Predictive value of oxidative stress biomarkers in drug-free patients with bipolar disorder.

OBJECTIVE: Oxidative stress is one of the primary etiological mechanisms of bipolar disorder (BD). METHODS: The present study was conducted over a period of 24 months on Tunisian on 34 drug­free male patients with BD (mean age: 34.5 years) and 101 age and gender matched controls (mean age: 34.20 years) were enrolled in the study. RESULTS: Plasma reduced glutathione (GSH) and total thiols levels were significantly decreased in patients compared to controls (respectively p < .001; p = .009). In addition, malondialdehyde (MDA), advanced oxidation protein products (AOPP), protein carbonyls (PC) and homocysteine (Hcys) concentrations and glutathione peroxidase (GSH-Px) activity were significantly increased in patients compared to controls (p = .002; p < .001; p = .001; p < .001 and p = .016, respectively). The binary logistic regression analysis revealed that MDA, AOPP and Hcys could be considered as independent risk factors for BD. When using CombiROC analysis, a remarkable increase in the area under the curve (AUC) with higher sensitivity (Se) and specificity (Sp) for MDA, AOPP, PC, GSH-Px and Hcys combined markers was observed. CONCLUSIONS: Overall, the identification of the predictive value of these five selected biomarkers related to oxidative stress in drug free patients should lead to a better identification of the etiological mechanism of BD.

Homozygous pArg610del Mutation Unusually Associated With Severe Delay of Growth in 2 Acid Sphingomyelinase Deficiency-affected Sibs.

BACKGROUND: Typically, patients with Acid Sphingomyelinase Deficiency (ASMD) because of p.Arg610del mutation, have mild phenotype with normal linear growth. OBSERVATION: We reported the case of 2 Tunisian brothers who have been referred for splenomegaly, polyadenopathies, pubertal, and growth delay. Molecular testing of SMPD1 gene revealed the presence of a homozygous p.Arg610del mutation. Lysosphingomyelin and its isoform-509 were both increased confirming ASMD for both cases. Growth hormone deficiency was highly suspected but growth hormone response after stimulating tests was acceptable for both patients. CONCLUSIONS: There is no correlation between phenotype-genotype in case of p.Arg610del mutation that could be associated to a severe delay of growth.

[Bipolar disorder vulnerability: The vitamin D path]. / Vulnérabilité au Trouble Bipolaire: La Piste de la Vitamine D.

OBJECTIVES: Bipolar disorder (BD) etiopathogenesis is still not well elucidated. It has recently been proven that 25-hydroxy vitamin D (25OHD) has an anti-inflammatory and neuroprotective role. Our objectives were to measure 25OHD plasma levels in patients with BD in acute decompensation and compare them with patients with schizophrenia (SCZ) or schizoaffective disorder (SAD) and with healthy controls. METHODS: This is a cross-sectional case-control study including male inpatients with a decompensation of their disease who were diagnosed with BD, SCZ or SAD according to DSM-5 criterias. The control group was constituted by unrelated healthy subjects, age-and-sex matched. RESULTS: The 25OHD level was significantly higher only in patients with BD compared to controls. 25OHD was also positively correlated to the PANSS scale (r = 0.282, p < 0.001) and to different MOCA scores (r = 0.326, p = 0.006) as well as aspects related to abstraction, attention and memory capacity. Multivariate analysis found that BD acute decompensation was independently related to the rise in plasma 25OHD (p = 0.012; OR =1.157, [1.032 -1.297]). CONCLUSION: Our study shows that BD acute decompensation is associated with the rise in plasma 25OHD synthesis. However, the vitamin D dosage relevance as a biomarker of this disease warrants a verification in other studies.

OBJECTIFS: L'étiopathogénie du trouble bipolaire (TB) demeure non encore bien élucidée. Récemment, il a été prouvé que la 25-hydroxy-vitamine D(25OHD) a un rôle anti-inflammatoire et neuroprotecteur. Nos objectifs étaient de mesurer les concentrations plasmatiques de la 25OHD chez des patients atteints de TB en décompensation aigue et de les comparer à celles de patients souffrant de schizophrénie (SCZ) ou de trouble schizo-affectif (TSA) et à celles de témoins sains. MÉTHODES: Il s'agissait d'une étude transversale de type cas-témoins qui a inclus des patients de sexe masculin hospitalisés pour une décompensation de leur maladie et chez qui les diagnostics de TB, SCZ, ou de TSA ont été retenus selon les critères du (DSM-5). Le groupe témoin a été constitué de sujets sains non apparentés, appariés selon l'age et le sexe. RÉSULTATS: La concentration de la 25OHD était significativement plus élevée uniquement chez les patients atteints de TB par rapport aux témoins. la 25OHD était aussi corrélée positivement à l'échelle PANSS (r = 0.282, p < 0.001) et aux différents scores de l'échelle MOCA (r = 0.326, p = 0.006) ainsi qu'aux dimensions concernant la capacité d'abstraction, d'attention et la mémoire . A l'analyse multivariée, la décompensation aigue du TB était liée de manière indépendante à l'élévation de la 25OHD plasmatique (p = 0.012; OR = 1.157, [1.032 -1.297]). CONCLUSION: Notre étude a montré que la décompensation aigue des TB était associée à une élévation de la synthèse de la 25OHD plasmatique. Toutefois, la pertinence du dosage de la vitamine D comme biomarqueur de cette maladie mérite d'être vérifiée par d'autres études.

Cardiotoxicity and myocardial infarction-associated DNA damage induced by thiamethoxam in vitro and in vivo: Protective role of Trigonella foenum-graecum seed-derived polysaccharide.

The risk of pesticides on the human health and environment has drawn increasing attention. Today, new tools are developed to reduce pesticide adverse effects. This study aimed to evaluate the toxicity induced by, thiamethoxam (TMX), and the cytoprotective effect of a novel polysaccharide, named fenugreek seed water polysaccharide (FWEP) in vitro using H9c2 cardiomyoblastes and in vivo using Wistar rat model. Animals were assigned into four groups per eight rats each: group 1 served as a control group, group 2 received TMX, group 3, and group 4 received both FWEP and TMX tested at two doses (100 and 200 mg/kg, respectively). Regarding the in vitro study, our results demonstrated that TMX induced a decrease in H9c2 cell viability up to 70% with the highest concentration. In vivo, TMX injection induced marked heart damage noted by a significant increase in plasma lactate dehydrogenase, creatine phosphokinase, troponin-T, aspartate amino transferase activities, cholesterol, and triglyceride levels. Concomitant alterations in cardiac antioxidant defense system revealed depletion in the levels of glutathione and non-protein thiol and an increase in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, a significant increase in heart lipid, malondialdehyde, advanced oxidation protein product and in protein carbonyls levels was also noted. In addition, heart tissues histo-architecture displayed major presence of apoptosis and necrosis as confirmed by DNA degradation. However, supplementation with FWEP alleviated heart oxidative damage and genotoxicity. In this manner, ABTS radical-scavenging activity, linoleic acid oxidation tests and heart genomic and DNA nicking assay had proved FWEP strong antioxidant potential. In conclusion, FWEP provided significant protection against TMX-induced heart injury, and could be a useful and efficient agent against cardiotoxicity and atherosclerosis.

Therapeutic potential of polysaccharide extracted from fenugreek seeds against thiamethoxam-induced hepatotoxicity and genotoxicity in Wistar adult rats.

This study aimed to evaluate the protective effect of a polysaccharide extracted from fenugreek seeds (Trigonella foenum-graecum) (FWEP) against insecticide-thiamethoxam (TMX)-induced hepatotoxicity. Obtained data exhibited potent antioxidant and antibacterial potentialities. On other trend, in vivo, adult female rats were divided into four groups: controls; TMX (100 mg/kg of body weight); TMX + FWEP at two graded doses, respectively (100 and 200 mg/kg of body weight) for 30 d. Up to TMX treatment, our data showed a significant increase in plasma markers of hepatotoxicity including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and in lactate dehydrogenase (LDH) activities, which is coordinated with decline in total protein and albumin levels. Remarkably, a clear sign of genotoxicity was delivered by total disruption in hematological parameters and micronucleus (MN) test shown by severe chromatin degradation. These data were also associated with oxidative stress set up, histological and DNA injuries. However, co-administration with FWEP succeeded significantly in a dose-dependent manner in reducing and healing liver's hematological and genotoxic induced by TMX injuries.

Nephrotoxicity of Kalach 360 SL: biochemical and histopathological findings.

Kalach 360 SL (KL) is a commercial herbicide which contains 360 g/l of glyphosate used in both agricultural and urban areas throughout the world including Tunisia. We aimed to evaluate the effects of KL on rats' renal system. Female Wistar rats were divided into three groups: group 1 (n = 6) received a standard diet and served as control, groups 2 and 3 (n = 12 each) received 0.07 ml (D1: 126 mg/kg), and 0.175 ml (D2: 315 mg/kg) of KL, respectively, for 60 d. The chronic exposure to KL induced a significant increase in plasma creatinine, urea, and uric acid levels. Creatinine clearance decreased in KL-treated groups, compared with controls. Several urine parameters, such as urine-specific gravity and urine osmolality, significantly decreased, while dieresis and urinary Na/K + ratio increased in KL-treated groups. These findings suggested a distal tubular damage caused by tubular necrosis. Moreover, the chronic exposure to KL induced an increase in lipid peroxidation (LPO) and a decrease in antioxidant status, enzymatic activities (superoxide dismutase and catalase) and non-enzymatic levels (vitamin C), which led to an oxidative stress. Histopathological studies showed a peritubular inflammatory reaction, nephrose, fragmented glomeruli, necrotic epithelial cells, and tubular dilatation. These results could have significant health implications for animal and human populations. Further data are necessary to investigate the potential consequences of chronic dose exposure during life.

Protective effect of Dunaliella sp., lipid extract rich in polyunsaturated fatty acids, on hepatic and renal toxicity induced by nickel in rats.

AIMS: The present study was undertaken to investigate the protective effect of lipid extract of Dunaliella sp. (LE) rich in polyunsaturated fatty acids (PUFA), against oxidative stress induced by nickel in experimental rats. METHODS: Our investigation evaluated the antioxidant activity of LE using both DPPH and NBT assays. Twenty female albino Wistar rats, randomly allocated into four experimental groups, namely (C): control, (Nit): nickel-treated rats with 5 mg/kg/d of NiCl2 during 30 days, (LEa): lipid extract-administered rats with 5 mg/kg BW/d during 30 days and (Nit + LEa): rats treated with Ni and LE-administered during 30 days. RESULTS: The in vitro antioxidant activity demonstrated that LE presents an important antioxidant potential. In vivo, the (Nit + LEa) cotreatment decreased the level of malondialdehyde and restored the antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase) in livers and kidneys in comparison with those treated with Ni only. LE administration to rats treated with Ni also ameliorated biochemical and histological parameters as compared to only Ni-treated group. LE of Dunaliella sp., rich in polyunsaturated fatty acids showed a significant hepato- and reno-protective effect against metal-induced toxicity. CONCLUSION: LE of Dunaliella sp., rich in PUFA has been proven to be effective in protection against Ni-induced toxicity.

Vitamin D deficiency in relation with the systemic and central inflammation during multiple sclerosis.

Background: During the last decade, vitamin D (VitD) has become a topic of interest in immune regulation, especially in multiple sclerosis (MS) disease. Amongst the wide range of effects reported for this vitamin on the immune system, a regulatory role on cytokines production has been described. Our aim is to analyze the status of VitD and its correlation with the circulating inflammation and the intrathecal humoral response during MS. Methods: We analyzed samples of 318 individuals: 108 MS patients and 210 controls. Determination of 25-(OH) VitD3 level in serum was made using electrochemiluminescence method. Circulating inflammatory cytokines (IL-6, IL-8, IL-10, TNF-a, IL12p70 and IL-1b) were investigated using Cytometer Bead Array Technology. The central humoral response was characterized using CSF isofocusing test and IgG Index calculation. Results: As expected, mean value of VitD was significantly lower in MS group (26 nmol/L) than in control group (34.75 nmol/L) (p=0.002), with a severe deficiency in 67% of MS patients. Mean value of VitD was significantly lower in MS female patients. Regarding cytokines, mean value of TNFa was significantly higher in MS patients with oligoclonal bands of IgG in the CSF. IL6 was positively correlated with IgG level in serum of MS patients. Conclusions: Our results support the association of VitD deficiency with MS, especially in female patients of our region. However, the vitamin level seems to not correlate with inflammatory cytokines nor with disability. Interestingly, TNFa and IL6 levels were correlated with the intrathecal synthesis of IgG and the circulating IgG level, respectively.

Plasma oxysterols in drug-free patients with schizophrenia.

Evidence from clinical, genetic, and medical studies has shown the neuronal developmental disorder aspect of schizophrenia (SZ). Whereas oxysterols are vital factors in neurodevelopment, it is still unknown whether they are involved in the pathophysiology of SZ. The current study aims to explore the profile of oxysterols in plasma, ratio to total cholesterol (Tchol) and the association with clinical factors in patients with SZ. Forty men diagnosed with SZ and forty healthy controls matched for age and sex were included in the study. The ratios of cholestane-3ß,5α,6ß-triol, 27-hydroxycholesterol (27-OHC) and Cholestanol to Tchol increased in the schizophrenic group compared to controls. However, levels of 24S-hydroxycholesterol (24-OHC) were not significantly different between patients and controls. For the SZ patients, the plasma 24-OHC levels were positively correlated with the positive and negative syndrome total scores (PANSS) but negatively correlated with the Montreal Cognitive Assessment scores (MOCA). Moreover, the ratio Cholestanol to Tchol was negatively correlated with MOCA scores and positively correlated with PANSS general. The binary logistic regression analysis revealed that the ratio Cholestane-3ß,5α,6ß-triol/TChol could be considered as an independent risk factor for SZ. On the other hand, the receiver's operating characteristics analysis corresponding to potential biomarkers on SZ showed Areas Under the Curve (AUCs) of 82.1%; 69.7% and 77.6% for the ratio of Cholestane-3ß,5α,6ß-triol/TChol, 27-OHC/TChol and Cholestanol/TChol respectively. The relevance of Cholestane-3ß,5α,6ß-triol, 27-OHC and Cholestanol assays as biomarkers of this disease deserves further investigation.

Plasma oxysterols: Altered level of plasma 24-hydroxycholesterol in patients with bipolar disorder.

Cholesterol and its oxygenated metabolites, including oxysterols, are intensively investigated as potential players in the pathophysiology of brain disorders. Altered oxysterol levels have been described in patients with numerous neuropsychiatric disorders. Recent studies have shown that Bipolar disorder (BD) is associated with the disruption of cholesterol metabolism. The present study was aimed at investigating the profile of oxysterols in plasma, their ratio to total cholesterol and their association with clinical parameters in patients with BD. Thirty three men diagnosed with BD and forty healthy controls matched for age and sex were included in the study. Oxysterol levels were measured by isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry. Significantly higher levels were observed for cholestane-3ß,5α,6ß-triol, 27-hydroxycholesterol (27-OHC) and Cholestanol in patients with BD. The concentration of 24-hydroxycholesterol (24-OHC) was significantly lower in patients compared to controls. 24-OHC was also negatively correlated to MAS subscale score (r =-0.343; p = 0.049). In patients, 24-OHC was inversely correlated with age (r = -0.240; p = 0.045). Multivariate analysis found that BD acute decompensation was independently related to the rise in plasma 24-OHC (p = 0.002; OR = 0.966, 95 % CI [0.945 - 0.987]). However, the 24-OHC assay relevance as a biomarker of this disease deserves further investigation in other studies.

Flavonoid-rich fraction attenuates permethrin-induced toxicity by modulating ROS-mediated hepatic oxidative stress and mitochondrial dysfunction ex vivo and in vivo in rat.

The present study explores the antioxidant, anti-microbial, and hepatoprotective potentials of flavonoid-rich fractions from Fumaria officinalis against permethrin-induced liver damage ex vivo/in vivo in rat. However, HPLC-DAD analysis revealed the richness of 6 components in ethyl acetate fraction (EAF) where ferulic acid, rosmarinic acid, and myricetin are the most abundant. The in vitro assays showed that EAFs have impressive antioxidant and anti-microbial properties. Ex vivo, permethrin (PER) (100 µM) induced a decrease of hepatic AST and ALT activities and 25-OH vitamin D and vitamin C levels and an increase of ALP and LDH activities, TBARS, and ϒ-GT levels with a disturbance of oxidative status. The hepatoprotective effect of EAF (1 mg/mL) against PER was confirmed by the amelioration of oxidative stress profile. In vivo, permethrin was found to increase absolute and relative liver weights, plasma transaminase activities, lactate-to-pyruvate ratio, hepatic and mitochondrial lipid peroxidation, and protein oxidation levels. This pesticide triggered a decrease of Ca2+ and Mg2+-ATPases and mitochondrial enzyme activities. The co-treatment with EAF reestablished the hepatic and mitochondrial function, which could be attributed to its richness in phenolic compounds.

Predictive value of oxidative stress biomarkers in drug­free patients with schizophrenia and schizo-affective disorder.

Several studies have suggested that oxidative stress may represent one of the primary etiological mechanisms of schizophrenia (SZ) and schizoaffective disorder (SAD) which can be targeted by therapeutic intervention. The present study was conducted over a period of 24 months, between June 2016 and June 2018. All enrolled subjects were Tunisian, forty five drug­free male patients with SZ (mean age: 37.6 years), twenty one drug­free male patients with SAD (mean age: 28.8 years) and hundred and one age and gender matched controls (mean age: 34.2 years) were enrolled in the study. Plasma reduced glutathione (GSH) and Total thiols levels were significantly decreased in patients compared to controls (respectively p<0.001; p=0.050). In addition, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and protein carbonyls (PC) concentrations and glutathione peroxidase (GSH-Px) activity were significantly increased in patients compared to controls (p<0.001; p<0.001; p<0.001 and p=0.003 respectively). The binary logistic regression analysis revealed that MDA, AOPP, PC and GSH-Px could be considered as independent risk factors for SZ and SAD. When using ROC analysis, a remarkable increase in the area under the curve (AUC) with higher sensitivity (Se) and specificity (Sp) for MDA, AOPP, PC and GSH-Px combined markers was observed. The present study indicated that the identification of the predictive value of this four-selected biomarkers related to oxidative stress in drug free patients should lead to a better identification of the etiological mechanism of SZ or SAD.

Sub-chronic exposure to Kalach 360 SL-induced damage in rats' liver and hematological system.

We investigated the effects of sub-chronic exposure to Kalach 360 SL (KL), glyphosate-based herbicide used in Tunisia, on liver and hematological system in different groups of female rats. Group 1 was used as a control, while animals of groups 2 and 3 received orally 0.07 mL and 0.175 mL of KL, respectively (126 and 315 mg of glyphosate/kg), for 60 days. As a result, the KL-exposed groups exhibited hypochromic microcytic anemia, systemic inflammation, cytolysis, decrease in hepatic enzyme activity, and cholestasis. Exposure to different doses of KL could induce erythrocyte destruction (hemolysis) in hematopoietic organs (bones). Moreover, lipid peroxidation contents and protein oxidation markers significantly increased in exposed groups, while enzymatic and non-enzymatic antioxidant activities decreased considerably, in both erythrocytes and liver tissues, compared with those in controls. Liver histological studies confirmed the presence of inflammatory reaction with pathology involving the damage or necrosis of hepatocytes, however, without fibrosis remodulation. Thus, KL sub-chronic exposure caused hepatonecrosis, systemic inflammation, and hemolysis.

Antihyperlipidemic and antioxidant effects of feather protein hydrolysate in high-fat diet-fed mice.

The hyperlipidemia is a serious health problem that increases the risk of many complications including cardiovascular disease. This study aims to evaluate the possible antihyperlipidemic effects of the feather protein hydrolysate (FPH) in a mice fed with a high-fat diet (HFD)-fed mice during 5 weeks. The FPH administration improved dose-dependent lipid profile, as well as the liver and renal dysfunction indices in hyperlipidemic mice. The FPH also restored the antioxidant status in liver, kidney, and heart by lowering the lipid peroxidation and enhancing the antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase [SOD]). Moreover, the histological studies proved that FPH administration prevents hepatic steatosis, glomerular hyperfiltration risk, and cardiac muscle hypertrophy. Accordingly, the FPH is a promising novel medicinal ingredient for possible use in the hyperlipidemic treatment and related complications.

Subchronic exposure to kalach 360 SL-induced endocrine disruption and ovary damage in female rats.

Kalach 360 SL (KL), glyphosate (G) surfactant-based herbicides, is a systemic herbicide effective against weeds. It was applied in agriculture in Tunisia and throughout the world, which can represent a risk to non-target organisms. The aim of this study was to investigate the morphological and biochemical aspects of ovary injury after exposure to KL. Female Wistar rats were divided into three groups: group 1 was used as a control; group 2 orally received 0.07 ml of KL, (126 mg of G/kg) and group 3 orally received 0.175 ml of KL (315 mg of G/kg) each day for 60 days. The subchronic exposure of KL induces impaired folliculogenesis, ovary development, decreased oestrogen secretion, promoted oxidative stress and impairments of ovary histological aspects. Histological finding shows necrosis cell, vacuolisation of follicles, dissociated oocytes and granulosa cell, associated with several atretic follicles. We conclude that KL induces endocrine disruption and ovary damage in female rats.

Plasma Saturated and Monounsaturated Fatty Acids in Behçet's Disease.

BACKGROUND: Fatty Acid (FA) composition of serum has been associated with many markers of inflammation. In this study, we tried to examine plasma Saturated Fatty Acid (SFA) and Monounsaturated Fatty Acid (MUFA) composition in Behçet's Disease (BD) patients. The associations between the circulating FA levels and some markers of inflammation have also been investigated. METHODS: This study is a cross-sectional one. In fact, a total of 101 BD patients and healthy controls group of 99 subjects are enrolled. Gas Chromatograph equipped with a Capillary Split/Splitless Injector and flame ionization detector was used to analyze the plasma SFA and MUFA compositions. The high sensitivity C-Reactive Protein (hsCRP) and fibrinogen levels were measured using standard techniques. RESULTS: BD patients had significantly higher proportions of Mystiric Acid (MA), Palmitic Acid (PAM), Palmitoleic Acid (POA) and Stearoyl-CoA Desaturase (SCD)-16, compared to controls.The results revealed that patients with severe involvements had high levels of POA and total MUFA associated with higher SCD-16 activity compared to those with minor ones. The receiver operator characteristic curve analysis revealed that POA could well discriminate BD patients with severe clinical manifestations. In the bivariate analysis, hsCRP was found to be positively correlated with total SAFA and POA elongase activity index but negatively correlated with SCD-18 activity index. The STA, POA, elongase and SCD-16 activity index are correlated with fibrinogen. On the other hand, the multivariate analysis showed that POA remained associated with higher levels of hsCRP. CONCLUSION: Unfavourable plasma SFA and MUFA profile were reported in BD patients. POA, which is associated with higher plasma hsCRP level, may play a role in the pathogenesis of BD.

[Impact of androgen therapy on metabolic and inflammatory profiles in male hypogonadism]. / Impact de l'androgénothérapie sur les profils métabolique et inflammatoire chez l'homme hypogonadique.

This study aims to evaluate the impact of androgen therapy on metabolic and inflammatoy profiles in male hypogonadic patients. Forty cases with isolated hypogonadism and 80 controls were enrolled. Clinical data were collected (age, weight, height, waist circonference and androgenothearapy). Blood tests were performed to evaluate testosterone, homeostasis index modal assessment (HOMA-IR), lipids and C reactive protein (CRP). Among hypogonadic patients, 14 of them were treated for 4 +/- 3.4 years. Amongst them testosterone levels were significantly elevated comparatively to non-treated patients and significantly lower than controls. Significant differences were noted on waist circumference between non treated patients and controls. Body mass index and HOMA-IR were significantly higher in non-treated patients. Triglycerides and HDLc were significantly decreased respectively in treated and non-treated patients. However, CRP levels were significantly decreased in controls. In conclusion, androgen therapy appeared to protect against obesity, insulin resistance, and hyperlipidemia. Effects on systemic inflammation seemed to be more discrete. Testosterone substitution should be strongly indicated in daily practice with careful prostate monitoring.