactivities were diffusely distributed in the cytoplasm of human breast cancer cells. Their staining patterns were very similar to each other.