The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.

The cellular prion protein (PrPC) plays many roles in the developing and adult brain. In addition, PrPC binds to several amyloids in oligomeric and prefibrillar forms and may act as a putative receptor of abnormal misfolded protein species. The role of PrPC in tau seeding and spreading is not known. In the present study, we have inoculated well-characterized sarkosyl-insoluble fractions of sporadic Alzheimer's disease (sAD) into the brain of adult wild-type mice (Prnp+/+), Prnp0/0 (ZH3 strain) mice, and mice over-expressing the secreted form of PrPC lacking their GPI anchor (Tg44 strain). Phospho-tau (ptau) seeding and spreading involving neurons and oligodendrocytes were observed three and six months after inoculation. 3Rtau and 4Rtau deposits from the host tau, as revealed by inoculating Mapt0/0 mice and by using specific anti-mouse and anti-human tau antibodies suggest modulation of exon 10 splicing of the host mouse Mapt gene elicited by exogenous sAD-tau. However, no tau seeding and spreading differences were observed among Prnp genotypes. Our results show that PrPC does not affect tau seeding and spreading in vivo.

Efficacy and safety of add-on sarcosine in patients with major depressive disorder: A randomized controlled trial.

The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (-8.7, 95% CI: -11.0 to -6.4, p < 0.001) and the test group (-13.3, 95% CI: -14.9 to -11.7, p < 0.001), but the change in the test group was significantly greater (-4.6, 95% CI: -7.5 to -1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD. ClinicalTrial.gov IdentifierNCT04975100.

Brucine Suppresses Malignant Progression of Prostate Cancer by Decreasing Sarcosine Accumulation via Downregulation of GNMT in the Glycine/sarcosine Metabolic Pathway.

Prostate cancer (PCa) remains a leading cause of cancer-related incidence and mortality in men. Disruptions in amino acid (AA) metabolism contribute to the disease progression, with brucine, a glycine antagonist, exhibiting antitumor effects. This study explores the antitumor impact of brucine on PCa and investigates its mechanisms in regulating AA metabolic pathways. The study employed the PCa cell line DU-145, characterized by high sarcosine (Sar) levels, for various assays including Cell Counting Kit-8 (CCK8), wound healing, Transwell, 5-Ethynyl-2'-deoxyuridine (EDU), TdT mediated dUTP Nick End Labeling (TUNEL), flow cytometry, Western blot, and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Network pharmacological analysis determined the anticancer mechanisms of brucine. Sar levels in DU-145 cells were significantly higher than in normal prostatic epithelial cells RWPE-1. Treatment with brucine resulted in a marked decrease in cell viability, proliferation, invasion, and migration, while promoting apoptosis in a dose-dependent manner. Sar levels decreased with increasing brucine concentration. Network pharmacology analysis linked brucine's anticancer effect to the AA metabolism and glycine N-methyltransferase (GNMT) pathways. GNMT expression in prostate cancer tissues and The Cancer Genome Atlas database was significantly elevated compared to controls. Treatment with brucine led to downregulation of GNMT expression in DU-145 cells without significant effect on sarcosine dehydrogenase (SARDH). Addition of recombinant GNMT partially reversed the inhibitory effects of brucine on DU-145 cells. Treatment with brucine downregulates GNMT expression in DU-145 cells, reducing Sar accumulation and inhibiting tumor progression. These findings provide new insights into the antitumor mechanisms of brucine in PCa.

GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-ß-Induced Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-ß-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-ß. NFPS pretreatment prevented amyloid-ß-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-ß injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-ß-induced hippocampal damage.

Glycine transporter-1 inhibition by NFPS promotes neuroprotection against striatal damage models.

The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage.

ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production.

N-methyl-glycine (sarcosine) is known to promote metastatic potential in some cancers; however, its effects on bladder cancer are unclear. T24 cells derived from invasive cancer highly expressed GNMT, and S-adenosyl methionine (SAM) treatment increased sarcosine production, promoting proliferation, invasion, anti-apoptotic survival, sphere formation, and drug resistance. In contrast, RT4 cells derived from non-invasive cancers expressed low GNMT, and SAM treatment did not produce sarcosine and did not promote malignant phenotypes. In T24 cells, the expression of miR-873-5p, which suppresses GNMT expression, was suppressed, and the expression of ERVK13-1, which sponges miR-873-5p, was increased. The growth of subcutaneous tumors, lung metastasis, and intratumoral GNMT expression in SAM-treated nude mice was suppressed in T24 cells with ERVK13-1 knockdown but promoted in RT4 cells treated with miR-873-5p inhibitor. An increase in mouse urinary sarcosine levels was observed to correlate with tumor weight. Immunostaining of 86 human bladder cancer cases showed that GNMT expression was higher in cases with muscle invasion and metastasis. Additionally, urinary sarcosine concentrations increased in cases of muscle invasion. Notably, urinary sarcosine concentration may serve as a marker for muscle invasion in bladder cancer; however, further investigation is necessitated.

Sarcosine sensitivity in Escherichia coli is mediated by activation of the glycine cleavage system.

Corynebacterium glutamicum AJ1511 and Escherichia coli BW25113 strains were compared in terms of resistance to sarcosine (N-methylglycine). The E. coli strain was more sensitive to sarcosine than C. glutamicum, especially when grown in minimal medium. Growth inhibition of the BW25113 strain in minimal M9 medium containing 0.5 m sarcosine was overcome by the addition of glycine. Inactivation of the glycine cleavage (GCV) system (∆gcvP) as well as the removal of its activator (∆gcvA) in BW25113 cells increased the threshold for sarcosine inhibition up to 0.75 m. Activation of the promoter of the E. coli gcvTHP operon by 0.1-0.4 m sarcosine added to M9 medium was demonstrated in vivo using dasherGFP as the reporter. Sensitivity to sarcosine on glucose minimal medium is suggested to be a characteristic of Gram-negative bacteria with GcvA/GcvR regulation of the GCV system.

N-methyl-d-aspartate receptors and glycinergic transmission, respectively, mediate muscle relaxation and immobility of pentobarbital in mice.

Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous system. However, it is unclear whether all components of anesthesia induced by pentobarbital, such as muscle relaxation, unconsciousness, and immobility in response to noxious stimuli, are mediated only through GABAergic neurons. Thus, we examined whether the indirect GABA and glycine receptor agonists gabaculine and sarcosine, respectively, the neuronal nicotinic acetylcholine receptor antagonist mecamylamine, or the N-methyl-d-aspartate receptor channel blocker MK-801 could enhance pentobarbital-induced components of anesthesia. Muscle relaxation, unconsciousness, and immobility were evaluated by grip strength, the righting reflex, and loss of movement in response to nociceptive tail clamping, respectively, in mice. Pentobarbital reduced grip strength, impaired the righting reflex, and induced immobility in a dose-dependent manner. The change in each behavior induced by pentobarbital was roughly consistent with that in electroencephalographic power. A low dose of gabaculine, which significantly increased endogenous GABA levels in the central nervous system but had no effect on behaviors alone, potentiated muscle relaxation, unconsciousness, and immobility induced by low pentobarbital doses. A low dose of MK-801 augmented only the masked muscle-relaxing effects of pentobarbital among these components. Sarcosine enhanced only pentobarbital-induced immobility. Conversely, mecamylamine had no effect on any behavior. These findings suggest that each component of anesthesia induced by pentobarbital is mediated through GABAergic neurons and that pentobarbital-induced muscle relaxation and immobility may partially be associated with N-methyl-d-aspartate receptor antagonism and glycinergic neuron activation, respectively.

Ketamine, benzoate, and sarcosine for treating depression.

Studies have demonstrated the beneficial therapeutic effects of sarcosine, benzoate, and ketamine (including esketamine and arketamine) on depression. These drugs mainly act by modulating N-methyl-d-aspartate glutamate receptors (NMDARs) and reducing inflammation in the brain. Although ketamine, benzoate, and sarcosine act differently as the antagonists or coagonists of NMDARs, they all have demonstrated efficacy in animal models or human trials. In vitro and in vivo studies have indicated that sarcosine, benzoate, and ketamine exert their anti-inflammatory effects by inhibiting microglial activity. This review summarizes and compares the efficacy of the possible therapeutic mechanisms of sarcosine, benzoate, ketamine, esketamine, and arketamine. These compounds act as both NMDAR modulators and anti-inflammatory drugs and thus can be effective in the treatment of depression.

Sarcosine (glycine transporter inhibitor) attenuates behavioural and biochemical changes induced by ketamine, in the rat model of schizophrenia.

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.

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.

Dimethylglycine sodium salt activates Nrf2/SIRT1/PGC1α leading to the recovery of muscle stem cell dysfunction in newborns with intrauterine growth restriction.

The objectives of this study were focused on the mechanism of mitochondrial dysfunction in skeletal muscle stem cells (MuSCs) from intrauterine growth restriction (IUGR) newborn piglets, and the relief of dimethylglycine sodium salt (DMG-Na) on MuSCs mitochondrial dysfunction by Nrf2/SIRT1/PGC1α network. In this study, six newborn piglets with normal birth weight (NBW) and six IUGR newborn piglets were slaughtered immediately after birth to obtain longissimus dorsi muscle (LM) samples. MuSCs were collected and divided into three groups: MuSCs from NBW newborn piglets (N), MuSCs from IUGR newborn piglets (I), and MuSCs from IUGR newborn piglets with 32 µmol DMG-Na (ID). Compared with the NBW group, the IUGR group showed decreased (P < 0.05) serum and LM antioxidant defense capacity, and increased (P < 0.05) serum and LM damage. Compared with the N group, the I group showed decreased (P < 0.05) MuSCs antioxidant defense capacity, mitochondrial ETC complexes, energy metabolites, and antioxidant defense-related and mitochondrial function-related gene and protein expression levels. The antioxidant defense capacity, mitochondrial ETC complexes, energy metabolites, and antioxidant defense-related and mitochondrial function-related gene and protein expression levels of MuSCs were improved (P < 0.05) in the ID group compared to those in the I group. The MuSCs of IUGR newborns activate the Nrf2/SIRT1/PGC1α network by taking in DMG-Na, thereby neutralizing excessive generated O2•- that may help to improve their unfavorable mitochondrial dysfunction in skeletal muscle.

Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.

Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N-methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action.

Structure-activity relationship study of amphipathic antimicrobial peptides using helix-destabilizing sarcosine.

Antimicrobial peptides (AMPs) are potential therapeutic agents against bacteria. We recently showed that a rationally designed AMP, termed Stripe, with an amphipathic distribution of native cationic and hydrophobic amino acids on its helical structure exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria with negligible hemolytic activity and cytotoxicity. In this study, the structure-activity relationship of Stripe was elucidated by designing a series of antimicrobial peptides whereby amino acid residues of Stripe were exchanged with helix-destabilizing sarcosine residues. Stripe 1-5 peptides with hydrophobic amino acids substituted with sarcosine were predominantly unstructured and showed no antimicrobial activity, except against Escherichia coli (E. coli) (DH5α) cells. The activity against E. coli (DH5α) cells and the helicity of Stripe 1-5 peptides decreased concomitantly as the number of sarcosine residue substitutions increased. Stripe 1-5 peptides showed no hemolytic activity or cytotoxicity. The results indicate that sarcosine substitutions provide an approach to study the structure-activity relationship of helical AMPs, and the helicity of Stripe is an important feature defining its activity.

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model.

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30-60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.

Sarcosine as an add-on treatment to antipsychotic medication for people with schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

Background: N-methyl-glycine (sarcosine) may improve symptoms of schizophrenia via NMDA-receptor modulation. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of sarcosine for schizophrenia.Research design and methods: The databases Medline, Scopus, EMBASE, Cochrane Library, and PsycINFO were searched. We included six independent randomized controlled trials of sarcosine as add-on treatment to current antipsychotic medication, involving 234 adult participants with schizophrenia, and reporting data on symptom severity. Standardized mean differences (SMDs) were used to assess continuous outcomes.Results: In all of the trials, sarcosine was administered orally at 2 g/day. Treatment with sarcosine did not show a significant effect size at any of the pre-established time points (2, 4, 6, or >6 weeks), due to marked quantitative heterogeneity. However, sarcosine was associated with significant reductions of symptom severity in the subgroups of people with chronic schizophrenia and no treatment resistance (namely, without added-on clozapine) in relation to the SMD after 6 weeks treatment at -0.36 and -0.31, respectively.Conclusions: People with chronic and non-refractory schizophrenia may benefit from the use of sarcosine as an add-on treatment to antipsychotic medication. Due to the good tolerability of this compound, future trials with larger sample sizes appear worthwhile.

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.

Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells.

Aberrant chromosome numbers in cancer cells may impose distinct constraints on the emergence of drug resistance-a major factor limiting the long-term efficacy of molecularly targeted therapeutics. However, for most anticancer drugs we lack analyses of drug-resistance mechanisms in cells with different karyotypes. Here, we focus on GSK923295, a mitotic kinesin CENP-E inhibitor that was evaluated in clinical trials as a cancer therapeutic. We performed unbiased selections to isolate inhibitor-resistant clones in diploid and near-haploid cancer cell lines. In diploid cells we identified single-point mutations that can suppress inhibitor binding. In contrast,transcriptome analyses revealed that the C-terminus of CENP-E was disrupted in GSK923295-resistant near-haploid cells. While chemical inhibition of CENP-E is toxic to near-haploid cells, knockout of the CENPE gene does not suppress haploid cell proliferation, suggesting that deletion of the CENP-E C-terminus can confer resistance to GSK923295. Together, these findings indicate that different chromosome copy numbers in cells can alter epistatic dependencies and lead to distinct modes of chemotype-specific resistance.

Efficacy and cognitive effect of sarcosine (N-methylglycine) in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials.

BACKGROUND: Sarcosine (N-methylglycine), a type 1 glycine transporter inhibitor (GlyT1), has shown therapeutic potential for treating schizophrenia; however, studies have reported conflicting results. This meta-analysis aimed to explore the efficacy and cognitive effect of sarcosine for schizophrenia. METHODS: In this study, PubMed, Cochrane Systematic Reviews, and Cochrane Collaboration Central Register of Controlled Clinical Trials were searched electronically for double-blinded randomised controlled trials that used sarcosine for treating schizophrenia. We used the published trials up to November 2019 to investigate the efficacy of sarcosine in schizophrenia. We pooled studies by using a random-effect model for comparing sarcosine treatment effects. Patients who were diagnosed with schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition were recruited. Clinical improvement and cognitive function scores between baseline and after sarcosine use were compared using the standardised mean difference (SMD) with 95% confidence intervals (CIs). The heterogeneity of the included trials was evaluated through visual inspection of funnel plots and through the I2 statistic. RESULTS: We identified seven trials with 326 participants with schizophrenia meeting the inclusion criteria. All these studies evaluated the overall clinical symptoms, and four of them evaluated overall cognitive functions. Sarcosine use achieved more significant effects than the use of its comparators in relieving overall clinical symptoms (SMD = 0.51, CI = 0.26-0.76, p < 0.01). Moreover, studies with the low Positive and Negative Syndrome Scale range of 70-79 showed significant effect size (ES)s of 0.67 (95% CI: 0.03-1.31, p = 0.04). In addition, trials enrolling patients with stable clinical symptoms had significant ESs: 0.53 (95% CI: 0.21-0.85, p < 0.01). Add-on sarcosine combined with first- and second-generation antipsychotics, except clozapine, had a positive effect. For overall cognitive functions, sarcosine showed a positive but insignificant effect compared with its comparators (SMD = 0.27, CI = -0.06 to 0.60, p = 0.10). The effects were correlated with increased female proportions and decreased illness duration, albeit nonsignificantly. CONCLUSIONS: The meta-analysis suggests that sarcosine may be associated with treatment effect on overall clinical symptoms in patients with schizophrenia but not cognitive functions.