Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome.

Introduction: A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed. Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC). Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores. Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

In Vitro and In Vivo Neuroprotective Effects of Sarcosine.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by behavioral and psychological symptoms in addition to cognitive impairment and loss of memory. The exact pathogenesis and genetic background of AD are unclear and there remains no effective treatment option. Sarcosine, an n-methyl derivative of glycine, showed a promising therapeutic strategy for some cognitive disorders. To our knowledge, the impacts of sarcosine supplementation against AD have not yet been elucidated. Therefore, we aimed to determine the neuroprotective potential of sarcosine in in vitro and in vivo AD model. In vitro studies have demonstrated that sarcosine increased the percentage of viable cells against aluminum induced neurotoxicity. In AlCl3-induced rat model of AD, the level of antioxidant capacity was significantly decreased and expression levels of APP, BACE1, TNF-α, APH1A, and PSENEN genes were elevated compared to the control group. Additionally, histopathological examinations of the hippocampus of AlCl3-induced rat brains showed the presence of neurofibrillary tangles (NFTs). However, the administration of sarcosine produced marked improvement and protection of AD-associated pathologies induced by AlCl3 in experimental rats. Therefore, this investigation may contribute to design novel therapeutic strategies using sarcosine for the management of AD pathologies.

Heat stress-induced intestinal barrier damage and dimethylglycine alleviates via improving the metabolism function of microbiota gut brain axis.

Heat stress, a widely occurred in subtropical climate regions, causes ecosystem destruction, and intestine injury in humans and animals. As an important compound in the metabolic pathway of choline, dimethylglycine (DMG) shows anti-inflammatory effects. This study examines the beneficial effects of dietary DMG against heat stress-induced intestine injury and further explores the underlying molecular mechanisms using a broiler model. Here, we showed that DMG supplements exhibited positive effects to growth performance, as evidenced by the significantly increased body weight and feed conversion rate. These therapeutic effects attributed to repaired gut barrier integrity, increased content of anti-inflammatory cytokines IL-10, decreased content of pro-inflammatory cytokines IL-6, and down-regulated gene expression of the NF-κB signaling pathway. DMG treatment led to the reshaping of the gut microbiota composition, mainly increasing the short-chain fatty acid (SCFAs) strains such as Faecalibacterium, and Marvinbryantia. DMG treatment also increased two main members of SCFAs, including acetate acid and isobutyrate. Particularly, distinct effects were found which mediated the tryptophan metabolism in intestines such as increased tryptophan and 5-HT, which further alleviate the occurrence of intestinal barrier damage caused by heat stress. Additionally, DMG treatment promoted neuroendocrine function and stimulated the hypothalamic neurotransmitter metabolism by activating tryptophan metabolism in the hypothalamus. Overall, DMG supplementation effectively reduced the occurrence of intestinal inflammation induced by heat stress through modulating cecal microbial communities and improving the metabolism function of microbiota gut brain axis. Our findings revealed a novel mechanism by which gut microbiota could improve host health.

SNAT2 is responsible for hyperosmotic induced sarcosine and glycine uptake in human prostate PC-3 cells.

Solute carriers (SLC) are important membrane transport proteins in normal and pathophysiological cells. The aim was to identify amino acid SLC(s) responsible for uptake of sarcosine and glycine in prostate cancer cells and investigate the impact hereon of hyperosmotic stress. Uptake of 14C-sarcosine and 3H-glycine was measured in human prostate cancer (PC-3) cells cultured under isosmotic (300 mOsm/kg) and hyperosmotic (500 mOsm/kg) conditions for 24 h. Hyperosmotic culture medium was obtained by supplementing the medium with 200 mM of the trisaccharide raffinose. Amino acid SLC expression was studied using RT-PCR, real-time PCR, and western blotting. siRNA knockdown of SNAT2 was performed. Experiments were conducted in at least 3 independent cell passages. The uptake of Sar and Gly was increased approximately 8-ninefold in PC-3 cells after 24 h hyperosmotic culture. PAT1 mRNA and protein could not be detected, while SNAT2 was upregulated at the mRNA and protein level. Transfection with SNAT2-specific siRNA reduced Vmax of Sar uptake from 2653 ± 38 to 513 ± 38 nmol mg protein-1 min-1, without altering the Km value (3.19 ± 0.13 vs. 3.42 ± 0.71 mM), indicating that SNAT2 is responsible for at least 80% of Sar uptake in hyperosmotic cultured PC-3 cells. SNAT2 is upregulated in hyperosmotic stressed prostate cancer cells and SNAT2 is responsible for cellular sarcosine and glycine uptake in hyperosmotic cultured PC-3 cells. Sar is identified as a substrate for SNAT2, and this has physiological implications for understanding cellular solute transport in prostate cancer cells.

Short-Term Supplementation of Sodium Nitrate vs. Sodium Chloride Increases Homoarginine Synthesis in Young Men Independent of Exercise.

The aim of the study was to investigate the effects of short-term oral administration of inorganic nitrate (NaNO3; n = 8) or placebo (NaCl; n = 9) (each 0.1 mmol/kg body weight/d for 9 days) on plasma amino acids, creatinine, and oxidative stress in healthy young men. At baseline, the plasma concentrations of amino acids did not differ between the groups. At the end of the study, the plasma concentrations of homoarginine (hArg; by 24%, p = 0.0001), citrulline and ornithine (Cit/Orn; by 16%, p = 0.015), and glutamine/glutamate (Gln/Glu; by 6%, p = 0.0003) were higher in the NaNO3 group compared to the NaCl group. The plasma concentrations of sarcosine (Sarc; by 28%, p < 0.0001), tyrosine (by 14%, p = 0.0051), phenylalanine (by 8%, p = 0.0026), and tryptophan (by 8%, p = 0.0047) were lower in the NaNO3 group compared to the NaCl group. These results suggest that nitrate administration affects amino-acid metabolism. The arginine/glycine amidinotransferase (AGAT) catalyzes two reactions: (1) the formation of l-homoarginine (hArg) and l-ornithine (Orn) from l-arginine (Arg) and l-lysine (Lys): Arg + Lys <−> hArg + Orn, with equilibrium constant Kharg; (2) the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly <−> GAA + Orn, with equilibrium constant Kgaa. The plasma Kgaa/KhArg ratio was lower in the NaNO3 group compared to the NaCl group (1.57 vs. 2.02, p = 0.0034). Our study suggests that supplementation of inorganic nitrate increases the AGAT-catalyzed synthesis of hArg and decreases the N-methyltransferase-catalyzed synthesis of GAA, the precursor of creatine. To our knowledge, this is the first study to demonstrate elevation of hArg synthesis by inorganic nitrate supplementation. Remarkably, an increase of 24% corresponds to the synthesis capacity of one kidney in healthy humans. Differences in the association between plasma concentrations of amino acids in the NaNO3 and NaCl groups suggest changes in amino-acid homeostasis. Plasma concentrations of the oxidative stress marker malondialdehyde (MDA) did not change after supplementation of NaNO3 or NaCl over the whole exercise time range. Plasma nitrite concentration turned out to be a more discriminant marker of NaNO3 ingestion than plasma nitrate (area under the receiver operating characteristic curve: 0.951 vs. 0.866, p < 0.0001 each).

Influence of humectants on the thermotropic behaviour and nanostructure of fully hydrated lecithin bilayers.

Humectants are used widely in topical formulations as they provide cosmetic and health benefits to skin. Of particular interest to our laboratories is the interaction of humectants in phospholipid based topical skin care formulations. This study probed the effects of three exemplary humectants on a fully hydrated lecithin system (DPPC) by use of X-ray scattering and differential scanning calorimetry. While the three humectants affected the nanostructure of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, bilayers in a similar manner, leading to an increased membrane order, differences in the effect on the thermal behaviour of DPPC suggest that betaine and sarcosine interacted via a different mechanism compared to acetic monoethanolamide, AMEA. At concentrations above 0.4 M, betaine and sarcosine stabilised the gel phase by depletion of the interfacial water via the preferential exclusion mechanism. At the same time, a slight increase in the rigidity of the membrane was observed with an increase in the membrane thickness. Overall, the addition of betaine or sarcosine resulted in an increase in the pre- and main transition temperatures of DPPC. AMEA, on the other hand, decreases both transition temperatures, and although the interlamellar water layer was also decreased, there was evidence from the altered lipid chain packing, that AMEA molecules are present also at the bilayer interface, at least at high concentrations. Above the melting point in the fluid lamellar phase, none of the humectants induced significant structural changes, neither concerning the bilayer stacking order nor its overall membrane fluidity. An humectant-induced increase in the Hamaker constant is the most plausible explanation for the observed reduction of the inter-bilayer distances, both in the gel and fluid phase.

Millennium Nutrient N,N-Dimethylglycine (DMG) and its Effectiveness in Autism Spectrum Disorders.

Autism is a neurodevelopmental disorder belonging to the autism spectrum disorder (ASD). In ASDs, the individuals show substantial impairments in social communication, repetitive behaviours, and sensory behaviours deficits in the early stages of their life. Globally, the prevalence of autism is estimated to be less than 1%, especially in high- -income countries. In recent decades, there has been a drastic increase in the incidence of ASD, which has put ASD into the category of epidemics. Presently, two US Food and Drug Administration-approved drugs, aripiprazole and risperidone, are used to treat symptoms of agitation and irritability in autistic children. However, to date, no medication has been found to treat the core symptoms of ASD. The adverse side effects of conventional medicine and limited treatment options have led families of autistic children to turn to complementary and alternative medicine (CAM) treatments, which are perceived as relatively safe compared to conventional medicine. Recently N, N-dimethylglycine (DMG), a dietary supplement, has emerged as a useful supplement to improve the mental and physical state of children with ASD. The current review discusses ASD, the prevalence of ASD, the CAM approach, and the efficacy of CAM treatment in children with ASD. Moreover, it highlights the chemistry, pharmacological effect, and clinical studies of DMG, highlighting its potential for improving the lifestyle of children with ASD.

Effects of dietary dimethylglycine supplementation on laying performance, egg quality, and tissue index of hens during late laying period.

In this study, the effects of 5 graded dietary levels (0.025, 0.05, 0.075, 0.1, and 0.125%) of dimethylglycine (DMG) were studied in laying hens during the late laying period (71-78 wk). Graded doses of DMG from 0.025 to 0.125% in the diet produced quadratic positive (P < 0.05) responses in the laying rate, egg-feed ratio, yolk color, grade follicular weight, and the number of large white follicles and linear positive (P < 0.05) responses in average egg weight, and the number of large white follicles. With 0.1% DMG, the laying rate and egg-feed ratio improved (P < 0.05), and the abdominal fat percentage decreased. Considering the laying performance under the conditions used in this study, the best-fit model for the DMG requirements of laying hens was estimated to range from 0.049 to 0.065% DMG during the late laying period based on a regression analysis. The addition of DMG did not affect the total cholesterol (TCH) and triglyceride (TG) contents in the plasma of laying hens; however, it significantly reduced the abdominal fat rate. DMG may change the course of lipid deposition in laying hens during the late laying period. In conclusion, supplementation with DMG can improve the laying rate and follicles development of laying hens.

N, N-dimethylglycine Protects Behavioral Disturbances and Synaptic Deficits Induced by Repeated Ketamine Exposure in Mice.

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) blocker, is gaining ground as a treatment option for depression. The occurrence of persistent psychosis and cognitive impairment after repeated use of ketamine remains a concern. N, N-dimethylglycine (DMG) is a nutrient supplement and acts as an NMDAR glycine site partial agonist. The objective of this study was to assess whether DMG could potentially prevent the behavioral and synaptic deficits in mice after repeated ketamine exposure. Male ICR mice received ketamine (20 mg/kg) from postnatal day (PN) 33-46, twice daily, for 14 days. The locomotor activity, novel location recognition test (NLRT), novel object recognition test (NORT), social interaction test, head twitch response induced by serotonergic hallucinogen, and the basal synaptic transmission and long-term potentiation (LTP) in the hippocampal slices were monitored after repeated ketamine treatment. Furthermore, the protective effects of repeated combined administration of DMG (30 and 100 mg/kg) with ketamine on behavioral abnormalities and synaptic dysfunction were assessed. The results showed that mice exhibited memory impairments, social withdrawal, increased head twitch response, reduced excitatory synaptic transmission, and lower LTP after repeated ketamine exposure. The ketamine-induced behavioral and synaptic deficits were prevented by co-treatment with DMG. In conclusion, these findings may pave a new path forward to developing a combination formula with ketamine and DMG for the treatment of depression and other mood disorders.

Dietary dimethylglycine sodium salt supplementation improves growth performance, redox status, and skeletal muscle function of intrauterine growth-restricted weaned piglets.

Few studies have focused on the role of dimethylglycine sodium (DMG-Na) salt in protecting the redox status of skeletal muscle, although it is reported to be beneficial in animal husbandry. This study investigated the beneficial effects of DMG-Na salt on the growth performance, longissimus dorsi muscle (LM) redox status, and mitochondrial function in weaning piglets that were intrauterine growth restricted (IUGR). Ten normal birth weight (NBW) newborn piglets (1.53 ± 0.04 kg) and 20 IUGR newborn piglets (0.76 ± 0.06 kg) from 10 sows were obtained. All piglets were weaned at 21 d of age and allocated to the three groups with 10 replicates per group: NBW weaned piglets fed a common basal diet (N); IUGR weaned piglets fed a common basal diet (I); IUGR weaned piglets fed a common basal diet supplemented with 0.1% DMG-Na (ID). They were slaughtered at 49 d of age to collect the serum and LM samples. Compared with the N group, the growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression deteriorated in group I (P < 0.05). The ID group showed improved growth performance, LM structure, serum, and, within the LM, mitochondrial redox status, mitochondrial respiratory chain complex activity, energy metabolites, redox status-related, cell adhesion-related, and mitochondrial function-related gene expression, and protein expression compared with those in the I group (P < 0.05). The above results indicated that the DMG-Na salt treatment could improve the LM redox status and mitochondrial function in IUGR weaned piglets via the nuclear factor erythroid 2-related factor 2/sirtuin 1/peroxisome proliferator-activated receptorγcoactivator-1α network, thus improving their growth performance.

Effect of N, N-Dimethylglycine on Homocysteine Metabolism in Rats Fed Folate-Sufficient and Folate-Deficient Diets.

OBJECTIVE: This study aimed to investigate the effects of N,N-dimethylglycine (DMG) on the concentration and metabolism of plasma homocysteine (pHcy) in folate-sufficient and folate-deficient rats. METHODS: In this study, 0.1% DMG was supplemented in 20% casein diets that were either folate-sufficient (20C) or folate-deficient (20CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system. RESULTS: Folate deprivation significantly increased pHcy concentration in rats fed 20C diet (from 14.19 ± 0.39 µmol/L to 28.49 ± 0.50 µmol/L; P < 0.05). When supplemented with DMG, pHcy concentration was significantly decreased (12.23 ± 0.18 µmol/L) in rats fed 20C diet but significantly increased (31.56 ± 0.59 µmol/L) in rats fed 20CFD. The hepatic methionine synthase activity in the 20CFD group was significantly lower than that in the 20C group; enzyme activity was unaffected by DMG supplementation regardless of folate sufficiency. The activity of hepatic cystathionine ß-synthase (CBS) in the 20CFD group was decreased but not in the 20C group; DMG supplementation enhanced hepatic CBS activity in both groups, in which the effect was significant in the 20C group but not in the other group. CONCLUSION: DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.

Effect of / 生物医学与环境科学（英文）

Objective@#This study aimed to investigate the effects of @*Methods@#In this study, 0.1% DMG was supplemented in 20% casein diets that were either folate-sufficient (20C) or folate-deficient (20CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system.@*Results@#Folate deprivation significantly increased pHcy concentration in rats fed 20C diet (from 14.19 ± 0.39 μmol/L to 28.49 ± 0.50 μmol/L; @*Conclusion@#DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.

N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice.

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.

Plasma Sarcosine Measured by Gas Chromatography-Mass Spectrometry Distinguishes Prostatic Intraepithelial Neoplasia and Prostate Cancer from Benign Prostate Hyperplasia.

OBJECTIVE: Sarcosine was postulated in 2009 as a biomarker for prostate cancer (PCa). Here, we assess plasma sarcosine as a biomarker that is complementary to prostate-specific antigen (PSA). METHODS: Plasma sarcosine was measured using gas chromatography-mass spectrometry (GC-MS) in adults classified as noncancerous controls (with benign prostate hyperplasia [BPH], n = 36), with prostatic intraepithelial neoplasia (PIN, n = 16), or with PCa (n = 27). Diagnostic accuracy was assessed using receiver operating characteristic curve analysis. RESULTS: Plasma sarcosine levels were higher in the PCa (2.0 µM [1.3-3.3 µM], P <.01) and the PIN (1.9 µM [1.2-6.5 µM], P <.001) groups than in the BPH (0.9 µM [0.6-1.4 µM]) group. Plasma sarcosine had "good" and "very good" discriminative capability to detect PIN (area under the curve [AUC], 0.734) and PCa (AUC, 0.833) versus BPH, respectively. The use of PSA and sarcosine together improved the overall diagnostic accuracy to detect PIN and PCa versus BPH. CONCLUSION: Plasma sarcosine measured by GC-MS had "good" and "very good" classification performance for distinguishing PIN and PCa, respectively, relative to noncancerous patients diagnosed with BPH.

Natural Choline from Egg Yolk Phospholipids Is More Efficiently Absorbed Compared with Choline Bitartrate; Outcomes of A Randomized Trial in Healthy Adults.

Choline is a vitamin-like essential nutrient, important throughout one's lifespan. Therefore, choline salts are added to infant formula, supplements and functional foods. However, if choline is present in a natural form, e.g. bound to phospholipids, it may be more efficiently absorbed. The study's aim was to evaluate if choline uptake is improved after consumption of an egg yolk phospholipid drink, containing 3 g of phospholipid bound choline, compared to a control drink with 3 g of choline bitartrate. We performed a randomized, double blind, cross-over trial with 18 participants. Plasma choline, betaine and dimethylglycine concentrations were determined before and up to six hours after consumption of the drinks. The plasma choline response, as determined by the incremental area under the curve, was four times higher after consumption of the egg yolk phospholipid drink compared with the control drink (p < 0.01). Similar outcomes were also observed for choline's main metabolites, betaine (p < 0.01) and dimethylglycine (p = 0.01). Consumption of natural choline from egg yolk phospholipids improved choline absorption compared to consumption of chemically produced choline bitartrate. This information is of relevance for the food industry, instead of adding choline-salts, adding choline from egg yolk phospholipids can improve choline uptake and positively impact health.

A possible role for sarcosine in the management of schizophrenia.

Sarcosine, which is freely sold as a dietary supplement, has pharmacological activity to boost functioning of the glutamatergic N-methyl-d-aspartate receptor (NMDAR) and hence it is a biologically rational treatment for schizophrenia. The small number of studies carried out to date provide some evidence for its efficacy and psychiatrists could consider suggesting its use to their patients.

Preclinical evaluation of a 64Cu-labeled disintegrin for PET imaging of prostate cancer.

A novel recombinant disintegrin, vicrostatin (VCN), displays high binding affinity to a broad range of human integrins in substantial competitive biological advantage over other integrin-based antagonists. In this study, we synthesized a new 64Cu-labeled VCN probe and evaluated its imaging properties for prostate cancer in PC-3 tumor-bearing mice. Macrocyclic chelating agent 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosine (DiAmSar) was conjugated with PEG unit and followed by coupling with VCN. The precursor was then radiolabeled with positron emitter 64Cu (t1/2 = 12.7 h) in ammonium acetate buffer to provide 64Cu-Sar-PEG-VCN, which was subsequently subjected to in vitro studies, small animal PET, and biodistribution studies. The PC-3 tumor-targeting efficacy of 64Cu-Sar-PEG-VCN was compared to a cyclic RGD peptide-based PET probe (64Cu-Sar-RGD). 64Cu labeling was achieved in 75% decay-corrected yield with radiochemical purity of > 98%. The specific activity of 64Cu-Sar-PEG-VCN was estimated to be 37 MBq/nmol. MicroPET imaging results showed that 64Cu-Sar-PEG-VCN has preferential tumor uptake and good tumor retention in PC-3 tumor xenografts. As compared to 64Cu-Sar-RGD, 64Cu-Sar-PEG-VCN produces higher tumor-to-muscle (T/M) imaging contrast ratios at 2 h (4.66 ± 0.34 vs. 2.88 ± 0.46) and 24 h (4.98 ± 0.80 vs. 3.22 ± 0.30) post-injection (pi) and similar tumor-to-liver ratios at 2 h (0.43 ± 0.09 vs. 0.37 ± 0.04) and 24 h (0.57 ± 0.13 vs. 0.52 ± 0.07) pi. The biodistribution results were consistent with the quantitative analysis of microPET imaging, demonstrating good T/M ratio (2.73 ± 0.36) of 64Cu-Sar-PEG-VCN at 48 h pi in PC-3 tumor xenografts. For both microPET and biodistribution studies at 48 h pi, the PC-3 tumor uptake of 64Cu-Sar-PEG-VCN is lower than that of 64Cu-Sar-RGD. 64Cu-Sar-PEG-VCN has the potential for in vivo imaging of prostate cancer with PET, which may provide a unique non-invasive method to quantitatively localize and characterize prostate cancer.

The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model.

BACKGROUND: N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. METHODS: By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. RESULTS: In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. CONCLUSIONS: We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

The Role of N,N,N-Trimethylglycine in Oviposition of Eurema mandarina on Albizia julibrissin.

The common grass yellow Eurema mandarina (Lepidoptera: Pieridae) uses the silk tree Albizia julibrissin (Fabaceae) as a primary host in Japan. We previously reported that D-pinitol, a cyclitol found in fresh leaves of A. julibrissin, solely elicits moderate oviposition responses from females. However, the aqueous neutral/amphoteric fraction of the fresh leaf extract containing D-pinitol weakly induces oviposition. Moreover, the aqueous neutral/amphoteric/basic fraction was significantly more active than the neutral/amphoteric fraction in eliciting responses, indicating that some basic compounds are involved in stimulating oviposition. High-resolution mass spectrometry and proton nuclear magnetic resonance measurements revealed that the aqueous basic faction contains N,N,N-trimethylglycine (trivial name: glycine betaine) in alkali metal salt form. The average concentration of this quaternary ammonium compound in fresh leaves was estimated to be 0.012% w/w in high performance liquid chromatography analyses. The authentic N,N,N-trimethylglycine induced oviposition at concentrations greater than 0.001% (w/v) and slightly enhanced female responses to the aqueous neutral fraction and authentic D-pinitol. However, its analogues, N,N-dimethylglycine, N-methylglycine, and glycine as well as its precursor choline were inactive. These results demonstrate that N,N,N-trimethylglycine, together with D-pinitol, serves as an stimulant of E. mandarina for oviposition on the leaves of A. julibrissin.

Meta-analysis of glyphosate contamination in surface waters and dissipation by biofilms.

One consequence of the intensive use of glyphosate is the contamination of rivers by the active substance and its metabolites aminomethyl phosphonic acid (AMPA) and sarcosine, inducing river eutrophication. Biofilms are the predominant lifestyle for microorganisms in rivers, providing pivotal roles in ecosystem functioning and pollutant removal. The persistence of glyphosate in these ecosystems is suspected to be mostly influenced by microbial biodegradation processes. The present study aimed to investigate the tripartite relationship among biofilms, phosphorus and glyphosate in rivers. The first part consists of a co-occurrence analysis among glyphosate, AMPA and phosphorus using an extensive dataset of measurements (n = 56,198) from French surface waters between 2013 and 2017. The second part investigated the capacity of natural river biofilms to dissipate glyphosate, depending on phosphorus availability and the exposure history of the biofilm, in a microcosm study. A strong co-occurrence among glyphosate, AMPA and phosphorus was found in surface waters. More than two-thirds of samples contained phosphorous with glyphosate, AMPA or both compounds. Seasonal fluctuations in glyphosate, AMPA and phosphorus concentrations were correlated, peaking in spring/summer shortly after pesticide spreading. Laboratory experiments revealed that natural river biofilms can degrade glyphosate. However, phosphorus availability negatively influenced the biodegradation of glyphosate and induced the accumulation of AMPA in water. An increase in alkaline phosphatase activity and phosphorus uptake was observed in glyphosate-degrading biofilms, evidencing the tight link between phosphorus limitation and glyphosate degradation by biofilms. The results of the present study show that phosphorus not only is a key driver of river eutrophication but also can reduce complete glyphosate degradation by biofilms and favour the accumulation of AMPA in river water. The predominant role of biofilms and the trophic status of rivers must therefore be considered in order to better assess the fate and persistence of glyphosate.