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Parkinson’s disease (PD) is a severe neurodegenerative disease associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although its pathogenesis remains unclear, microglia-mediated neuroinflammation significantly contributes to the development of PD. Here we showed that the sine oculis homeobox (SIX) homologue family transcription factors SIX2 exerted significant effects on neuroinflammation. The SIX2 protein, which is silenced during development, was reactivated in lipopolysaccharide (LPS)-treated microglia. The reactivated SIX2 in microglia mitigated the LPS induced inflammatory effects, and then reduced the toxic effect of conditioned media (CM) of microglia on co-cultured MES23.5 DA cells. Using the LPS-stimulated Cx3cr1-CreERT2 mouse model, we also demonstrated that the highly-expressed SIX2 in microglia obviously attenuated neuroinflammation and protected the DA neurons in SN. Further RNA-Seq analysis on the inflammatory activated microglia revealed that the SIX2 exerted these effects via up-regulating the FXYD domain containing ion transport regulator 2 (FXYD2). Taken together, our study demonstrated that SIX2 was an endogenous anti-inflammatory factor in microglia, and it exerted anti-neuroinflammatory effects by regulating the expression of FXYD2, which provides new ideas for anti-neuroinflammation in PD.

Abstract Background Testosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression. Methods The human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin–eosin staining and immunohistochemistry. Results Testosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm. Conclusion Testosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation. Graphical Abstract The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.

Heat stress-induced biochemical alterations in ovarian follicles compromise the function of granulosa cells (GCs) and the developmental competence of oocytes. Summer heat stress can have a far-reaching negative impact on overall fertility and reproductive success. Together with the heat stress, the rise of assisted reproductive technologies (ART), potential confounding hazards of in vitro handling and the absence of systemic body support in ART makes it imperative to study the heat stress ameliorative effects of vitamin C under in vitro conditions. Using in vitro heat stress treatment of 43 °C for two hours in bovine GCs, we studied the effects of vitamin C on cell growth, oxidative stress, apoptosis and cell cycle progression together with a comprehensive metabolomics profiling. This study investigates the molecular milieu underlying the vitamin C (VC)-led alleviation of heat-related disruptions to metabolic processes in bovine GCs. The supplementation of VC ameliorated the detrimental effects of heat stress by reducing oxidative stress and apoptosis while restoring cell proliferation. Normal cell function restoration in treated GCs was demonstrated through the finding of significantly high levels of progesterone. We observed a shift in the metabolome from biosynthesis to catabolism, mostly dominated by the metabolism of amino acids (decreased tryptophan, methionine and tyrosine) and the active TCA cycle through increased Succinic acid. The Glutathione and tryptophan metabolism were important in ameliorating the inflammation and metabolism nexus under heat stress. Two significant enzymes were identified, namely tryptophan 2,3-dioxygenase (TDO2) and mitochondrial phenylalanyl-tRNA synthetase (FARS2). Furthermore, our findings provide insight into the significance of B-complex vitamins in the context of heat stress during VC supplementation. This study underscores the importance of VC supplementation in heat stress and designates multiple metabolic intervention faucets in the context of ameliorating heat stress and enhancing reproductive efficiency.

Previous studies have found that deficiency in nuclear receptor-related factor 1 (Nurr1), which participates in the development, differentiation, survival, and degeneration of dopaminergic neurons, is associated with Parkinson’s disease, but the mechanism of action is perplexing. Here, we first ascertained the repercussion of knocking down Nurr1 by performing liquid chromatography coupled with tandem mass spectrometry. We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency, 14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis. To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms, we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model. The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes, the preponderance of which encode components of the major histocompatibility II complex. Cd74, H2-Ab1, H2-Aa, H2-Eb1, Lyz2, Mrc1, Slc6a3, Slc47a1, Ms4a4b, and Ptprc2 were the top 10 differentially expressed genes. Immunofluorescence staining showed that, after Nurr1 knockdown, the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased. In addition, Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine. Taken together, our results suggest that Nurr1 deficiency results in an increase in Cd74 expression, thereby leading to the destruction of dopaminergic neurons. These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.

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Abstract Background Nuclear translocation of several oncogenic proteins have previously been reported, but neither the translocation of doublecortin (DCX) nor the mechanism involved has been studied. DCX is a neuronal microtubule-associated protein (MAP) that is crucial for adult neurogenesis and neuronal migration and has been associated with poor prognosis in gliomas. Methods We probed DCX expression in different grades of glioma tissues and conventional cells via western blotting. Then we analyzed the expression pattern in the Oncomine cancer profiling database. Confocal Immunofluorescence was used to detect DCX expression in the cellular compartments, while subcellular fractionation was probed via western blotting. Pulse shape height analysis was utilized to verify DCX localization in a larger population of cells. Co-immunoprecipitation was used in detecting DCX-import receptors interactions. To probe for DCX functions, stable cells expressing high DCX expression or knockdown were generated using CRISPR-Cas9 viral transfection, while plasmid site-directed mutant constructs were used to validate putative nuclear localization sequence (NLS) predicted via conventional algorithms and comparison with classical NLSs. in-silico modeling was performed to validate DCX interactions with import receptors via the selected putative NLS. Effects of DCX high expression, knockdown, mutation, and/or deletion of putative NLS sites were probed via Boyden’s invasion assay and wound healing migration assays, and viability was detected by CCK8 assays in-vitro, while xenograft tumor model was performed in nude mice. Results DCX undergoes nucleocytoplasmic movement via the RanGTPase signaling pathway with an NLS located on the N-terminus between serine47-tyrosine70. This translocation could be stimulated by MARK’s phosphorylation of the serine 47 residue flanking the NLS due to aberrant expression of glial cell line-derived neurotrophic factor (GDNF). High expression and nuclear accumulation of DCX improve invasive glioma abilities in-vitro and in-vivo. Moreover, knocking down or blocking DCX nuclear import attenuates invasiveness and proliferation of glioma cells. Conclusion Collectively, this study highlights a remarkable phenomenon in glioma, hence revealing potential glioma dependencies on DCX expression, which is amenable to targeted therapy. Video abstract Graphical Abstract

Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family background of glioma constitute are risk factors of glioma initiation. Gliomas are categorized on a scale of four grades according to their growth rate. Grades one and two grow slowly, while grades three and four grow faster. Glioblastoma is a grade four gliomas and the deadliest due to its aggressive nature (accelerated proliferation, invasion, and migration). As such, multiple therapeutic approaches are required to improve treatment outcomes. Recently, studies have implicated the significant roles of immune cells in tumorigenesis and the progression of glioma. The energy demands of gliomas alter their microenvironment quality, thereby inducing heterogeneity and plasticity change of stromal and immune cells via the PI3K/AKT/mTOR pathway, which ultimately results in epigenetic modifications that facilitates tumor growth. PI3K is utilized by many intracellular signaling pathways ensuring the proper functioning of the cell. The activation of PI3K/AKT/mTOR regulates the plasma membrane activities, contributing to the phosphorylation reaction necessary for transcription factors activities and oncogenes hyperactivation. The pleiotropic nature of PI3K/AKT/mTOR makes its activity unpredictable during altered cellular functions. Modification of cancer cell microenvironment affects many cell types, including immune cells that are the frontline cells involved in inflammatory cascades caused by cancer cells via high cytokines synthesis. Typically, the evasion of immunosurveillance by gliomas and their resistance to treatment has been attributed to epigenetic reprogramming of immune cells in the tumor microenvironment, which results from cancer metabolism. Hence, it is speculative that impeding cancer metabolism and/or circumventing the epigenetic alteration of immune cell functions in the tumor microenvironment might enhance treatment outcomes. Herein, from an oncological and immunological perspective, this review discusses the underlying pathomechanism of cell-cell interactions enhancing glioma initiation and metabolism activation and tumor microenvironment changes that affect epigenetic modifications in immune cells. Finally, prospects for therapeutic intervention were highlighted.

Background: Constipation is a significant symptom of Parkinson's disease (PD). Glial-derived neurotrophic factor (GDNF) is important for the morphogenesis of the enteric nervous system and plays a critical role in the preservation of mucosal integrity under enteric glia surveillance. The aim of this work was to evaluate the serum levels of GDNF in patients with PD with and without constipation.Methods: This work included 128 patients with PD. The patients were classified into three groups: those with PD but no constipation (nCons-PD) (n = 49), those with prodromal stage constipation (Cons-Pro-PD) (n = 48), and those with clinical stage constipation (Cons-Clinic-PD) (n = 31). The association between serum GDNF concentration and constipation was explored using logical regression.Results: The nCons-PD group's mean GDNF levels were 528.44 pg/ml, which was higher than the Cons-Pro-PD group's 360.72 pg/ml and the Cons-Clinic-PD group's 331.36 pg/ml. The results of binary logistic regression indicated that GDNF was a protective factor in the prevention of constipation. Cons-Clinic-PD group had a higher score of MDS-UPDRS-II, MDS-UPDRS-III, MDS-UPDRS-IV, and a higher H-Y staging as compared with nCons-PD group. Relative to the nCons-PD group, Cons-Clinic-PD had higher NMSS scores, lower MoCA and PDSS scores, and were more likely to have RBD.Conclusions: GDNF serum levels are lower in patients with PD who are constipated. A low GDNF level is a potential risk factor for constipation in patients with PD.

Human immunodeficiency virus-1 (HIV-1)-associated neurodegenerative disorder (HAND) is frequently reported in HIV-infected individuals. The gp120 envelope viral protein has been implicated in the pathogenesis of HAND in HIV-1-infected patients; however, its pathogenic mechanism remains unclear. In this study, we first overexpressed gp120 proteins in pc12 cells and used PI staining, a CCK8 assay, a TUNEL assay, and caspase-9/caspase-3-induced apoptosis to ascertain the mediated cell death. Subsequently, the gp120-overexpressed cells were subjected to RNA transcriptomics and mass spectrometry. The obtained results were integrated and validated using a quantitative polymerase chain reaction (qPCR) and the postmortem brain samples with HIV-associated dementia were analyzed against the normal control (using the GSE35864 data set on gene ontology omnibus repository). Upon the integration of the RNA transcriptomic and proteomic results, 78 upregulated genes were revealed. Fut8, Unc13c, Cdk1, Loc100359539, and Hspa2 were the top five upregulated genes. Upon the analysis of the GSE35864 data set, the results indicate that Cdk1 was upregulated in HIV-associated dementia in comparison to the normal control. Moreover, the protein expression of Cdk1 was significantly higher in the gp120 transfected group compared to the normal control and decreased significantly upon inhibition using Roscovitine (a known Cdk1 inhibitor). Taken together, our results provide a possible molecular signature of the neurological impairment secondary to HIV glycoprotein 120.

The glutathione S-transferase (GST) family of detoxification enzymes can regulate the malignant progression and drug resistance of various tumors. Hematopoietic prostaglandin D synthase (HPGDS, also referred to as GSTS1), GSTZ1, and GSTA1 are abnormally expressed in multiple cancers, but their roles in tumorigenesis and development remain unclear. In this study, we used bioinformatics tools to analyze the connections of HPGDS, GSTZ1, and GSTA1 to a variety of tumors in genetic databases. Then, we performed biochemical assays in GBM cell lines to investigate the involvement of HPGDS in proliferation and drug resistance. We found that HPGDS, GSTZ1, and GSTA1 are abnormally expressed in a variety of tumors and are associated with prognoses. The expression level of HPGDS was significantly positively correlated with the grade of glioma, and high levels of HPGDS predicted a poor prognosis. Inhibiting HPGDS significantly downregulated GBM proliferation and reduced resistance to temozolomide by disrupting the cellular redox balance and inhibiting the activation of JNK signaling. In conclusion, this study suggested that HPGDS, GSTZ1, and GSTA1 are related to the progression of multiple tumors, and HPGDS is expected to be a prognostic factor in GBM.

The external and internal factors of the cell are critical to glioma initiation. Several factors and molecules have been reported to be implicated in the initiation and progression of brain cancer. However, the exact sequence of events responsible for glioma initiation is still unknown. Existing reports indicate that glioma stem cells are the cell of glioma origin. During cell division, chromosome breakage, DNA alteration increases the chance of cell genome modifications and oncogene overexpression. Although there is a high risk of gene alteration and oncogene overexpression, not everyone develops cancer. During embryogenesis, the same oncogenes that promote cancers have also been reported to be highly expressed, but this high expression which does not lead to carcinogenesis raises questions about the role of oncogenes in carcinogenesis. The resistance of cancer cells to drugs, apoptosis, and immune cells does not rely solely on oncogene overexpression but also on the defect in cell organelle machinery (mitochondria, endoplasmic reticulum, and cytoskeleton). This review discusses factors contributing to cancer; we report the dysfunction of the cell organelles and their contribution to carcinogenesis, while oncogene overexpression promotes tumorigenesis, maintenance, and progression through cell adhesion. All these factors together represent a fundamental requirement for cancer and its development.

Parkinson’s disease (PD) is one of the most common neurodegenerative maladies with unforeseen complex pathologies. While this neurodegenerative disorder’s neuropathology is reasonably well known, its etiology remains a mystery, making it challenging to aim therapy. Glial cell-line derived neurotrophic factor (GDNF) remains an auspicious therapeutic molecule for treating PD. Neurotrophic factor derived from glial cell lines is effective in rodents and nonhuman primates, but clinical findings have been equivocal. Laborious exertions have been made over the past few decades to improve and assess GDNF in treating PD (clinical studies). Definitive clinical trials have, however, failed to demonstrate a survival advantage. Consequently, there seemed to be a doubt as to whether GDNF has merit in the potential treatment of PD. The purpose of this cutting edge review is to speculate as to why the clinical trials have failed to meet the primary endpoint. We introduce a hypothesis, “Failure of GDNF in clinical trials succumbed by nuclear receptor-related factor 1 (Nurr1) shortfall.” We demonstrate how Nurr1 binds to GDNF to induce dopaminergic neuron synthesis. Due to its undisputable neuro-protection aptitude, we display Nurr1 (also called Nr4a2) as a promising therapeutic target for PD.