Removal of ochratoxin A in wine by Cryptococcus albidus and safety assessment of degradation products.

BACKGROUND: Ochratoxin A (OTA) is a mycotoxin that contaminates grape-based products and is extremely harmful to the health of the host. It is effectively removed by yeast during the fermentation of wine, whereas the removal mechanism of OTA remains unclear. Therefore, the present study aimed to investigate the removal mechanism of ochratoxin A by yeast and to evaluate the safety of its degradation products. RESULTS: Cryptococcus albidus (20-G) with better effect on ochratoxin A (OTA) was screened out in the main fermentation stage of wine. The results showed that 20-G removed OTA through biosorption and biodegradation. Intracellular enzymes played the main role (18.44%) and yeast cell walls adsorbed a small amount of OTA (8.44%). Furthermore, the identification of proteins in 20-G revealed that the decrease in OTA content was mainly a result of the action of peroxidase, and validation tests were carried out. By analyzing the degradation products of OTA, OTα and phenylalanine with lower toxicity were obtained. Animal experiments showed that the intervention of yeast 20-G reduced the damage and adverse effects caused by OTA toxicity to the mice. CONCLUSION: The present study demonstrates the mechanism of OTA removal by 20-G and the toxicity of OTA was reduced by peroxidase in 20-G. © 2023 Society of Chemical Industry.

Risk prediction of second primary malignancies in patients after rectal cancer: analysis based on SEER Program.

BACKGROUND: This study will focus on exploring the clinical characteristics of rectal cancer (RC) patients with Second Primary Malignancies (SPMs) and constructing a prognostic nomogram to provide clinical treatment decisions. METHODS: We determined the association between risk factors and overall survival (OS) while establishing a nomogram to forecast the further OS status of these patients via Cox regression analysis. Finally, we evaluated the performance of the prognostic nomogram to predict further OS status. RESULTS: Nine parameters were identified to establish the prognostic nomogram in this study, and, the C-index of the training set and validation set was 0.691 (95%CI, 0.662-0.720) and 0.731 (95%CI, 0.676-0.786), respectively. The calibration curve showed a high agreement between the predicted and actual results, and the receiver operating characteristic (ROC) curves verified the superiority of our model for clinical usefulness. In addition, the nomogram classification could more precisely differentiate risk subgroups and improved the discrimination of SPMs' prognosis. CONCLUSIONS: We systematically explored the clinical characteristics of SPMs after RC and constructed a satisfactory nomogram.

Integrative analysis of cancer-associated fibroblast signature in gastric cancer.

Background: CAFs regulate the signaling of GC cells by promoting their migration, invasion, and proliferation and the function of immune cells as well as their location and migration in the TME by remodeling the extracellular matrix (ECM). This study explored the understanding of the heterogeneity of CAFs in TME and laid the groundwork for GC biomarker and precision treatment development. Methods: The scRNA-seq and bulk RNA-seq datasets were obtained from GEO and TCGA. The prognostic significance of various CAFs subtypes was investigated using ssGSEA combined with Kaplan-Meier analysis. POSTN expression in GC tissues and CAFs was detected using immunohistochemistry, immunofluorescence, and Western blotting. Differential expression analysis identified the differentially expressed genes (DEGs) between normal and tumor samples in TCGA-STAD. Pearson correlation analysis identified DEGs associated with adverse prognosis CAF subtype, and univariate Cox regression analysis determined prognostic genes associated with CAFs. LASSO regression analysis and Multivariate Cox regression were used to build a prognosis model for CAFs. Results: We identified five CAFs subtypes in GC, with the CAF_0 subtype associated with poor prognosis. The abundance of CAF_0 correlated with T stage, clinical stage, histological type, and immune cell infiltration levels. Periostin (POSTN) exhibited increased expression in both GC tissues and CAFs and was linked to poor prognosis in GC patients. Through LASSO and multivariate Cox regression analysis, three genes (CXCR4, MATN3, and KIF24) were selected to create the CAFs-score. We developed a nomogram to facilitate the clinical application of the CAFs-score. Notably, the CAFs signature showed significant correlations with immune cells, stromal components, and immunological scores, suggesting its pivotal role in the tumor microenvironment (TME). Furthermore, CAFs-score demonstrated prognostic value in assessing immunotherapy outcomes, highlighting its potential as a valuable biomarker to guide therapeutic decisions. Conclusion: CAF_0 subtype in TME is the cause of poor prognosis in GC patients. Furthermore, CAFs-score constructed from the CAF_0 subtype can be used to determine the clinical prognosis, immune infiltration, clinicopathological characteristics, and assessment of personalized treatment of GC patients.

Neutrophil extracellular traps-related signature predicts the prognosis and immune infiltration in gastric cancer.

Introduction: Gastric cancer (GC) is the fifth most prevalent cancer globally, with the third highest case fatality rate. Neutrophil extracellular traps (NETs) are a reticulated structure of DNA, histones, and antimicrobial peptides produced by active neutrophils that trap pathogens. Even though NETs are associated with poorer recurrence-free survival (RFS) and overall survival (OS), the specifics of this interaction between NETs and cancer cells are yet unknown. Methods: The keywords "neutrophil extracellular traps and gastric cancer" were used in the GEO database for retrieval, and the GSE188741 dataset was selected to obtain the NETs-related gene. 27 NETs-related genes were screened by univariate Cox regression analysis (p < 0.05). 27 NETs-related genes were employed to identify and categorize NETs-subgroups of GC patients under the Consensus clustering analysis. 808 GC patients in TCGA-STAD combined with GES84437 were randomly divided into a training group (n = 403) and a test group (n = 403) at a ratio of 1:1 to validate the NETs-related signature. Results: Based on Multivariate Cox regression and LASSO regression analysis to develop a NETs-related prognosis model. We developed a very specific nomogram to improve the NETs-clinical score's usefulness. Similarly, we also performed a great result in pan-cancer study with NETs-score. Low NETs scores were linked to higher MSI-H (microsatellite instability-high), mutation load, and immune activity. The cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity were also connected to the NET score. Our comprehensive analysis of NETs in GC suggests that NETs have a role in the tumor microenvironment, clinicopathological features, and prognosis. Discussion: The NETs-score risk model provides a basis for better prognosis and therapy outcomes in GC patients.

A green versatile packaging based on alginate and anthocyanin via incorporating bacterial cellulose nanocrystal-stabilized camellia oil Pickering emulsions.

This study aims to develop a versatile intelligent packaging based on alginate (Alg) and anthocyanin (Ant) by incorporating bacterial cellulose nanocrystal-stabilized camellia oil Pickering emulsions. Firstly, bacterial cellulose nanocrystals (BCNs) matrix produced from kombucha was incorporated with camellia oil into via ultrasonic triggering, forming a stable and multifunctional camellia oil-bacterial cellulose nanocrystal Pickering nanoemulsions (CBPE). The microstructure and rheology results of the emulsion confirmed the stabilized preparation of CBPE. Subsequently, the CBPE was integrated into the three-dimensional network structure composed of alginate/anthocyanin. The composite film (Alg-Ant-CBPE) was designed through Ca2+ crosslinking, intermolecular hydrogen bonding and dehydration condensation. The fabricated color indicator films with different concentrations of CBPE (0.1 %-0.4 %), showed varying degree of improvement in hydrophobicity, UV shielding, mechanical strength, thermal stability, water vapor barrier properties and antioxidant capacities. When applied to yogurt, the Alg-Ant-CBPE4 exhibited more pronounced color changes compared to Alg-Ant, enabling visual detection of food freshness. In conclusion, the incorporation of Pickering nanoemulsion provides an effective and promising approach to enhance the performance of polysaccharide-based intelligent packaging.

Whole exome sequencing of well-differentiated liposarcoma and dedifferentiated liposarcoma in older woman: a case report.

Background: Common kinds of soft tissue sarcomas (STS) include well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In this case, we present a comprehensive clinical profile of a patient who underwent multiple recurrences during the progression from WDLPS to DDLPS. Case presentation: A 62-year-old Asian female underwent retroperitoneal resection of a large tumor 11 years ago, the initial pathology revealed a fibrolipoma-like lesion. Over the next six years, the patient underwent three resections for recurrence of abdominal tumors. Postoperative histology shows mature adipose tissue with scattered "adipoblast"-like cells with moderate-to-severe heterogeneous spindle cells, pleomorphic cells, or tumor giant cells. Immunohistochemistry (IHC) demonstrated positive staining for MDM2 and CDK4, confirming that the abdominal tumor was WDLPS and gradually progressing to DDLPS. Post-operative targeted sequencing and IHC confirmed the POC1B::ROS1 fusion gene in DDLPS. Whole-exome sequencing (WES) revealed that WDLPS and DDLPS shared similar somatic mutations and copy number variations (CNVs), whereas DDLPS had more mutated genes and a higher and more concentrated amplification of the chromosome 12q region. Furthermore, somatic mutations in DDLPS were significantly reduced after treatment with CDK4 inhibitors, while CNVs remained elevated. Conclusion: Due to the high likelihood of recurrence of liposarcoma, various effective treatments should be taken into consideration even if surgery is the primary treatment for recurrent liposarcoma. To effectively control the course of the disease following surgery, combination targeted therapy may be a viable alternative to chemotherapy and radiotherapy in the treatment of liposarcoma.

The DNA damage repair-related lncRNAs signature predicts the prognosis and immunotherapy response in gastric cancer.

Background: Gastric cancer (GC) is one of the most prevalent cancers, and it has unsatisfactory overall treatment outcomes. DNA damage repair (DDR) is a complicated process for signal transduction that causes cancer. lncRNAs can influence the formation and incidence of cancers by influencing DDR-related mRNAs/miRNAs. A DDR-related lncRNA prognostic model is urgently needed to improve treatment strategies. Methods: The data of GC samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. A total of 588 mRNAs involved in DDR were selected from MSigDB, 62 differentially expressed mRNAs from TCGA-STAD were obtained, and 137 lncRNAs were correlated with these mRNAs. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to develop a DDR-related lncRNA prognostic model. Based on the risk model, the differentially expressed gene signature A/B in the low-risk and high-risk groups of TCGA-STAD was identified for further validation. Results: The prognosis model of 5 genes (AC145285.6, MAGI2-AS3, AL590705.3, AC007405.3, and LINC00106) was constructed and classified into two risk groups. We found that GC patients with a low-risk score had a better OS than those with a high-risk score. We found that the high-risk group tended to have higher TME scores. We also found that patients in the high-risk group had a higher proportion of resting CD4 T cells, monocytes, M2 macrophages, resting dendritic cells, and resting mast cells, whereas the low-risk subgroup had a greater abundance of activated CD4 T cells, follicular helper T cells, M0 macrophages, and M1 macrophages. We observed significant differences in the T-cell exclusion score, T-cell dysfunction, MSI, and TMB between the two risk groups. In addition, we found that patients treated with immunotherapy in the low-RS score group had a longer survival and a better prognosis than those in the high-RS score group. Conclusion: The prognostic model has a significant role in the TME, clinicopathological characteristics, prognosis, MSI, and drug sensitivity. We also discovered that patients treated with immunotherapy in the low-RS score group had a better prognosis. This work provides a foundation for improving the prognosis and response to immunotherapy among patients with GC.

Antimicrobial activity and mechanism of preservatives against Alicyclobacillus acidoterrestris and its application in apple juice.

Alicyclobacillus acidoterrestris has great influence on the quality of apple juice products. In this study, the antibacterial activity of five preservatives (ε-polylysine, propylparaben, monocaprin, octyl gallate and heptylparaben) against A. acidoterrestris and its underlying mechanism were investigated. Results showed that these five preservatives all exerted antibacterial activity through a multiple bactericidal mechanism, and monocaprin and octyl gallate had the highest antibacterial activity, with the minimum inhibitory concentration (MIC) values of 22.5 and 6.25 mg/L, respectively. Five preservatives all changed the permeability of the cell membrane and destroyed the complete cell morphology, with the leakages of the intracellular electrolytes. Moreover, the treatment of ε-polylysine, propylparaben and monocaprin increased the leakage of intracellular protein; propylparaben and octyl gallate reduced the levels of cellular adenosine triphosphate. Also, monocaprin and octyl gallate may stimulate bacteria to release a large amount of reactive oxygen species, so that certain oxidative damage can kill the bacteria. Furthermore, monocaprin and octyl gallate could effectively inactivate the contamination of A. acidoterrestris in apple juices, with the slightly decrease of soluble sugars and organic acids, without significant adverse effects on total sugars and titratable acids. This research highlights the great promise of using monocaprin and octyl gallate as the safe multi-functionalized food additives for food preservations.

Generation of perfect optical vortex by Laguerre-Gauss beams with a high-order radial index.

Perfect optical vortex (POV) beams have attracted extensive attention because they have the advantage of a radial profile that is independent of orbital angular momentum. To date, it is usually obtained by means of the Fourier transform performed by a lens on Bessel beams. We theoretically and experimentally demonstrate that POV can be generated by performing the Fourier transform on Laguerre-Gauss beams with a high-order radial index. Furthermore, we derive an analytical expression for the increase in vortex radius, which is beneficial to compensate for the influence of the radius change in actual experiments. Our results may shed new light for a variety of research utilizing POV.

LEM domain containing 1 promotes pancreatic cancer growth and metastasis by p53 and mTORC1 signaling pathway.

Pancreatic cancer (PC) is a common type of malignancy originating from the epithelium of the pancreatic duct, with the most lethal feature and worst prognosis. LEM domain containing 1 (LEMD1) is overexpressed in multiple tumor tissues and plays a key role in cancer carcinogenesis and progression. However, little is known about the potential of LEMD1 in PC. In this study, we explored the clinical values, as well as the potential roles and mechanisms of LEMD1 in PC. We, for the first time, showed that LEMD1 was upregulated in PC and negatively correlated with the overall and disease-free survival of patients with PC. Of the function, LEMD1 knockdown inhibited cancer cell growth, migration and invasion, while LEMD1 overexpression promoted tumor aggressiveness. The tumor-promoting influences of LEMD1 in PC were also proved by in vivo assays. Mechanistically, GSEA identified that LEMD1 promoted PC aggressiveness, as well as affecting cell cycle dysregulation and apoptosis resistance, by p53 suppression and the activation of the mTORC1 signal pathway. In short, LEMD1 could serve as a valuable prognostic candidate and a potential therapeutic target of PC.Abbreviations: ATCC: American Type Culture Collection; CCK-8: Cell counting kit 8; CDK: Cyclin-dependent kinases; CTA: Cancer-testis antigen; DMEM: Dulbecco's Modified Eagle's Medium; ECL: enhanced chemiluminescence; FBS: Fetal bovine serum; GEO: Gene Expression Omnibus; LEMD1: LEM domain containing 1; mTOR: mammalian target of rapamycin; NC: Negative control; PC: Pancreatic cancer; PVDF: Polyvinylidene difluoride membranes; qRT-PCR: Quantitative real-time polymerase chain reaction; SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis; SD: Standard deviation; SKP2: S-Phase kinase-associated protein 2; TAA: Tumor-associated antigen; TBST: Tris-buffered Saline Tween-20; TCGA: The Cancer Genome Atlas.

CircCBFB is a mediator of hepatocellular carcinoma cell autophagy and proliferation through miR-424-5p/ATG14 axis.

This study aims to investigate the role of circCBFB in hepatocellular carcinoma (HCC) cell proliferation and autophagy. qRT-PCR and Western blotting analyses quantified the expression levels of circCBFB, miR-424-5p, and ATG14 in HCC tissues and/or HCC cell lines. After transfection with pcDNA3.1-CircCBFB, sh-CircCBFB, miR-424-5p mimic, miR-424-5p inhibitor, pcDNA3.1-ATG14, sh-ATG14, sh-CircCBFB + miR-424-5p inhibitor, pcDNA3.1-CircCBFB + miR-424-5p mimic, sh-CircCBFB + pcDNA3.1-ATG14, or pcDNA3.1-CircCBFB + sh-ATG14, the proliferation, cell cycle, and apoptosis of Huh-7 and HCCLM3 cells were detected, respectively, through MTT assay and flow cytometry. Western blotting measured the expression levels of ATG14 and autophagy-related proteins (LC3-ΙΙ/LC3-Ι, Beclin1, and p62). The interactions among circCBFB, miR-424-5p, and ATG14 were identified through RNA fluorescence in situ hybridization and RNA immunoprecipitation. In HCC tissues, circCBFB and ATG14 were highly expressed, and miR-424-5p expression was downregulated. Transfection of pcDNA3.1-CircCBFB, miR-424-5p inhibitor, or pcDNA3.1-ATG14 into HCC cells facilitated HCC cell proliferation and autophagy, while suppressing cell apoptosis, evidenced by elevated cell viability, increased protein levels of autophagosome markers (LC3-ΙΙ/LC3-Ι and Beclin1), repressed apoptosis rate, and suppressed protein level of autophagy receptor p62. miR-424-5p was a target gene of circCBFB, and miR-424-5p negatively mediated ATG14. CircCBFB inhibits miR-424-5p and upregulates ATG14, thus promoting HCC cell proliferation and autophagy.

Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms.

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O2) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aß) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.

Low oxygen post conditioning prevents thalamic secondary neuronal loss caused by excitotoxicity after cortical stroke.

In the current study, we were interested in investigating whether Low oxygen post-conditioning (LOPC) was capable of limiting the severity of stroke-induced secondary neurodegeneration (SND). To investigate the effect of LOPC we exposed adult male C57/BL6 mice to photothrombotic occlusion (PTO) of the motor and somatosensory cortex. This is known to induce progressive neurodegeneration in the thalamus within two weeks of infarction. Two days after PTO induction mice were randomly assigned to one of four groups: (i) LOPC-15 day exposure group; (ii) a LOPC 15 day exposure followed by a 15 day exposure to normal atmosphere; (iii) normal atmosphere for 15 days and (iv) normal atmosphere for 30 days (n = 20/group). We observed that LOPC reduced the extent of neuronal loss, as indicated by assessment of both area of loss and NeuN+ cell counts, within the thalamus. Additionally, we identified that LOPC reduced microglial activity and decreased activity within the excitotoxic signalling pathway of the NMDAR axis. Together, these findings suggest that LOPC limits neuronal death caused by excitotoxicity in sites of secondary damage and promotes neuronal survival. In conclusion, this work supports the potential of utilising LOPC to intervene in the sub-acute phase post-stroke to restrict the severity of SND.

Low Oxygen Post Conditioning as an Efficient Non-pharmacological Strategy to Promote Motor Function After Stroke.

Low oxygen post conditioning (LOPC) has shown promising results in terms of neuroprotection after stroke, but the effects on motor function have not been considered. Cortical stroke targeting the motor and sensory cortex was induced by photothrombotic occlusion and after 48 h allocated to LOPC (11% O2) for 2 weeks. Motor impairment was assessed using the cylinder and grid walk tests during the exposure period and for two further weeks upon completion of the intervention. Neuroprotection was evaluated by histological and molecular analysis at two time points. Two weeks of LOPC was sufficient to significantly reduce motor deficits and tissue loss after stroke. This functional improvement was associated with increased capillary density, enhanced levels of BDNF, decreased neuronal loss and decreased microglia activation. These improvements, in most instances, were maintained up to 2 weeks after the end of the treatment. To our knowledge, this is the first study to demonstrate that LOPC induces a persistent improvement in motor function and neuroprotection after stroke, and in doing so provides evidence to support a case for considering taking LOPC forward to early stage clinical research.

Chronic stress induced disturbances in Laminin: A significant contributor to modulating microglial pro-inflammatory tone?

Over the last decade, evidence supporting a link between microglia enhanced neuro-inflammatory signalling and mood disturbance has continued to build. One issue that has not been well addressed yet are the factors that drive microglia to enter into a higher pro-inflammatory state. The current study addressed the potential role of the extracellular matrix protein Laminin. C57BL6 adult mice were either exposed to chronic stress or handled for 6 consecutive weeks. Changes in Laminin, microglial morphology and pro-inflammatory cytokine expression were examined in tissue obtained from mice exposed to a chronic restraint stress procedure. These in vivo investigations were complemented by an extensive set of in vitro experiments utilising both a primary microglia and BV2 cell line to examine how Laminin influenced microglial pro-inflammatory tone. Chronic stress enhanced the expression of Laminin, microglial de-ramification and pro-inflammatory cytokine signalling. We further identified that microglia when cultured in the presence of Laminin produced and released significantly greater levels of pro-inflammatory cytokines; took longer to return to baseline following stimulation and exhibited enhanced phagocytic activity. These results suggest that chronic restraint stress is capable of modulating Laminin within the CNS, an effect that has implications for understanding environmental mediated disturbances of microglial function.

Chronic stress induced disruption of the peri-infarct neurovascular unit following experimentally induced photothrombotic stroke.

How stress influences brain repair is an issue of considerable importance, as patients recovering from stroke are known to experience high and often unremitting levels of stress post-event. In the current study, we investigated how chronic stress modified the key cellular components of the neurovascular unit. Using an experimental model of focal cortical ischemia in male C57BL/6 mice, we examined how exposure to a persistently aversive environment, induced by the application of chronic restraint stress, altered the cortical remodeling post-stroke. We focused on systematically investigating changes in the key components of the neurovascular unit (i.e. neurons, microglia, astrocytes, and blood vessels) within the peri-infarct territories using both immunohistochemistry and Western blotting. The results from our study indicated that exposure to chronic stress exerted a significant suppressive effect on each of the key cellular components involved in neurovascular remodeling. Co-incident with these cellular changes, we observed that chronic stress was associated with an exacerbation of motor impairment 42 days post-event. Collectively, these results highlight the vulnerability of the peri-infarct neurovascular unit to the negative effects of chronic stress.

Chronic stress exposure following photothrombotic stroke is associated with increased levels of Amyloid beta accumulation and altered oligomerisation at sites of thalamic secondary neurodegeneration in mice.

Exposure to severe stress following stroke is recognised to complicate the recovery process. We have identified that stress can exacerbate the severity of post-stroke secondary neurodegeneration in the thalamus. In this study, we investigated whether exposure to stress could influence the accumulation of the neurotoxic protein Amyloid-ß. Using an experimental model of focal cortical ischemia in adult mice combined with exposure to chronic restraint stress, we examined changes within the contra- and ipsilateral thalamus at six weeks post-stroke using Western blotting and immunohistochemical approaches. Western blotting analysis indicated that stroke was associated with a significant enhancement of the 25 and 50 kDa oligomers within the ipsilateral hemisphere and the 20 kDa oligomer within the contralateral hemisphere. Stroked animals exposed to stress exhibited an additional increase in multiple forms of Amyloid-beta oligomers. Immunohistochemistry analysis confirmed that stroke was associated with a significant accumulation of Amyloid-beta within the thalami of both hemispheres, an effect that was exacerbated in stroke animals exposed to stress. Given that Amyloid-beta oligomers, most notably the 30-40 and 50 kDa oligomers, are recognised to correlate with accelerated cognitive decline, our results suggest that monitoring stress levels in patients recovering from stroke may merit consideration in the future.

Reconsidering the role of glial cells in chronic stress-induced dopaminergic neurons loss within the substantia nigra? Friend or foe?

Exposure to psychological stress is known to seriously disrupt the operation of the substantia nigra (SN) and may in fact initiate the loss of dopaminergic neurons within the SN. In this study, we aimed to investigate how chronic stress modified the SN in adult male mice. Using a paradigm of repeated restraint stress (an average of 20h per week for 6weeks), we examined changes within the SN using western blotting and immunohistochemistry. We demonstrated that chronic stress was associated with a clear loss of dopaminergic neurons within the SN. The loss of dopaminergic neurons was accompanied by higher levels of oxidative stress damage, indexed by levels of protein carbonylation and strong suppression of both microglial and astrocytic responses. In addition, we demonstrated for the first time, that chronic stress alone enhanced the aggregation of α-synuclein into the insoluble protein fraction. These results indicate that chronic stress triggered loss of dopaminergic neurons by increasing oxidative stress, suppressing glial neuroprotective functions and enhancing the aggregation of the neurotoxic protein, α-synuclein. Collectively, these results reinforce the negative effects of chronic stress on the viability of dopaminergic cells within the SN.

Dynamic structural remodelling of microglia in health and disease: a review of the models, the signals and the mechanisms.

Microglia are unique cells within the central nervous system because of their biophysical independence. As a result of this unusual property the cells must undergo significant structural remodelling in order to engage and connect with other elements within the central nervous system. Efficient remodelling is required for all activities that microglia are involved in ranging from monitoring synaptic information flow through to phagocytosis of tissue debris. Despite the fact that morphological remodelling is a pre-requisite to all microglial activities, relatively little research has been undertaken on the topic. This review examines what is known about how microglia transform themselves during development, under physiological conditions in response to changes in neuronal activity, and under pathological circumstances. Specific attention is given to exploring a variety of models that have been proposed to account for microglial transformation as well as the signals that are known to trigger these transformations.

Stress as necessary component of realistic recovery in animal models of experimental stroke.

Over the last decade there has been a considerable effort directed toward reformulating the standard approach taken to preclinically model stroke and stroke recovery. The principal objective of this undertaking has been to improve the success with which preclinical findings can be translated. Although several advancements have already been introduced, one potentially critical feature that appears to have been overlooked is psychological stress. Stroke is well recognized to produce high levels of stress in patients, and ongoing exposure to stress is recognized to deleteriously interfere with recovery. The presence of high levels of stress (distress) in stroke patients is also relevant because nearly all clinically deployed neurorestorative interventions occur against this background. Somewhat perplexingly, however, we could find no preclinical stroke studies concerned with investigating the efficacy of putative neurorestorative compounds that did so in the presence of stress. The following article will make the case that failure to recognize or compensate for the effects of ongoing stress in standard preclinical experimental models of recovery is likely to result in overestimation of the effectiveness of pharmacological or behavioral neurorestorative interventions.