Does Toxoplasma gondii Related to Schizophrenic Symptoms? A Narrative Systematic Review

Background: Accumulating evidence associated infectious agents with schizophrenia. Majority of these studies analyzed Toxoplasma. gondii association with schizophrenia. Aims and Objectives: the present study aimed to perform systematic search on studies conducted on investigating association between T. gondii and schizophrenia using IgG antibodies against T. gondii. Secondary objective was to discuss possible mechanisms by which T. gondii linked to schizophrenia. Methods: Systematic search performed using Google Scholar, PubMed, Web of Science and University of Manchester databases. Key words Schizo* AND Toxoplasm* used to find articles published from years 2010-2020, used IgG antibodies against T. gondii, and patients participated in these studies definitively diagnosed with schizophrenia using DSM-IV or ICD- 10. Results: Total of 122 articles was identified after duplicated were removed, of these 24 were included in review. Two-third of studies found that schizophrenic patients had significantly higher IgG antibodies versus controls. Conclusion: These findings suggest that T. gondii is associated with schizophrenia and that T. gondii might be risk factor for schizophrenia development. If causative link is ascertained, then it would be possible to treat and prevent schizophrenia.

Interrelation between Sleep Bruxism and Obstructive Sleep Apnea: Literature Review

Obstructive sleep apnea (OSA) is a clinical risk factor for sleep bruxism (SB). Although no clear causative link has been defined, both conditions are inter related to sleep-related arousal reactions [1]. A literature review was conducted on PubMed and ScienceDirect databases for 2000–2021 period. The majority of studies revealed an association between OSA and SB events.

A new physiologically realistic and clinically relevant model of sleep apnoea for investigating it’s effect as a comorbidity on neurodegenerative disease

Sleep apnoea is a highly prevalent disease but often goes undetected and is associated with poor clinical prognoses when combined with many different disease states. However, most animal models of sleep apnoea (e.g., intermittent hypoxia) have recently been dispelled as physiologically unrealistic. Due to a lack of appropriate models, little is known about the causative link between sleep apnoea and it’s co-morbidities. To overcome these problems, we have created a realistic animal model of moderate sleep apnoea by reducing the excitability of the respiratory network. This has been achieved through controlled genetically-mediated lesions to the preBötzinger Complex (preBötC), the inspiratory oscillator. This novel model shows increases in sleep disordered breathing with alterations in breathing during wakefulness (decreased frequency and increased tidal volume) as observed clinically. The increase in apnoea episodes leads to a reduction in REM sleep, with all lost active sleep being spent in an awake state. The increase in hypoxic and hypercapnia insults leads to both systemic and neural inflammation. Alterations in neurophysiology, an inhibition of hippocampal long-term potentiation (LTP), reflect deficits in both long and short term spatial memory. This new physiologically relevant and clinically realistic model of sleep apnoea may be the key to understanding why sleep apnoea has such far reaching and often fatal effects on end organ function.

Heavy Metals in the Environment and Thyroid Cancer

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the “normal” range.

Global Lysine Acetylome Analysis of LPS-Stimulated HepG2 Cells Identified Hyperacetylation of PKM2 as a Metabolic Regulator in Sepsis

Sepsis-induced liver dysfunction (SILD) is a common event and is strongly associated with mortality. Establishing a causative link between protein post-translational modification and diseases is challenging. We studied the relationship among lysine acetylation (Kac), sirtuin (SIRTs), and the factors involved in SILD, which was induced in LPS-stimulated HepG2 cells. Protein hyperacetylation was observed according to SIRTs reduction after LPS treatment for 24 h. We identified 1449 Kac sites based on comparative acetylome analysis and quantified 1086 Kac sites on 410 proteins for acetylation. Interestingly, the upregulated Kac proteins are enriched in glycolysis/gluconeogenesis pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) category. Among the proteins in the glycolysis pathway, hyperacetylation, a key regulator of lactate level in sepsis, was observed at three pyruvate kinase M2 (PKM2) sites. Hyperacetylation of PKM2 induced an increase in its activity, consequently increasing the lactate concentration. In conclusion, this study is the first to conduct global profiling of Kac, suggesting that the Kac mechanism of PKM2 in glycolysis is associated with sepsis. Moreover, it helps to further understand the systematic information regarding hyperacetylation during the sepsis process.

The mitochondrial Na+/Ca2+ exchanger, NCLX, mediates PDE2 dependent neuronal survival and learning

Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ - [Ca2+]m signaling leads to cardiac failure, ischemic damage and dysfunctional learning and memory. Yet, a causative link between these pathways is unknown. Here, we fluorescently monitored [Ca2+]m transients in hippocampal neurons evoked by caffeine followed by depolarization. [Ca2+]m efflux was apparent in WT but diminished in neurons deficient in the mitochondrial Na+/Ca2+ exchanger NCLX. Surprisingly, neuronal depolarization-induced Ca2+ transients alone failed to evoke strong [Ca2+]m efflux in WT neurons. Caffeine is also a PDE inhibitor. Pretreatment with the PDE2 inhibitor Bay 60-7550 rescued [Ca2+]m efflux triggered by neuronal depolarization. Inhibition of PDE2 acted by diminishing the Ca2+ dependent reduction of mitochondrial cAMP, thereby promoting NCLX phosphorylation. Selective PDE2 inhibition also enhanced [Ca2+]m efflux triggered by neuromodulators. We found that protection of neurons against excitotoxic insults, conferred by PDE2 inhibition, was diminished in NCLX KO neurons, thus is NCLX dependent. Finally, administration of Bay 60-7550 enhanced new object recognition learning in WT but not in NCLX KO mice. Our results identify a long-sought link between PDE and [Ca2+]m signaling thereby providing new therapeutic targets.

Zika virus induces neuronal and vascular degeneration in developing mouse retina

Zika virus (ZIKV), a mosquito-borne flavivirus, can cause severe eye disease and even blindness in newborns. However, ZIKV-induced retinal lesions have not been studied in a comprehensive way, mechanisms of ZIKV-induced retinal abnormalities are unknown, and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients. Here, we developed a novel mouse model of ZIKV infection to evaluate its impact on retinal structure. ZIKV (20 plaque-forming units) was inoculated into neonatal wild type C57BL/6J mice at postnatal day (P) 0 subcutaneously. Retinas of infected mice and age-matched controls were collected at various ages, and retinal structural alterations were analyzed. We found that ZIKV induced progressive neuronal and vascular damage and retinal inflammation starting from P8. ZIKV-infected retina exhibited dramatically decreased thickness with loss of neurons, initial neovascular tufts followed by vessel dilation and degeneration, increased microglia and leukocyte recruitment and activation, degeneration of astrocyte network and gliosis. The above changes may involve inflammation and endoplasmic reticulum stress-mediated cell apoptosis and necroptosis. Moreover, we evaluated the efficacy of preclinical drugs and the safety of ZIKV vaccine candidate in this mouse model. We found that ZIKV-induced retinal abnormalities could be blocked by a selective flavivirus inhibitor NITD008 and a live-attenuated ZIKV vaccine candidate could potentially induce retinal abnormalities. Overall, we established a novel mouse model and provide a direct causative link between ZIKV and retinal lesion in vivo, which warrants further investigation of the underlying mechanisms of ZIKV-induced retinopathy and the development of effective therapeutics.

Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis

It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6C57, which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6NZB ) mice develop less severe OA compared to the BL/6C57original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.