Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.

Obesity has become a global health-threat for every age group. It is well known that young mice (10-12 weeks of age) fed a western-type diet (WD) become obese and develop higher cholesterol levels and liver steatosis whereas insulin sensitivity is reduced. Less is known, however, about the effect of a WD on advanced-age mice. Therefore, 10 week-old (young) and 22 month-old (advanced-age), male C57BL/6JRj mice were kept on either a WD or a control diet (SFD) for 15 weeks. In contrast to young mice, advanced-age mice on WD did not show a higher body weight or adipose tissue (AT)-masses, suggesting a protection against diet-induced obesity. Furthermore, plasma adiponectin and leptin levels were not affected upon WD-feeding. A WD, however, did induce more hepatic lipid accumulation as well as increased hepatic expression of the macrophage marker F4/80, in advanced-age mice. There were no significant differences in mRNA levels of uncoupling protein-1 or F4/80 in brown AT (BAT) or of several intestinal integrity markers in colon suggesting that the protection against obesity is not due to excessive BAT or to impaired intestinal absorption of fat. Thus, advanced-age mice, in contrast to their younger counterparts, appeared to be protected against diet-induced obesity.

Background Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms. Methods T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy. Results Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum. Conclusion The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population.

Intestinal alkaline phosphatase 3 (AKP3) is an enzyme that was reported to play a role in lipid metabolism and to prevent high fat diet-induced metabolic syndrome in mice. To investigate a potential functional role of AKP3 in diet-induced adiposity and metabolic health, we have kept male and female wild-type or AKP3 deficient mice on a high fat diet for 15 weeks to induce obesity and compared those with mice kept on standard fat diet. Body weight as well as adipose tissue mass were statistically significantly higher upon high fat diet feeding for mice of both genders and genotypes. Female mice of either genotype kept on high fat diet gained less weight, resulting in smaller adipose tissue depots with smaller adipocytes. However, AKP3 deficiency had no significant effect on body weight gain or adipose tissue mass and did not affect adipocyte size or density. Gene expression analysis revealed no effect of the genotype on inflammatory parameters in adipose tissue, except for tumor necrosis factor alpha, which was higher in mesenteric adipose tissue of female obese mice. Plasma glucose and insulin levels were also not affected in obese AKP3 deficient mice. Overall, our data do not support a functional role of AKP3 in adipose tissue development, or insulin sensitivity.

<b><i>Introduction:</i></b> The biggest risk factor for obesity and its associated comorbidities is a Western diet. This Western diet induces adipose tissue (AT) inflammation, which causes an AT dysfunction. Since AT is a vital endocrine organ, its dysfunction damages other organs, thus inducing a state of chronic inflammation and causing various comorbidities. Even though it is evident a Western diet, high in fat and carbohydrates, induces obesity and its complications, it is not known yet which macronutrient plays the most important role. Therefore, the aim of this study was to investigate the effect of macronutrient composition on obesity and to reverse the Western diet-induced metabolic risk via caloric restriction (CR) or a change of diet composition. <b><i>Materials and Methods:</i></b> Male, C57BL/6JRj mice were fed with a diet high in fat, sucrose, fructose, sucrose and fructose, starch, a Western diet, or a control diet for 15 weeks. To assess reversibility of the metabolic risk, mice were first made obese via 15 weeks of WD and then put on either a CR or switched to a sucrose-rich diet. <b><i>Results:</i></b> A sucrose-rich and high-starch diet induced less obesity and a better metabolic profile than a Western diet, evidenced by less hepatic steatosis, lower plasma cholesterol, and less insulin resistance. Furthermore, these diets induced less intra-abdominal AT inflammation than a Western diet, since mRNA levels of pro-inflammatory markers were lower and there was less macrophage infiltration. Expression of tight junction markers in colon tissue was higher in the sucrose-rich and high-starch group than the Western group, indicating a better intestinal integrity upon sucrose-rich and high-starch feeding. Additionally, CR induced weight loss and decreased both metabolic abnormalities and AT inflammation, regardless of macronutrient composition. However, effects were more pronounced upon CR with sucrose-rich or high-starch diet. Even without CR, switching obese mice to a sucrose-rich diet induced weight loss and decreased AT inflammation and metabolic aberrations. <b><i>Discussion:</i></b> A diet high in sucrose or starch induces less obesity and obesity-associated complications. Moreover, switching obese mice to a sucrose-rich diet elicits weight loss and decreases obesity-induced metabolic complications, highlighting the potential of carbohydrates to treat obesity.

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Background Type 2 diabetes (T2D) impairs post-stroke functional recovery, and the underlying mechanisms are mostly unknown. Insulin resistance (IR), which is a hallmark of T2D, also afflicts up to 50% of the elderly without T2D. IR has been associated with impaired recovery after stroke. However, the causative role of IR in impaired stroke recovery has not been demonstrated. By using different mouse models of early IR, we investigated the potential crosstalk between IR and stroke recovery as well as some of the cellular mechanisms possibly involved. Methods We used three different models of IR. Early IR with or without fasting hyperglycaemia was respectively induced by 4 months of high fat diet or by 30% sucrose supplementation in the drinking water. In addition, we used 10-month-old mice that spontaneously develop IR, but not hyperglycaemia, and where IR was targeted pharmacologically pre-stroke with 10 mg/kg/day Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and neuroplasticity mediated by cholinergic interneurons were assessed by immunohistochemistry/quantitative microscopy. Results The induction of IR before stroke, with or without hyperglycaemia, impaired post-stroke neurological recovery. Moreover, the results indicate the involvement of increased neuroinflammation and decreased cholinergic interneuron-mediated neuroplasticity in the recorded effects. Importantly, the pharmacological normalization of IR, significantly improved post-stroke neurological recovery. Conclusion The global diabetes epidemic and world population aging are dramatically increasing the percentage of people in need of post-stroke treatment and care. Targeting hyperglycaemia acutely post-stroke has so far provided negative results to improve stroke outcome and new targets are highly needed. The results of our study suggest that future clinical studies should focus on the specific targeting of pre-stroke IR to reduce the sequelaeof stroke in both diabetic patients and the elderly suffering from prediabetes.

<p>Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. </p> <p>Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice. </p> <p>We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. </p> <p>This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects.  </p>