Efficacy and safety of basal insulin degludec 100 IU/mL versus glargine 300 IU/mL for type 1 diabetes: The single-center INEOX randomized controlled trial.

AIMS: To compare efficacy and safety of degludec 100 IU/mL (Deg-100) and glargine 300 IU/mL (Gla-300) in adults with type 1 diabetes. METHODS: Open-label, single-center, randomized, parallel-group, 24-week trial in adults with type 1 diabetes, on basal-bolus insulin therapy, HbA1c ≤ 10%, using self-monitoring blood glucose. Participants were randomized 1:1 to a basal-bolus insulin regimen with Deg-100 (N = 129) or Gla-300 (N = 131). Primary efficacy endpoint: mean change in HbA1c from baseline to week-24. Main safety outcome: incidence rate of hypoglycemia during the study. Quality of life (DQOL) and satisfaction with diabetes treatment (DTSQ) were assessed. RESULTS: At week 24, after adjusting for baseline HbA1c, the decrease in HbA1c did not differ between groups: Deg-100 (-0.07 ± 0.7%) and Gla-300 (-0.16 ± 0.77%) (P = 0.320). There were no significant differences between groups in HbA1c, nocturnal hypoglycemia, severe hypoglycemia, DQOL, or DTSQ scores. The incidence rates of hypoglycemia < 3.9 mmol/L (Deg-100: 115.24 events/person-year vs Gla-300: 99.01 events/person-year, p < 0.001); and < 3.0 mmol/L (Deg-100: 41.17 events/person-year vs Gla-300: 34.29 events/person-year, p < 0.001) were different between groups. CONCLUSIONS: Deg-100 and Gla-300 have similar metabolic efficacy, incidence ratio of nocturnal and severe hypoglycemia, DQOL and DTSQ scores. Differences in the incidence rate of hypoglycemia < 3.9 mmol/L and < 3.0 mmol/L should be confirmed.

Acute Lung Injury Biomarkers in the Prediction of COVID-19 Severity: Total Thiol, Ferritin and Lactate Dehydrogenase.

SARS-CoV-2 (COVID-19) patients who develop acute respiratory distress syndrome (ARDS) can suffer acute lung injury, or even death. Early identification of severe disease is essential in order to control COVID-19 and improve prognosis. Oxidative stress (OS) appears to play an important role in COVID-19 pathogenesis; we therefore conceived a study of the potential discriminative ability of serum biomarkers in patients with ARDS and those with mild to moderate disease (non-ARDS). 60 subjects were enrolled in a single-centre, prospective cohort study of consecutively admitted patients: 29 ARDS/31 non-ARDS. Blood samples were drawn and marker levels analysed by spectrophotometry and immunoassay techniques. C-reactive protein (CRP), lactate dehydrogenase (LDH), and ferritin were significantly higher in ARDS versus non-ARDS cases at hospital admission. Leukocytes, LDH, ferritin, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) were also significantly elevated in ARDS compared to non-ARDS patients during the hospital stay. Total thiol (TT) was found to be significantly lower in ARDS. Conversely, D-dimer, matrix metalloproteinase-9 (MMP-9) and advanced glycosylated end products (AGE) were elevated. Leukocytes, LDH, CRP, ferritin and IL-6 were found to be significantly higher in non-survivors. However, lymphocyte, tumour necrosis factor beta (TGF-ß), and TT were lower. In summary, our results support the potential value of TT, ferritin and LDH as prognostic biomarkers for ARDS development in COVID-19 patients, distinguishing non-ARDS from ARDS (AUCs = 0.92; 0.91; 0.89) in a fast and cost-effective manner. These oxidative/inflammatory parameters appear to play an important role in COVID-19 monitoring and can be used in the clinical management of patients.

Insulin-like growth factor II prevents oxidative and neuronal damage in cellular and mice models of Parkinson's disease.

Oxidative distress and mitochondrial dysfunction, are key factors involved in the pathophysiology of Parkinson's disease (PD). The pleiotropic hormone insulin-like growth factor II (IGF-II) has shown neuroprotective and antioxidant effects in some neurodegenerative diseases. In this work, we demonstrate the protective effect of IGF-II against the damage induced by 1-methyl-4-phenylpyridinium (MPP+) in neuronal dopaminergic cell cultures and a mouse model of progressive PD. In the neuronal model, IGF-II counteracts the oxidative distress produced by MPP + protecting dopaminergic neurons. Improved mitochondrial function, increased nuclear factor (erythroid-derived 2)-like2 (NRF2) nuclear translocation along with NRF2-dependent upregulation of antioxidative enzymes, and modulation of mammalian target of rapamycin (mTOR) signalling pathway were identified as mechanisms leading to neuroprotection and the survival of dopaminergic cells. The neuroprotective effect of IGF-II against MPP + -neurotoxicity on dopaminergic neurons depends on the specific IGF-II receptor (IGF-IIr). In the mouse model, IGF-II prevents behavioural dysfunction and dopaminergic nigrostriatal pathway degeneration and mitigates neuroinflammation induced by MPP+. Our work demonstrates that hampering oxidative stress and normalising mitochondrial function through the interaction of IGF-II with its specific IGF-IIr are neuroprotective in both neuronal and mouse models. Thus, the modulation of the IGF-II/IGF-IIr signalling pathway may be a useful therapeutic approach for the prevention and treatment of PD.

Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids.

Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.

Obesity-dependent cannabinoid modulation of proliferation in adult neurogenic regions.

Endocannabinoid signalling participates in the control of neurogenesis, especially after brain insults. Obesity may explain alterations in physiology affecting neurogenesis, although it is unclear whether cannabinoid signalling may modulate neural proliferation in obese animals. Here we analyse the impact of obesity by using two approaches, a high-fat diet (HFD, 60% fat) and a standard/low-fat diet (STD, 10% fat), and the response to a subchronic treatment with the cannabinoid receptor type 1 (CB1) inverse agonist AM251 (3 mg/kg) on cell proliferation of two relevant neurogenic regions, namely the subventricular zone in the striatal wall of the lateral ventricle (SVZ) and the subgranular zone of the dentate gyrus (SGZ), and also in the hypothalamus given its role in energy metabolism. We found evidence of an interaction between diet-induced obesity and CB1 signalling in the regulation of cell proliferation. AM251 reduced caloric intake and body weight in obese rats, as well as corrected plasma levels of cholesterol and triglycerides. AM251 is shown, for the first time, to modulate cell proliferation in HFD-obese rats only. We observed an increase in the number of 5-bromo-2-deoxyuridine-labelled (BrdU+) cells in the SGZ, but a decrease in the number of BrdU+ cells in the SVZ and the hypothalamus of AM251-treated HFD rats. These BrdU+ cells expressed the neuron-specific ßIII-tubulin. These results suggest that obesity may impact cell proliferation in the brain selectively, and provide support for a role of CB1 signalling regulation of neurogenesis in response to obesity.

Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndrome.

Fragile X syndrome is the most common form of inherited mental retardation. It is typically caused by a mutation of the Fragile X mental-retardation 1 (Fmr1) gene. To better understand the role of the Fmr1 gene and its gene product, the fragile X mental-retardation protein in central nervous system functions, an fmr1 knockout mouse that is deficient in the fragile X mental-retardation protein was bred. In the present study, fragile X mental retardation 1-knockout and wild-type mice are used to determine behaviour and oxidative stress alterations, including reduced glutathione, oxidized glutathione and thiobarbituric acid-reactive substances, before and after chronic treatment with melatonin or tianeptine. Reduced glutathione levels were reduced in the brain of fmr1-knockout mice and chronic melatonin treatment normalized the glutathione levels compared with the control group. Lipid peroxidation was elevated in brain and testes of fmr1-knockout mice and chronic melatonin treatment prevents lipid peroxidation in both tissues. Interestingly, chronic treatment with melatonin alleviated the altered parameters in the fmr1-knockout mice, including abnormal context-dependent exploratory and anxiety behaviours and learning abnormalities. Chronic treatment with tianeptine (a serotonin reuptake enhancer) did not normalize the behaviour in fmr1-knockout mice. The prevention of oxidative stress in the fragile X mouse model, by an antioxidant compound such as melatonin, emerges as a new and promising approach for further investigation on treatment trials for the disease.

Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmr1 deficiency.

Fragile X syndrome is the most common genetic cause of mental disability. The mechanisms underlying the pathogenesis remain unclear and specific treatments are still under development. Previous studies have proposed an abnormal hypothalamic-pituitary-adrenal axis and high cortisol levels are demonstrated in the fragile X patients. Additionally, we have previously described that NADPH-oxidase activation leads to oxidative stress in the brain, representing a pathological mechanism in the fragile X mouse model. Fmr1-knockout mice develop an altered free radical production, abnormal glutathione homeostasis, high lipid and protein oxidation, accompanied by stress-dependent behavioral abnormalities and pathological changes in the first months of postnatal life. Chronic pharmacological treatment with alpha-tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and alpha-PKC activation, macroorchidism, and also behavior and learning deficits. The restoration of the oxidative status in the fragile X mouse emerges as a new and promising approach for further therapeutic research in fragile X syndrome.

Enhanced markers of oxidative stress, altered antioxidants and NADPH-oxidase activation in brains from Fragile X mental retardation 1-deficient mice, a pathological model for Fragile X syndrome.

Fragile X syndrome is the most common form of inherited mental retardation in humans. It originates from the loss of expression of the Fragile X mental retardation 1 (FMR1) gene, which results in the absence of the Fragile X mental retardation protein. However, the biochemical mechanisms involved in the pathological phenotype are mostly unknown. The availability of the FMR1-knockout mouse model offers an excellent model system in which to study the biochemical alterations related to brain abnormalities in the syndrome. We show for the first time that brains from Fmr1-knockout mice, a validated model for the syndrome, display higher levels of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activation, lipid peroxidation and protein oxidation than brains from wild-type mice. Furthermore, the antioxidant system is deficient in Fmr1-knockout mice, as shown by altered levels of components of the glutathione system. FMR1-knockout mice lacking Fragile X mental retardation protein were compared with congenic FVB129 wild-type controls. Our results support the hypothesis that the lack of Fragile X mental retardation protein function leads to a moderate increase of the oxidative stress status in the brain that may contribute to the pathophysiology of the Fragile X syndrome.