Familial Mediterranean Fever in Algeria - A Retrospective of Three Molecular Studies

Background: Familial Mediterranean fever (FMF, OMIM 249100) is an autosomal recessive disease characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis can complicate FMF. MEFV is the gene responsible for FMF and is involved in the regulation of inflammation. Although FMF is endemic in the Mediterranean region, its diagnosis is very recent in Algeria. We present here a retrospective of three genetic studies carried out on the Algerian patients. Methods: 183 unrelated patients with symptoms suggestive of FMF were recruited from various hospitals between 2007 and 2015. Molecular studies included three cohorts of patients: 71 (35 males, 36 females), 84 (42 males, 42 females), and 28 (15 males, 13 females) with renal AA-amyloidosis. We searched for mutations in exon 10 of the MEFV gene by allele-specific PCR (p.M694V, p.M694I, p.M680I and p.A744S) and by resequencing the entire coding region of the same exon after PCR amplification. Results: Molecular analysis identified 152 mutant alleles among 94/183 patients (51.36%). p.M694I was the most predominant mutation accounting for 63.2% of mutated alleles, followed by p.M694V (15.13%), p.M680I (13.81%), p.I692del (1.32%) and p.K695R (0.66%). More importantly, the M694I/M694I genotype was the most prevalent among the patients with AA-amyloidosis than the M694V/M694V genotype. Conclusion: Our results provide the first genetic data concerning FMF in Algeria. They show that p.M694I mutation could be responsible for the severe phenotype for Algerian FMF patients

Genotyping of MEFV and SAA1 Genes and Their Correlation to the AA-Amyloidosis Development

Background: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease caused by recessive mutations in the MEFV gene. If not treated, FMF patients may develop renal AA-amyloidosis that leads to renal failure and death. Both mutations and polymorphisms in MEFV and SAA1 genes, respectively, have been associated with AA-amyloidosis in several populations. In Algeria, as FMF is still under-estimate and misdiagnosed, genetic data on renal complication are largely lacking. We thus explored the contribution of MEFV and SAA1 loci in the development of amyloidosis in Algerian patients with FMF.  Methods: This study included 64 unrelated FMF patients (21 without and 43 with renal amyloidosis) and 13 healthy controls. The entire exon 10 was sequenced after PCR amplification to detect MEFV mutations. Genotypes of SAA1 locus (SAA1.1, SAA1.5, and SAA1.3) were determined by PCR-RFLP (restriction fragment length polymorphism). Results: Analyze of MEFV gene showed that the percentage of homozygous for p.M694I mutation was significantly higher in patients with amyloidosis compared to patients without amyloidosis (p=0.032). The SAA1.1/1.1 genotype was significantly predominant in patients with amyloidosis compared to those without AA-amyloidosis (p=0.001) and controls (0.001). The SAA1.5/1.5 genotype was identified only in patients without amyloidosis and controls. The most patients with renal complications were homozygous for p.M694I and SAA1.1 alleles. Conclusion: Our data suggest a positive correlation between the p.M694I/M694I and SAA1.1/1.1 genotypes and the development of AA-amyloidosis secondary to FMF in Algerian patients

Redox status in benign prostatic hyperplasia and non-metastatic prostate cancer in the Algerian population

Background: Depletion of cellular antioxidants can result from free radical formation due to normal endogenous reactions and the ingestion of exogenous substances and environmental factors. The levels of reactive oxygen species (ROS) have been shown to be significantly altered in malignant cells and in primary cancer tissues. We undertook the present study to investigate the possible alteration of oxidant/antioxidant status in Algerian patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Methods: In total, 89 subjects made up of 26 patients with non-metastatic prostate cancer, 31 with benign prostatic hyperplasia (BPH), and 32 controls participated in this study. The concentrations of plasmatic malondialdehyde (MDA), erythrocytes catalase activity (CAT), and the plasma glutathione levels (GSH) were estimated using standard procedures. Results: The results showed that MDA concentrations were significantly increased while erythrocyte catalase activity was significantly decreased in the prostate cancer group versus controls (P < 0.01) and BPH group (P < 0.05). GSH levels were lowered in prostate cancer patients versus control group with no significant changes. Conclusions: Our results suggest that an alteration in the lipid peroxidation index with concomitant changes in the antioxidant defense system in prostate cancer patients compared with controls. We hypothesize that an altered pro-oxidant–antioxidant balance may lead to an increase in oxidative damage and consequently may play an important role in prostate carcinogenesis

Serum Total Homocysteine Level in Association with Folate and Vitamin B12 Status Among Algerian Prostate Cancer Patients

Background: Folate, vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation and metabolic disorders may lead to carcinogenesis metabolic disorders, which may lead to carcinogenesis. In the present study, we proposed to evaluate the associations between folate and vitamin B12, with fasting plasma tHcy concentration in prostate cancer (PCa) patients. Methods: A case –control study was conducted with 40 newly patients with prostate cancer diagnosed with prostate cancer and 50 age matched healthy controls. Serum level of total homocysteine, folate and vitamin B12 were measured by enzyme conversion immunoassay and radioassay, respectively using the ARCHITECT system (both Abbott–Diagnostics Division). Results: The average rate of total PSA was 20.97 ng / ml (ranged between 8- 60 ng / ml). 53% of patients had a PSA≥20ng/ml. Histology confirmed that all patients accounted for prostatic adenocarcinoma with prognostic Gleason score that ranged between 7 and 8 . There are no significant differences between cases and controls about serum Hcy levels (adjusted OR = 0.160% CI = 0.832-1.031), folate levels (adjusted OR = 0.428% CI  = 0.977-1.008) and vitamin B12 (adjusted OR = 0.103% CI  = 0.992-1.001). Conclusion: In this study, the results show that homocysteine is not involved in prostate cancer. However, this study shows that the sporadic form is much more prevalent than familial one. The diagnosis is often made too late in advanced stage with a high PSA levels and biopsy showing high levels of Gleaso

Caffeic acid and quercetin exert caspases-independent apoptotic effects on Leishmania major promastigotes, and reactivate the death of infected phagocytes derived from BALB/c mice

Objective: To investigate the leishmanicidal effects of two antioxidants, caffeic acid and quercetin on Leishmania major (L. major) promastigotes in vitro, and their immuno-modulatory effects on infected phagocytes derived from susceptible BALB/c mice. Methods: Caffeic acid and quercetin-induced cell death was examined by Pi-Hoechst double staining of L. major promastigotes and MTT assay, in the presence or absence of protease inhibitors in vitro. Caffeic acid or quercetin were administered subcutaneously to BALB/c mice infected with L. major promastigotes through a dorsal air pouch. Nitric oxide and superoxide anion production by phagocytes infiltrating the air pouch and the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and nuclear factor kappa B in the air pouch membrane were therefore evaluated using appropriate methods. Results: Caffeic acid and quercetin displayed a dose-dependent cytotoxic effect against L. major promastigotes, and induced cell death via caspases-independent pathways. In vivo, L. major promastigotes inoculation into air pouch cavity of BALB/c mice leads to a sequential influx of neutrophils (hours), followed by macrophages (days). Results showed that L. major delayed apoptosis of infected neutrophils and macrophages by the cleavage of the nuclear factor kappa B p65RelA subunit, and persisted by inhibiting TNF-α and iNOS expression and reactive oxygen species generation. Caffeic acid or quercetin restored reactive oxygen species production and TNF-α-induced iNOS activity, and abrogate apoptosis delay of infected phagocytes. Conclusions: The leishmanicidal effect of caffeic acid and quercetin on promastigotes and amastigotes, as well as reactivation of infected phagocytes apoptosis, suggested a potential therapeutic role against cutaneous leishmaniasis

Low-dose curcumin reduced TNBS-associated mucin depleted foci in mice by scavenging superoxide anion and lipid peroxides, rebalancing matrix NO synthase and aconitase activities, and recoupling mitochondria

Background The role of mitochondrial dysfunction in the pathogenesis of inflammatory bowel diseases (IBD) is still being investigated. This study evaluated the therapeutic effect of curcumin (Cur), a polyphenolic electrophile in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis and mitochondrial dysfunction, in mice. Methods Colitis was induced by rectal instillation to mice of 30 mg kg(-1)TNBS, alone or followed by daily intraperitoneal injections of Cur 25 mg kg(-1). Animals were euthanized at days 3, 7, and 14, post TNBS challenge. Colon mitochondria of control mice were treated with 5 mu M Cur, and TNBS (50, 100 mu M)-toxicity was evaluated by measuring swelling, respiration, and aconitase and fumarase activities. Redox status was evaluated in colon mucosa and in mitochondria. Results In vitro, a short-term Cur treatment controlled the dose and time dependent mitochondrial toxicity induced by TNBS, by collapsing the generation of superoxide anion and hydroperoxy lipids, rebalancing nitric oxide synthase and aconitase activities, and recoupling mitochondria. In vivo, a daily low-dose Cur abolished mice mortality which reached 27% in model group. Cur improved in a time dependent manner mucosal redox homeostasis, cell apoptosis, mucin depleted crypts and crypt abscesses by controlling prooxidant activity of myeloperoxidase and NO synthase associated to phagocytes influx, quenching hydroperoxy lipids, and reboosting GSH levels. Conclusion Cur, by quenching intra and extra mitochondrial ROS generation, rebalancing aconitase/fumarase and MDA/GSH ratios, and recoupling mitochondria, may support mithormesis priming and remitting in IBD. Graphic abstrac

Lysophosphatidylcholine exacerbates Leishmania major-dendritic cell infection through interleukin-10 and a burst in arginase1 and indoleamine 2,3-dioxygenase activities

Leishmania major is an obligate intracellular parasite hosted by phagocytes, including dendritic cells (DCs). Lysophosphatidylcholine (LPC) a pro-oxidant by-product of phospholipase A2 activity can modulate the maturation and function of DCs. However, little is known about its role in L. major infection. This study examined the effects of LPC and lipopolysaccharide (LPS) in BALB/c mouse-derived DC infection by L. major promastigotes, in vitro. Our results showed early divergent effects of LPS and LPC, which lasted up to 24 h. In contrast to LPS, LPC worsened DC infection by reversing the immune balance IL-10 vs. TNF-α and IL-6, and inducing a sharp down regulation of CD40 and iNOsynthase activity. In addition, LPC potentiated xanthine oxidase stress, the production of kynurenine by indoleamine 2,3 dioxygenase (IDO), and arginase1 activity in the expense of iNOsynthase. Taken together, our results highlight some biochemical events bypassing the protective Th1 response. They suggest that LPC could facilitate the proliferation of this obligate intracellular parasite by neutralizing oxidative and nitrosative stresses and sustaining both IDO and arginase1 activities.SCOPUS: ar.jinfo:eu-repo/semantics/publishe