Microglial purinergic signaling in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of ß-amyloid (Aß) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aß production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.

Connectome-based prediction of craving for gaming in internet gaming disorder.

BACKGROUND: Craving-related brain responses have been associated with the emergence and maintenance of addictions. However, little is known about brain network organizations underlying cravings in internet gaming disorder (IGD). METHODS: Sixty-six IGD subjects and 61 matched individuals with recreational game use (RGU) were scanned while performing a cue-craving task. A recently developed whole-brain analysis approach, connectome-based predictive modelling (CPM) with leave-one-out cross-validation was conducted to identify networks that predicted craving responses in IGD. Then, the craving network was tested in different brain states (cue-craving under deprivation) to investigate replicability. RESULTS: CPM identified an IGD craving network, as indicated by a significant correspondence between predicted and actual craving values (r = 0.49, p < 0.001), characterized by within-network default mode (DMN) connectivity and connectivity between canonical networks implicated in executive/cognitive control (frontoparietal, medial frontal, DMN) and reward responsiveness (subcortical, motor/sensory). Network strength in the cue-craving task during gaming deprivation also predicted IGD craving scores (r = 0.43, p = 0.017), indicating network replication across brain states. CONCLUSIONS: The CPM results demonstrate that individual differences in cognitive, attention, and control network function can predict craving intensities in IGD subjects. These networks may be targets for potential interventions using brain modulation.

Full-Scale Clinical Data and Reshaped Intestinal Microbiome on a Short-Term Low-Phosphorus Diet among Healthy Adults.

OBJECTIVES: During the past few decades, phosphorus intake has dramatically increased along with higher protein intake and overuse of inorganic phosphate additives worldwide. The detrimental effects of overconsumption of phosphorus are well recognized for patients with chronic kidney disease (CKD), and dietary phosphorus restriction was recommended for these patients. However, the effects of dietary phosphorus restriction in healthy people have not been fully studied. METHODS: In this open-label crossover study, healthy adult men (n = 12) consumed normal phosphorus diet (NPD, 1,500 mg/d) for five days. After a 10-day washout period, healthy adults took low phosphorus diet (LPD, 500 mg/d) for another five days. On the fifth day of each intervention, blood, urine and saliva samples were collected at ten time points, and fecal specimens were collected for bacterial taxa identification. RESULTS: We found that 24-h mean levels of serum phosphate (Pi), urinary Pi, serum parathyroid hormone and fibroblast growth factor 23 decreased, while serum calcium (Ca) and 1,25-dihydroxy vitamin D increased significantly under LPD compared with those under NPD. Dietary phosphorus intake did not change salivary Pi, urinary Ca, salivary Ca and magnesium (Mg) metabolism. Compared with NPD, LPD increased the relative abundance of beneficial microbes including Bacteroidetes, Ruminococcaceae and Lachnospiraceae, indicating that multiple bacterial metabolic pathways have been shifted. CONCLUSIONS: Full-scale data of dietary phosphorus restriction on Pi, Ca and Mg metabolism in healthy male adults are provided. More importantly, for the first time, dietary phosphorus restriction was found to reshape the intestinal microbiome, which provides information for benefits of dietary phosphorus restriction in healthy people, and potential clues for treating patients with CKD.

Altered modular segregation of brain networks during the cue-craving task contributes to the disrupted executive functions in internet gaming disorder.

BACKGROUND: Previous studies have shown that gaming-related cues could induce gaming cravings and bring about changes in brain activities in subjects with Internet gaming disorder (IGD). However, little is known about the brain network organizations in IGD subjects during a cue-craving task and the relationship between this network organization and IGD severity. METHODS: Sixty-one IGD subjects and 61 matched recreational game users (RGUs) were scanned while performing a cue-craving task. We calculated and compared the participation coefficient (PC) among brain network modules between IGD subjects and RGUs. Based on the results, further group comparison analyses were performed to explain the PC changes and to explore the relationship between PCs and IGD severity. RESULTS: While performing a cue-craving task, compared with RGUs, IGD subjects showed significantly decreased PCs in the default-mode network (DMN) and the frontal-parietal network (FPN). Specifically, the number of connections between nodes in the ventromedial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex and other nodes in the DMN of IGD subjects was much larger than that in RGUs. Correlation results showed that the number of DMN intra-modular connections was positively correlated with addiction severity and craving degree. CONCLUSIONS: These results provide neural evidence that can explain why cognitive control, emotion, attention and other functions are impaired in IGD subjects in the face of gaming cues, which leads to compulsive behavior toward games. These findings extend our understanding of the neural mechanism of IGD and have important implications for developing effective interventions to treat IGD subjects.

High-phosphorus diet controlled for sodium elevates blood pressure in healthy adults via volume expansion.

Whether increasing exposure to dietary phosphorus can lead to adverse clinical outcomes in healthy people is not clear. In this open-label prospective cross-over study, we are to explore the impact of various dietary phosphorus intake on mineral, sodium metabolisms and blood pressure in young healthy adults. There were 3 separate study periods of 5 days, each with a 5 days washout period between different diets interventions. Six young healthy male volunteers with normal nutrition status were recruited in Phase I Clinical Research Center and sequentially exposed to the following diets: (a) normal-phosphorus diet (NPD): 1500 mg/d, (b) low-phosphorus diet (LPD): 500 mg/d, (c) high-phosphorus diet (HPD): 2300 mg/d. HPD induced a significant rise in daily average serum phosphate (1.47 ± 0.02 mmol/L [4.56 ± 0.06 mg/dl]) compared to NPD (1.34 ± 0.02 mmol/L [4.15 ± 0.06 mg/dL]) and LPD (1.17 ± 0.02 mmol/L [3.63 ± 0.06 mg/dL]) (p < .05). Daily average levels of serum parathyroid hormone and fibroblast growth factor 23 in HPD were significantly higher, and serum 1,25(OH)2 D3 was remarkably lower than those in LPD. HPD induced a significant decrease in daily average serum aldosterone and an increase in daily average atrial natriuretic peptide level compared to LPD. The 24-hour urine volume in HPD subjects was less than that in LPD subjects. HPD significantly increased daily average systolic blood pressure by 6.02 ± 1.24 mm Hg compared to NPD and by 8.58 ± 1.24mm Hg compared to LPD (p < .05). Our study provides the first evidence that 5-day high-phosphorus diet can induce elevation in SBP in young healthy adults, which may due to volume expansion.

The imbalance between goal-directed and habitual systems in internet gaming disorder: Results from the disturbed thalamocortical communications.

BACKGROUND: Converging evidence has identified the imbalance between goal-directed systems and habitual systems in the addiction process. The thalamocortical loop plays an important role in the habitual/goal-directed system. However, little is known about the role of the thalamus in goal-directed and habitual systems in Internet gaming disorder (IGD) patients. This study investigated whether thalamocortical circuit was disrupted and how they affected goal-directed and habitual behaviors in IGD patients. METHODS: This is a functional magnetic resonance imaging (fMRI) study. Twenty-five IGD patients and 25 matched recreational game users (RGUs) were scanned when they were in a resting state and were performing an instrumental learning task to obtain behavioral data related to habitual/goal-directed behavior. We used the whole-brain seed-based functional connectivity (FC) of the four thalamic nuclei (bilateral) and correlation analyses to examine the thalamocortical loop difference and relationship with habitual/goal-directed performance. RESULTS: Compared with RGUs, IGD patients demonstrated significantly increased FC between the left midline nucleus (MN) and the right postcentral gyrus (PCG), and between the pulvinar and medial frontal gyrus (MFG). Correlation results showed that within the IGD group, the correct response rates of the participants to inconsistent stimulus-result pairs were positively correlated with the FC between the pulvinar and MFG. Inhibition-control scores were negatively correlated with the FC between the left MN and the PCG. CONCLUSIONS: IGD patients showed disrupted thalamocortical communication that could further result in an imbalance between the goal-directed and habitual systems in IGD patients. These findings provide more information about the involvement of the thalamus in the pathophysiology of IGD, and as potential circuit-level biomarkers of IGD patients, these circuit alterations may be useful in treatment development and in monitoring treatment outcomes.

[Pharmacodynamics of liposomes modified with different chain length of sialic acid derivatives].

A large number of experimental and clinical data indicates that tumor-associated macrophages(TAMs) were involved in the whole process of tumor growth, invasion and metastasis. Like macrophages in other tissues, TAMs originate from blood monocytes, which are recruited to the tumor tissues by cytokines and then differentiated into TAMs. It is interesting that the monocytes overexpress siglec receptor in their surface, which has a high binding specificity to sialic acid(SA). From this point of view, we hypothesize that if SA was used as a ligand in the surfaces of drug delivery systems, SA would enhance the targeting efficiency to monocytes, and thus to achieve a higher specificity to TAMs. In our previous study, an SA derivative of SA-octadecylamine(SA-18) was synthesized and was found to enhance cytotoxicity on TAMs in vitro. The chain length is a critical factor for SA efficiency in liposomes and it has a significant influence on the TAM targeting effects of the carriers. So in this study, four kinds of different chain length of SA fatty amine derivatives were synthesized, including SA-18, SA-hexadecylamine(SA-16), SA-tetradecylamine(SA-14) and SA-dodecylamine(SA-12), and were modified on the surfaces of blank liposomes(BLK-Sn L, n = 18, 16, 14, 12) and pixantrone maleate-loaded liposomes(Pix-Sn L, n = 18, 16, 14, 12). TAM targeting effects of these SA derivatives were evaluated by acute toxicity and antitumor efficacy in vivo. The results of acute toxicity experiments showed that the toxicities of the SA derivatives deceased gradually with the reduction in the length of lipophilic chain. The in vivo antitumor efficacies of SA-modified blank liposomes showed that these blank formulations had no effect on the tumor inhibition except BLK-S14L(61.4% ± 18.8%), and BLK-S16 L even promoted the tumor growth(-31.7% ± 13.1%, the 18 th day). The in vivo antitumor efficacies of SA-modified Pix liposomes showed that the tumor inhibition effects were Pix-S18L(97.4% ± 2.1%) > Pix-S14L(73.1% ±21.1%) > Pix-S12L(53.9% ± 17.8%) > Pix-S16L(32.9%). Because of the relatively strong binding ability of SA-18, it was hard to fall off from the liposomes in the transport process, leading to a good TAM targeting ability and less toxicity to the normal tissues. Meanwhile, 50% of the mice in Pix-S18 L group showed "tumor shedding" and "wound healing" phenomena without recurrence in two months following the treatment. Therefore, SA-18 is the most potential TAM targeting material among these SA fatty amine derivatives.