The effects of voluntary running exercise on the astrocytes of the medial prefrontal cortex in APP/PS1 mice.

Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to effectively delay AD. However, the effects of voluntary running on mPFC astrocytes in AD are unclear. A total of 40 10-month-old male amyloid precursor protein/presenilin 1 (APP/PS1) mice and 40 wild-type (WT) mice were randomly divided into control and running groups, and the running groups underwent voluntary running for 3 months. Mouse cognition was assessed by the novel object recognition (NOR), Morris water maze (MWM), and Y maze tests. The effects of voluntary running on mPFC astrocytes were investigated using immunohistochemistry, immunofluorescence, western blotting, and stereology. APP/PS1 mice performed significantly worse than WT mice in the NOR, MWM, and Y maze tests, and voluntary running improved the performance of APP/PS1 mice in these tests. The total number of mPFC astrocytes was increased, cell bodies were enlarged, and protrusion number and length were increased in AD mice compared with WT mice, but there was no difference in component 3 (C3) levels in the mPFC (total mPFC level); however, C3 and S100B levels in astrocytes were increased in AD mice. Voluntary running reduced the total number of astrocytes and S100B levels in astrocytes and increased the density of PSD95+ puncta in direct contact with astrocyte protrusions in the APP/PS1 mouse mPFC. Three months of voluntary running inhibited astrocyte hyperplasia and S100B expression in astrocytes, increased the density of synapses in contact with astrocytes, and improved cognitive function in APP/PS1 mice.

Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice.

BACKGROUND: The role of physical exercise in the prevention of Alzheimer's disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear. METHODS: Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia. RESULTS: Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2'-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice. CONCLUSIONS: Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.

Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice.

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aß) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

Fatal and Rapid Progressive Isolated Cerebral Mucormycosis Involving the Bilateral Basal Ganglia: A Case Report.

Isolated cerebral mucormycosis is a clinical type of mucormycosis that is estimated to account for 8% of all mucormycosis cases. The clinical symptoms of isolated cerebral mucormycosis are elusive, and thus conventional techniques often lake sensitivity and specificity. Moreover, cultures are often negative, even when direct microscopy examination is positive. Although histopathology will probably remain the gold standard for the diagnosis of mucormycosis, obtaining a biopsy specimen is not always feasible in most vulnerable populations. Thus, molecular approaches are currently used as an advantageous assistant examination method to improve the early identification of the causative agent and subsequently guide therapy to improve the prognosis of patients. Here, we report a case of isolated cerebral mucormycosis caused by Rhizopus microspores in a healthy young adult that was identified using next-generation sequencing technology.

Diuretic Effect and Metabolomics Analysis of Crude and Salt-Processed Plantaginis Semen.

Plantaginis Semen (PS) is well recognized in traditional Chinese medicine (TCM) and health products. Crude PS (CPS) and salt-processed CPS (SPS) are the two most commonly used decoction pieces of PS, and are included in the 2020 edition of Chinese Pharmacopoeia. Although they all have multiple effects, the mechanisms for treating diseases are different and remain unclear, the processing mechanism of SPS is also indeterminate, which hinders their clinical application to a certain extent. In order to solve these problems and further develop PS in the clinical application. Here, we used saline-loaded model rats for experiments, and utilized an integrated approach consisting of pharmacological methods and metabolomics, which could assess the diuretic impact of CPS and SPS ethanol extracts on saline-loaded rats and elucidate the underlying mechanism. The results showed that CPS and SPS both produced increased urine volume excretion and urine electrolyte excretion, but the levels of aldosterone (ALD) and aquaporin 2 (AQP2) were decreased. And 30 differential metabolites such as linoleic acid, lysoPC(O-18:0), sphingosine-1-phosphate, lysoPC(18:0) were found, mainly involving three metabolic pathways. In conclusion, CPS and SPS both have a diuretic effect, and that of SPS is better. This work investigated the possible diuretic mechanisms of CPS and SPS which may also be the mechanism of PS for anti-hypertension. In addition, a holistic approach provided novel and helpful insights into the underlying processing mechanisms of TCM.

Problem/case-based learning with competition introduced in severe infection education: an exploratory study.

BACKGROUND: Problem/case-based learning (PCBL) is one of the most commonly used educational methods in medical schools. AIM: To further improve PCBL in clinical course of severe infection by introducing competition mode. METHODS: Two classes of medical students were divided into two groups by class-based simple randomization and were taught the course of severe infection by PCBL. A team-based competition was introduced in the study group (n = 35) while not in the control group (n = 36). After the course, four closely associated references were recommended. All the students were notified about a group consultation on a similar case. In the final examination, a case with severe infection complicated with infectious shock was presented for the students to analyze and resolve listed questions. Their performances were qualitatively evaluated to justify the effectiveness of the competition-based PCBL. RESULTS: The students in the study group were more active and initiative in case discussion and interaction, in referring to case-related articles and attending clinical group-consultation. They had better performance in the case analysis in the final examination. The typical case analysis test easily figured out more excellent students in the study group. CONCLUSIONS: The PCBL with competition mode introduced in is an effective approach to guide students to fully understand the clinical diagnoses and treatment of severe infection. It also prompts medical students' initiative in referring to case-related articles and attending group-consultation, both of which are essential to equip medical students with sufficient competency for clinical practice.

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives.

The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP's beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.

Optimal target range for blood glucose in hyperglycaemic patients in a neurocritical care unit.

BACKGROUND: Hyperglycaemia is common among patients with critical neurological injury, even if they have no history of diabetes. The optimal target range for normalizing their blood glucose is unknown. METHODS: Retrospective data were extracted from 890 hyperglycaemic individuals (glucose > 200 mg/dL) admitted to neuroscience critical care unit (NCCU) and these patients were divided into two groups: intensive glucose control group with target glucose of < 140 mg/dL achieved and moderate control with glucose levels 140-180 mg/dL. The groups were also stratified according to the hyperglycaemia type (pre-existing diabetes or stress-related). We defined the primary endpoint as death from any cause during NCCU admission. RESULTS: In NCCU, tighter control of blood glucose at ≤ 140 mg/dL was associated with increased, mortality of individuals with pre-existing diabetes compared with moderate control [29 of 310 patients (9.4%) vs 15 of 304 patients (4.9%), p = 0.034]. Patient age [adjusted odds ratio (OR) = 1.12; 95% confidence interval (CI) = 1.05-1.19; p < 0.001], level of glycated haemoglobin (adjusted OR = 1.24; 95% CI = 1.04-1.48; p = 0.017) and hypoglycaemia (adjusted OR = 10.3; 95% CI = 2.92-36.6; p < 0.001) were positively associated with higher mortality. Death rate was lower among stress-related hyperglycaemic patients with tighter glucose controlled at ≤ 140 mg/dL [6 of 140 patients (4.3%) vs 15 of 136 patients (11.0%), p = 0.035]. CONCLUSION: A differential association is evident between glucose levels and mortality in diabetes and stress-related hyperglycaemia patients. However, given the observational nature of our work, no clinical recommendations can be given and prospective studies are required to further investigate these findings.

Vulnerability for apoptosis in the hippocampal dentate gyrus of STZ-induced diabetic rats with cognitive impairment.

BACKGROUND: Hyperglycemia impaired hippocampal network via triggering suicide program of immanent neurons, this is regarded as an etiological factor for diabetic cognition deficits. AIM: To investigate the occurrence of apoptosis in the hippocampal dentate gyrus of streptozotocin (STZ)-induced diabetic rats with cognitive impairment and assess the gene and protein expression of the apoptotic proteins bax, bcl-2, and caspase-3. MATERIALS AND METHODS: Four weeks after the verification of STZ-induced diabetes, diabetic rats with and without cognitive decline subgroups were subsequently assigned according to Morris water maze test. The expression levels of apoptotic proteins were measured using real-time RT-PCR and western blotting, respectively. Neuronal apoptosis was detected by TUNEL staining and electron microscopy. RESULTS: In the dentate gyrus of the rats with cognitive decline, Bcl-2 exhibited lower gene and protein levels, whereas a higher expression of bax was detected contributing to a significant increase in their mean bax/bcl-2 ratio. However, caspase-3 was not activated. Statistically different numbers of TUNEL-staining cells and features of apoptosis were no found. CONCLUSIONS: The higher bax/bcl ratio probably represents neurons of dentate gyrus vulnerable to apoptosis in the diabetes with cognitive decline. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase.

Prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in a Chinese hospital.

BACKGROUND: Accumulating evidence indicates that dyslipidaemia plays an important role in the progression of kidney disease in patients with diabetes. Hyperlipidaemia is a risk factor for microalbuminuria in patients with diabetes. Little information exists on the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in China. The aims of this study were to investigate the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in a Chinese hospital as well as factors affecting the disease. METHODS: A total of 1060 type 2 diabetic inpatients were assigned to the with-microalbuminuria group (n = 635) or the without-microalbuminuria group on the basis of urinary albumin-to-creatinine ratios (UACRs = 30-299 mg/g). Serum levels and the control of lipid profiles were assessed and classified according to the 2011 American Diabetes Association (ADA) guidelines, and low-density lipoprotein-cholesterol (LDL-C) was also assessed and classified according to Chinese intensified control criteria. Multiple regression analyses were performed to examine the factors affecting lipid variables. RESULTS: Among patients with microalbuminuria, a significantly lower prevalence was found (33.1% vs. 58.6%; 35.3% vs. 52.5%, all p < 0.001) at target levels [LDL-C < 2.60 mmol/L or high-density lipoprotein-cholesterol (HDL-C) > 1.0 mmol/L for men and >1.3 mmol/L for women]. According to the intensified LDL-C goal (<2.07 mmol/L), a lower prevalence was found in male patients (15.5% vs. 32.7%, p < 0.001). Fewer patients with microalbuminuria were adherent to the therapy prescribed for dyslipidaemia (28.8% vs. 43.3%, p < 0.001). Even among patients who were on lipid-lowering treatment, the majority of individuals remained uncontrolled for all three lipid fractions [LDL-C, HDL-C and triglyceride (TG)] (82.5% vs. 69.0%, p = 0.003). Lipid and lipoprotein parameters were associated with gender and age. CONCLUSION: In China, diabetic patients with microalbuminuria displayed typical dyslipidaemias and were not adequately controlled. Intensified LDL-C and overall lipid-lowering clinical goals are potential precautions taken against diabetic nephropathy.

PPARγ-mediated advanced glycation end products regulate neural stem cell proliferation but not neural differentiation through the BDNF-CREB pathway.

AIMS: To investigate the roles of PPARγ in advanced glycation end product (AGE)-mediated characteristics of neural stem cells (NSCs) and the molecular mechanisms of action. METHODS: We prepared pLentiLox3.7 lentiviral vectors expressing short hairpin RNA (shRNA) against PPARγ and transduced NSCs. MTT absorbance and cell counts were used to assay cell growth, and cell differentiation was analysed by confocal laser-scanning and western blots for the expression of MAP2/nestin. The protein and gene expression of the BDNF-CREB pathway components were examined by western blotting and real-time PCR. RESULTS: Immunoblot analysis indicated that shRNA delivered by lentiviral vectors silenced PPARγ expression in NSCs. The proliferation of NSCs and expression of BDNF pathway components dropped in AGE-BSA culture medium (400 mg/L and 200 mg/L) on Day 3 and Day 7, respectively (all P<0.001). PPARγ-silenced NSCs exhibited a significant increase in cell growth and expression of BDNF pathway components compared with NSCs incubated with AGE-BSA (all P<0.001). Immunocytochemistry and western blotting analysis showed that AGE-BSA (400 mg/L) induced a significant decrease in the expression of MAP2 both in NSCs and PPARγ-silenced NSCs, as standardised by nestin. There was no significant difference between NSCs and PPARγ-silenced NSCs in the presence of AGE-BSA. CONCLUSIONS: PPARγ plays roles in the AGE-mediated regulation of NSC proliferation but not neural differentiation through the BDNF-CREB pathway.

Meticillin-resistant Staphylococcus aureus isolated from foot ulcers in diabetic patients in a Chinese care hospital: risk factors for infection and prevalence.

A retrospective case-control study of 118 (male : female, 68 : 50) Chinese type 2 diabetic patients with foot ulcers (Wagner's grade 3-5) was conducted to determine the prevalence and risk factors for meticillin-resistant Staphylococcus aureus (MRSA) infection in relation to the original community or hospital parameters. Ulcer specimens were processed for Gram staining, aerobic culture and antimicrobial susceptibility testing. Staphylococcus species were tested for meticillin resistance using oxacillin. S. aureus was the most frequent pathogen (25.6 %) in diabetic patient specimens (160 isolates), and a high proportion of S. aureus isolates were MRSA (63.4 %). A high percentage of S. aureus isolates (65.4 %) satisfied the definition for hospital-associated MRSA (HA-MRSA) infection. The size of ulcers [adjusted odds ratio (OR) 1.61; 95 % confidence interval (CI) 1.22-2.12] and osteomyelitis (adjusted OR 18.51, 95 % CI 2.50-137.21) were independent predictors of MRSA infection. The HA-MRSA group had a significantly different distribution from the community-associated MRSA group with respect to age, history of diabetes and length of hospital stay (all P<0.001). Neuropathy, vascular disease (all P=0.049) and osteomyelitis (P=0.026) were the most common underlying conditions observed in the HA-MRSA group. This study contributes to the establishment of precautions against the emergence of MRSA including MRSA acquired from different sources among the Chinese population with diabetic foot ulcers based on their original or clinical parameters.

Involvement of serotonin neurotransmission in hippocampal neurogenesis and behavioral responses in a rat model of post-stroke depression.

Ischemia-stimulated dentate gyrus (DG) neurogenesis is hypothesized to be an etiological factor of post-stroke depression (PSD) and a potential target of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in PSD. Clinical investigations have explored the strategy of augmenting SSRIs action by combination with a 5-HT1A receptor antagonist. We investigated the relative importance of the effects on ischemia-stimulated neurogenesis and depressive-like behavior of WAY-100635 versus citalopram at different dose levels in PSD animals. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Decreased sucrose consumption was indicative of the core depressive syndrome anhedonia. Proliferating cells and their fate were monitored by bromodeoxyuridine labeling protocols up to 28 days after ischemia. Expression of the 5-HT1A receptor in DG was also examined. The current findings confirmed the ability of WAY-100635 to augment SSRIs pharmacological efficacy and SSRIs-induced elevation of post-stroke DG neurogenesis. Specifically, WAY-100635 and citalopram in different dose combinations display their relative importance in ischemia-stimulated neurogenesis probably through reinforcing serotonergic neurotransmission and/or density of 5-HT1A receptor in DG. The present data extend our understanding that increase of ischemia-induced DG neurogenesis can be interpreted as a valid index, to an extent, or even a prerequisite for an efficient co-treatment strategy.

Notch1 signaling related hippocampal neurogenesis in adult poststroke depression rats: a valid index for an efficient combined citalopram and WAY100635 pharmacotherapy.

We investigated the hypothesis that hippocampal neurogenesis related to Notch1 signaling could be a valid index for a combined citalopram and WAY100635 pharmacotherapy for the treatment of depression arising after stroke. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Behavioral tests included the open-field test and a sucrose consumption test. Proliferating cells in the hippocampus ipsilateral to ischemia and their fate were monitored by bromodeoxyuridine labeling and confocal laser scanning microscopy for up to 28 days (day 28) after ischemia. Expression of the Notch1 signaling cascade, including its ligand and downstream target genes, was also examined. WAY100635 shortened the onset of citalopram action to less than the day 21 required with citalopram alone and also proved more effective. The activity of the Notch1 signaling pathway in the hippocampus fluctuated in its function in proliferation (day 21) and differentiation (day 28) of newly formed cells in animals receiving the combination treatment. This indicated that augmentation of citalopram by cotreatment with a selective 5-hydroxytryptamine 1A antagonist would be an efficacious strategy for poststroke depression. The observed effects are most likely because of enhanced poststroke neurogenesis mediated by the Notch1 signaling cascade.

Dyslipidaemia among diabetic patients with ischemic stroke in a Chinese hospital.

BACKGROUND: Dyslipidaemia is a potential independent risk factor for cerebrovascular disease in patients with diabetes. The aim of this study was to investigate dyslipidaemia, treatment and control of dyslipidaemia among diabetic patients with ischemic stroke in a Chinese hospital. METHODS: A total of 1046 type 2 diabetic patients were assigned to diabetes with (n = 522) and diabetes without stroke groups. The two groups were matched by gender, age and diabetes duration. Lipid and lipoprotein profile were measured. Serum level and control of lipids were assessed and classified according to American Diabetes Association (ADA) guidelines and an intensified low density lipoprotein-cholesterol (LDL-C) target recommended in Chinese dyslipidaemia control criteria. RESULTS: Diabetic patients suffering stroke displayed not only poorly-controlled lipid and lipoprotein profiles, including the significantly lower proportion of patients achieving intensified LDL-C target of < 2.07 mmol/L (80 mg/dl), and high density lipoprotein-cholesterol (HDL-C) target (14.4% vs 21.0%, P = 0.005; 45.8% vs 51.9%, P = 0.048 respectively), but also less adherence to therapy prescribed for dyslipidaemia (30.8% vs 41.0%, P = 0.001), when compared with diabetic patients without stroke. For the diabetic women with stroke, situation of dyslipidaemia was worse, with significantly lower serum level of HDL-C and apoA1, higher LDL-C level and higher ratio of apoB/apoA1 when compared with diabetic counterparts without stroke. CONCLUSIONS: Many diabetic patients with ischemic stroke remain uncontrolled for dyslipidaemia. Intensified LDL-C and overall lipid lowering clinical goals are potential precautions taken against ischemic stroke among diabetic patients in China.

Decreased expression of serotonin 1A receptor in the dentate gyrus in association with chronic mild stress: a rat model of post-stroke depression.

Alterations of serotonin (5-HT) neurotransmission are implicated in post-stroke depression (PSD). Serotonin 1A (5-HT(1A)) receptor-based abnormalities have been the focus of intensive study in depression. Here we investigated the expression of the 5-HT(1A) receptor and gene in the hippocampal dentate gyrus (DG) by chronic mild stress (CMS) after stroke and the effect of citalopram. Male Sprague-Dawley rats were separated into control, stress only, ischemic stroke, PSD and citalopram-treated groups. The putative PSD animal model involved cerebral ischemia induced by left middle cerebral artery occlusion (MCAO) followed by exposure to CMS combined with single housing. All animals were assessed for depression-like behavior. The 5-HT(1A) receptor and mRNA level in DG were quantified by Western immunoblotting and Real-time RT-PCR, respectively, on the 19th and 28th days after initiating CMS. PSD animals displaying a behavioral index of depression (anhedonia) have significantly decreased protein expression of 5-HT(1A) receptors and mRNA level relative to ischemic stroke animals at each timepoint, respectively, and all these were reversed by citalopram. The dysfunction of the of 5-HT(1A) receptor in DG may play an important role in the pathogenesis of PSD and become a potential target for therapeutic intervention in the rat. The results provide partial support for the psychosocial and biological etiology of PSD and further predict the etiologic validity of the PSD model.

PPARgamma-mediated advanced glycation end products regulation of neural stem cells.

Hyperglycemia is accompanied by an accelerated rate of advanced glycation end products (AGEs) formation, which is found to be associated with the pathogenesis of diabetic cognitive deficit, including Alzheimer's disease (AD). Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling the proliferation of neural stem cells (NSCs) and their neuronal differentiation. We investigate the hypothesis that PPARgamma could mediate AGEs-related regulation of NSCs, by which AGEs possibly fulfill important roles in diabetic-related cognitive impairment. We found that AGEs down-regulated the proliferation and neurogenic differentiation of NSCs, and protein level of PPARgamma. PPARgamma agonist reversed the proliferation through the aid of AGE-BSA, with the exclusion of the neuronal differentiation of the NSCs which were also downregulated by AGE-BSA. These findings extend our understanding of the central role of PPARgamma in AGEs-related neurogenesis impairment, which probably increased risks of cognitive deficits or AD in diabetic patients.

Diabetes impairs hippocampal function via advanced glycation end product mediated new neuron generation in animals with diabetes-related depression.

The diabetes-induced reduction of neurogenesis in hippocampal dentate and its reversal with antidepressant medications implies a potential mechanism for diabetes-related depression and cognitive decline. In the following article, the role of advanced glycation end products (AGEs) in hippocampal neurogenesis deficits in diabetic animals with depression has been further explained in the light of an in vitro study. Diabetes was induced in animals with the use of streptozotocin (55 mg/kg, i.p.), and the animals then divided into those with and those without depression-like behaviors as analyzed by behavioral tests. The AGE formation inhibitor aminoguanidine (10 mg/kg) was administrated for an additional 4 weeks. Proliferating cells, their survival, and their phenotype fate were monitored with bromodeoxyuridine labeling and confocal laser microscopy. The presence of AGE peptides was determined with the use of a flow injection assay. Animals with diabetes and depressive symptoms displayed a reduction in hippocampal neurogenesis and an elevated serum level of AGE peptides, both of which were reversed by a 4-week regimen of aminoguanidine (10 mg/kg, i.p.), which inhibits AGE formation; in addition, the depressive behaviors were improved. These findings provided in vivo evidence that diabetes impairs hippocampal function via the AGE-mediated generation of new neurons. This likely represents a putative mechanism that is responsible for diabetes-related depression and cognitive decline, and it suggests a potential approach for future research.