Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.

BACKGROUND: Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease. METHODS: We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development. RESULTS: Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice. CONCLUSIONS: These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

Suicidality in Patients with Brain Tumors: A Brief Literature Review with Clinical Exemplar.

Background: Suicidality and brain tumors are two life-threatening conditions and, somewhat unexpectedly, the associations between them have scarcely been reported. Objective: In this study, we aimed to provide a brief literature review of epidemiological studies on suicidal ideation (SI) and suicidal behavior (SB) in patients with brain tumors. To illustrate various aspects of brain tumors that potentially underlie the emergence of suicidality, the review is supplemented with a clinical exemplar of a long-term survivor of brain tumor (glioblastoma) who experienced persistent SI. Furthermore, we discuss putative both neurobiological (including anatomical and immunological) and psychosocial mechanisms that might be accountable for the development of SI and SB in patients with brain tumors. Conclusions: While the etiology of this phenomenon appears to be multifactorial and still remains a subject of much debate, it is of critical importance to identify patients for which a psychiatric evaluation could recognize, in a timely manner, a possible suicide risk and alleviate the deep related suffering, by appropriate psychopharmacological and supportive and psychotherapeutic interventions.

In vitro and in vivo metabolite identification of a novel benzimidazole compound ZLN005 by liquid chromatography/tandem mass spectrometry.

RATIONALE: A novel benzimidazole compound ZLN005 was previously identified as a transcriptional activator of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in certain metabolic tissues. Upregulation of PGC-1α by ZLN005 has been shown to have a beneficial effect in a diabetic mouse model and in a coronary artery disease model in vitro. ZLN005 could also have therapeutic potential in neurodegenerative diseases involving down-regulation of PGC-1α. Given the phenotypic efficacy of ZLN005 in several animal models of human disease, its metabolic profile was investigated to guide the development of novel therapeutics using ZLN005 as the lead compound. METHODS: ZLN005 was incubated with both rat and human liver microsomes and S9 fractions to identify in vitro metabolites. Urine from rats dosed with ZLN005 was used to identify in vivo metabolites. Extracted metabolites were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using a hybrid linear ion trap triple quadrupole mass spectrometer in full scan, enhanced product ion scan, neutral loss scan and precursor scan modes. Metabolites in plasma and brain of ZLN005-treated rats were also profiled using multiple reaction monitoring. RESULTS: Identified in vitro transformations of ZLN005 include mono- and dihydroxylation, further oxidation to carboxylic acids, and mono-O-glucuronide and sulfate conjugation to hydroxy ZLN005 as well as glutathione conjugation. Identified in vivo metabolites are mainly glucuronide and sulfate conjugates of dihydroxyl, carboxyl, and hydroxy acid of the parent compound. The parent compound as well as several major phase I metabolites were found in rat plasma and brain. CONCLUSIONS: Using both in vitro and in vivo methods, we elucidated the metabolic pathway of ZLN005. Phase I metabolites with hydroxylation and carboxylation, as well as phase II metabolites with glucuronide, sulfate and glutathione conjugation, were identified.

The diagnostic performance of AFP and PIVKA-II models for non-B non-C hepatocellular carcinoma.

OBJECTIVE: This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC). RESULTS: A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.

Effects of non-surgical periodontal treatment in rheumatoid arthritis patients: A randomized clinical trial.

BACKGROUND: The periodontal condition has a reciprocal relationship with rheumatoid arthritis (RA). Rheumatoid arthritis patients are reported to present with more serious periodontal disease (PD) as compared to non-RA patients. OBJECTIVES: This study aimed to evaluate the effects of non-surgical periodontal treatment on Vietnamese patients with active RA and PD, where the clinical characteristics and serum indices of the patients were of interest. MATERIAL AND METHODS: We conducted a randomized clinical trial (RCT) on 82 RA patients with PD. The patients were randomly divided into 2 groups: the intervention group, consisting of patients who received oral hygiene instructions, scaling and root planing; and the control group, consisting of patients who received oral hygiene instructions only. Both groups received the same treatment plan for RA. The Disease Activity Score 28 based on C-reactive protein (DAS28-CRP), disease activity classification, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), anti-citrullinated protein autoantibodies (ACPAs), and C-reactive protein (CRP) were monitored, with the measurements taken at 3 months and 6 months following the treatment. RESULTS: The 2 groups exhibited similar parameters at baseline. In the intervention group, DAS28-CRP and disease activity classification were significantly reduced at 3 months after treatment as compared to the baseline data. At 6 months following the treatment there was a significant decrease in ESR, ACPAs and DAS28-CRP in the intervention group, while the control group showed a decrease only in ACPAs. Further, when comparing the intervention and control groups at 6 months following the treatment, there were no differences between the groups in the ACPAs, RF and CRP serum levels. CONCLUSIONS: Non-surgical periodontal treatment can significantly reduce DAS28-CRP, disease activity classification, ESR, and the ACPAs level in serum, and can be applied to reduce RA severity in RA patients with PD.

Chloroquine/Hydroxychloroquine Use and Suicide Risk: Hypotheses for Confluent Etiopathogenetic Mechanisms?

Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical anti-malarial and anti-inflammatory treatments, which were used as first-line therapy at the beginning of the 2019 coronavirus disease (COVID-19) pandemic. Besides the emerging data on their lack of efficacy against COVID-19 infection, such treatments have been associated with some severe health concerns, including those of neuropsychiatric nature, such as a possible increase in suicide risk. Here we report a case of a patient with no history of psychiatric illnesses, who abruptly developed depression with melancholic features, severe suicidal ideation (SI), and attempted suicide (SA) shortly after receiving HCQ for his COVID-19 infection. The case was followed by a mini-review of the heterogeneous scientific literature on the hypothetical association between neuropsychiatric symptoms, with a focus on SI and suicidal behavior (SB, including SA and death by suicide), when CQ and HCQ are used in COVID-19, rheumatologic diseases, and malaria settings. Considering the anti-inflammatory properties of CQ and HCQ and the implications for neuroinflammation in suicide pathogenesis, the possible increase in suicide risk caused by these medications appears paradoxical and suggests that other underlying pathological trajectories might account for this eventuality. In this regard, some of these latter mechanistic postulates were proposed. Certainly the role and contribution of psycho-social factors that a COVID-19 patient had to face can neither be minimized nor excluded in the attempt to understand his suffering until the development of SI/SB. However, while this case report represents a rare scenario in clinical practice and no consensus exists in the literature on this topic, a psychiatric screening for suicide risk in patients using of CQ and HCQ could be carefully considered.