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Melanoma is a skin cancer that arises from melanocytes and can spread quickly to the other organs of the body, if not treated early. Generally, melanoma shows an inherent resistance to conventional therapies. In this regard, new potential drugs are being developed as possible treatments for melanoma. In this paper, we report the synthesis of a new decavanadate compound with organic molecules for a potential therapeutic application. The tetra-[methylimidazolium] dihydrogen decavanadate(V) salt (C 4 H 7 N 2 ) 4 [H 2 V 10 O 28 ] is characterized by single-crystal X-ray diffraction, by FT-IR, UV-Vis and 51 V NMR spectroscopy, as well as by thermal analysis (TGA and DSC). The compound crystallizes in the monoclinic centrosymmetric space group P2 1 /c. Its formula unit consists of one dihydrogen decavanadate anion [H 2 V 10 O 28 ] 4- and four organic 4-methylimidazolium cations (C 4 H 7 N 2 ) + . Important intermolecular interactions are N-H···O and O-H···O hydrogen bonds and π-π stacking interactions between the organic cations, revealed by analysis of the Hirshfeld surface and its two-dimensional fingerprint plots. Interestingly, this compound inhibits the viability of IGR39 cells with IC 50 values of 14.65 μM and 4 μM after 24 h and 72 h of treatment, respectively. The analysis of its effect by flow cytometry using an Annexin V-FITC/IP cell labeling, showed that (C 4 H 7 N 2 ) 4 H 2 V 10 O 28 compound induced IGR39 cell apoptosis and necrosis. Molecular docking studies performed against TNFR1 and GPR40, as putative targets, suggest that the (C 4 H 7 N 2 ) 4 [H 2 V 10 O 28 ] compound may act as inhibitor of these proteins, known to be overexpressed in melanoma cells. Therefore, we could consider it as a new potential metallodrug against melanoma., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Allium roseum is amongst the most important wild medicinal plants. It is known for its diverse biological properties, including antioxidant, antibacterial and antidiabetic activities. In this work, the polysaccharides (PARLs) were ultrasonically extracted from Allium roesum leaves then purified and analyzed by several techniques. Chemical composition and GC-MS analysis showed that the obtained polysaccharides were composed mainly of glucose (40.20 %), mannose (25.30 %), fructose (10.60 %) and galacturonic acid (15.11 %). Moreover, PARLs exhibited a potent antioxidant effect with higher capacities up to 69.61 % and 71.72 % for DPPH and ABTS free radicals, respectively. Furthermore, PARLs significantly modulated inflammatory response by reducing TNF-α, IL-6, and IL-8 pro-inflammatory mediators and promoting the anti-inflammatory IL-10 mediator in LPS stimulated THP-1 derived macrophages. The in-vivo tests proved that the extract was able to decrease carrageenan-induced rat paw swelling by around 68.15 % after 4 h of treatment. PARLs, significantly reduced the growth of U87 (glioblastoma) and IGROV-1 cancer cells with IC 50 values of about 4.27 and 7.89 mg/mL respectively. This research clearly shows that Allium roseum polysaccharides can be used as natural antioxidants with anti-inflammatory and anticancer properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two bases-decavanadates coordination compounds [(C 6 H 13 N 4 ) 2 ][Mg(H 2 O) 6 ] 2 [O 28 V 10 ].6H 2 O (1) and [(C 7 H 11 N 2 ) 4 ][Mg(H 2 O) 6 ][O 28 V 10 ].4H 2 O (2) have been synthesized and well characterized using vibrational spectroscopy (infrared), UV-Visible analysis and single crystal X-ray diffraction technique. The formula unit, for both compounds, is composed by the decavanadate [V 10 O 28 ] 6- , hydrated magnesium ion, a counter anion and free water molecules. The transition metal adopts octahedral geometries in both compound (1) and (2). The existence of a multitude of hydrogen bonding interactions for both compounds provides a stable three-dimensional supramolecular structure. Optical absorption reveals a band gap energy indicating the semi-conductive nature of the compound. In this study, the cytotoxic and the anti-proliferative activities of compounds (1) and (2) on human cancer cells (U87 and MDA-MB-231) were investigated. Both compounds demonstrated dose-dependent anti-proliferative activity on U87 and MDA-MB-231 with respective IC 50 values of 0.82 and 0.31 μM and 1.4 and 1.75 μM. These data provide evidence on the potential anticancer activity of [(C 6 H 13 N 4 ) 2 ][Mg(H 2 O) 6 ] 2 [O 28 V 10 ].6H 2 O and [(C 7 H 11 N 2 ) 4 ][Mg(H 2 O) 2 ][O 28 V 10 ].4H 2 O. Molecular docking of the compounds was also examined. Molecular docking studies were performed for both compounds against four target receptors and revealed better binding affinity with these targets in comparison to Cisplatin. Moreover, molecular docking investigations suggest that these compounds may function as potential inhibitors of proteins in brain and breast cells, exhibiting greater efficiency compared to Cisplatin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: TRAVERSE (NCT02134028), a phase 3 open-label extension study, assessed dupilumab safety and efficacy in patients with asthma aged ≥12 years who completed a previous dupilumab asthma study. This analysis evaluated changes in multiple lung function parameters in patients with moderate-to-severe asthma with elevated type 2 biomarkers (baseline eosinophils ≥150 cells·μL -1 or fractional exhaled nitric oxide ≥25 ppb) who completed QUEST (parent study) and 2 years of dupilumab treatment in TRAVERSE., Methods: Endpoints analyzed included: pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), forced expiratory flow (FEF 25 - 75 % ), and pre- and post-bronchodilator FEV 1 /FVC at parent study baseline (PSBL) at Weeks 0, 2, 48, and 96 in TRAVERSE, as well as pre- and post-bronchodilator FEV 1 slopes in QUEST and TRAVERSE. Statistical analyses were descriptive., Results: Dupilumab improved pre-bronchodilator FEV 1 , FVC, and FEF 25-75 % in QUEST; these improvements were sustained in TRAVERSE. In QUEST patients who received placebo, dupilumab initiation in TRAVERSE resulted in rapid lung function improvements. Mean (standard deviation) changes from PSBL at TRAVERSE Weeks 48 and 96 in pre-bronchodilator FEV 1 were 0.52 (0.59) and 0.45 (0.49) L in the dupilumab/dupilumab group and 0.47 (0.42) and 0.44 L (0.45) in the placebo/dupilumab group, respectively. Similar trends were observed for FVC and FEF 25-75 % . Dupilumab also improved FEV 1 slopes in QUEST and TRAVERSE., Conclusion: Dupilumab demonstrated sustained improvements across multiple spirometric lung function measurements for up to 3 years; patients who received placebo in QUEST experienced rapid lung function improvement upon initiation of dupilumab in TRAVERSE., Competing Interests: Declaration of competing interest A. Papi reports grants, personal fees, and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, and Teva; personal fees and non-financial support from Menarini, Novartis, and Zambon; and grants from Sanofi. M. Castro reports research support from the American Lung Association, AstraZeneca, GSK, NIH, Novartis, PCORI, Pulmatrix, sanofi-aventis, and Shionogi; consultancy fees from Genentech, Novartis, sanofi-aventis, and Teva; speaker fees from AstraZeneca, Genentech, GSK, Regeneron Pharmaceuticals, Inc., Sanofi and Teva; and royalties from Elsevier. J. Corren reports research grants from AstraZeneca, Genentech, Novartis and Regeneron Pharmaceuticals Inc.; research grants and consultancy fees from Sanofi; and speaker fees from AstraZeneca, Genentech, and Novartis. I.D. Pavord reports speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Teva; payments for organizing educational events from AstraZeneca and Teva; consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals Inc., RespiVert, Sanofi, Schering-Plough, and Teva; international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, and Teva; and research grants from Chiesi. Y. Tohda reports consultancy fees from AstraZeneca, Kyorin Pharmaceutical, Novartis, Sanofi, and Teijin Pharma. A. Altincatal, N. Pandit-Abid, E. Laws, L.P. Mannent, J.A. Jacob-Nara, P.J. Rowe, and M. Hardin are employees of Sanofi and may hold stock and/or stock options in the company. B. Akinlade, R. Gall, Y. Deniz, and D.J. Lederer are employees and shareholders of Regeneron Pharmaceuticals Inc., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Patients with short bowel syndrome (SBS) may exhibit enteric hyperoxaluria (EH), and the prevalence of oxalate nephropathy in SBS is likely underestimated. Plasma oxalate (POx) is a surrogate of systemic oxalate deposition and, consequently, may increase the risk of developing chronic kidney disease (CKD). The main objective of this study was to explore the distribution of POx levels in patients with SBS., Methods: Patients followed for SBS were recruited prospectively in the OXAGO study (NCT04119765) to assess POx during their annual renal follow-up including iohexol clearance. The inclusion criteria were age ≥18 years, and SBS type 2 and type 3 for more than 6 months., Results: A total of 47 patients were included but only 45 patients has a measured POx (55% males, 80% SBS type 2, 66% parenteral nutrition, 61% kidney stone history). POx levels were 6.8 ± 4.4 μmol/l, 29% of patients had POx ≥5 μmol/l. In the whole cohort, mean urinary oxalate (UOx) was 648±415 and 54% were >500 μmol/24h. In the group of patients with high POx levels (HPO), 24-hour urine oxalate was significantly higher than in the group with normal POx levels (NPO) (919 ± 566 vs. 526 ± 257 μmol/l; P  = 0.003). Glomerular filtration rate (GFR) was 66 ± 22 ml/min per 1.73 m 2 , and 91% had CKD. GFR was significantly lower in the HPO than in the NPO group (49 ± 23 vs. 73 ± 18 ml/min per 1.73 m 2 ; P  = 0.0005., Conclusion: Patients with SBS can display increased POx levels even with GFR >30 ml/min per 1.73 m 2 . POx may be an interesting biomarker to assess the severity of EH., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Mayaro virus (MAYV) is an emergent arthropod-borne virus that causes an acute febrile illness accompanied by arthralgia, similar to chikungunya virus. Increasing urbanization of MAYV outbreaks in the Americas has led to concerns for geographic expansion and spillover. Given the potential importance of this pathogen, we sought to fill critical gaps in knowledge regarding MAYV infectivity and geographic variation. This study describes the cytopathogenicity of MAYV in human dermal fibroblasts, human skeletal muscle satellite cells, human embryonic kidney cells (HEK), peripherally derived human macrophages, and Vero cells. We found that regional differences between these viruses do not affect replication kinetics, with high titers peaking at 37 h post infection. MAYV-U, did however, cause the most cytopathic effect in a time-dependent manner. Compared to the other two prototypic isolates, MAYV-U harbors unique mutations in the E2 protein, D60G and S205F, that are likely to interact with the host cell receptor and could affect infectivity. We further demonstrate that pre-treatment of cells with interferon-β inhibited viral replication in a dose-dependent manner. Together, these findings advance our understanding of MAYV infection of human target cells and provide initial data regarding variation according to geography., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023. Published by Elsevier B.V.)

Potassium ion channels are expressed on the cell membranes, implicated in wide variety of cell functions and intimately linked to cancer cell behaviors. This work reports the first bioplatform described to date allowing simple and rapid detection of ion channel activity and the effect of their inhibitors in cancer cells. The methodology involves interrogation of the channel of interest from cells specifically captured on magnetic immunoconjugates using specific detection antibodies that are labeled with horseradish peroxidase enzyme. The channel activity is reflected by an amperometric signal transduction of the resulting magnetic bioconjugates onto screen-printed carbon electrodes. The bioplatform feasibility was proven for the detection of the Kv channels in U87 human glioblastoma cells and their blocking by scorpion venom KAaH1 and KAaH2 peptides. The obtained results confirm the high sensitivity (detection of 5 U87 cells⋅mL -1 and 0.06 μg mL -1 of KAaH2) of the proposed bioplatform and their versatility to detect both potassium channel activity and their potential inhibitors, in a given cancer cell line, with high sensitivity in a simple and fast way. This bioplatform presents potential applications in cancer and theranostic of channelopathies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Noureddine Raouafi reports financial support was provided by Tunisian Ministry of Higher Education and Scientific Research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Many patients with severe asthma require chronic corticosteroid treatment to maintain asthma control., Research Question: Are the reduction in oral corticosteroid (OCS) use and the clinical efficacy observed with dupilumab treatment maintained long-term in patients with severe OCS-dependent asthma?, Study Design and Methods: The LIBERTY ASTHMA TRAVERSE study (ClinicalTrials.gov identifier: NCT02134028) was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, we present the data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study (ClinicalTrials.gov identifier: NCT02528214), a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma, and continued in the TRAVERSE study. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control., Results: Ninety patients treated with dupilumab/dupilumab and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV 1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile., Interpretation: In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function., Trial Registry: ClinicalTrials.gov; Nos.: NCT02134028 (TRAVERSE) and NCT02528214 (VENTURE); URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to prepare chitosan/zein (CS/Zein) edible films reinforced with Mosla chinensis essential oils (EOs) nanoemulsions (NEs) and nanoparticles (NPs) in order to compare their properties. NEs and NPs containing EOs could be used to fabricate films with functional properties, and the films were prepared using a casting method. The influence of EO concentration and mixing methods on the physical, mechanical, and functional properties of the films was investigated. The results indicated that the films formulated with EO NEs generated favorable fundamental and functional characteristics with excellent mechanical properties, moisture barrier capacity, and significant antioxidant and antibacterial activity. In addition, the use of NEs-based films improved the release of bioactive compounds, and the mechanism of EO release was found to follow a first order model. In summary, EO NEs were more effective in preserving the fundamental and functional properties of CS/Zein nanocomposite edible films than NP-based films. These differences may reflect different forms and methods of dispersing EOs in NEs and NPs. This study demonstrated that NEs reinforced films could be used to enhance the effectiveness of EOs in food products and develop new strategies for their delivery and application., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Since the onset of the COVID-19 pandemic, cases of reinfection with SARS-CoV-2 have been reported, raising additional public health concerns. SARS-CoV-2 reinfection was assessed in healthcare workers (HCWs) in Tunisia because they are at the greatest exposure to infection by different variants., Methods: We conducted whole-genome sequencing of the viral RNA from clinical specimens collected during the initial infection and the suspected reinfection from 4 HCWs, who were working at the Habib Bourguiba University Hospital (Sfax, Tunisia) and retested positive for SARS-CoV-2 through reverse transcriptase-polymerase chain reaction (RT-PCR) after recovery from a first infection. A total of 8 viral RNAs from the patients' respiratory specimens were obtained, which allowed us to characterize the differences between viral genomes from initial infection and positive retest. The serology status for total Ig, IgG, and IgM against SARS-CoV-2 was also determined and followed after the first infection., Results: We confirmed through whole-genome sequencing of the viral samples that all 4 cases experienced a reinfection event. The interval between the 2 infection events ranged between 45 and 141 days, and symptoms were milder in the second infection for 2 patients and more severe for the remaining 2 patients. Reinfection occurred in all 4 patients despite the presence of antibodies in 3 of them., Conclusion: This study adds to the rapidly growing evidence of COVID-19 reinfection, where viral sequences were used to confirm infection by distinct isolates of SARS-CoV-2 in HCWs. These findings suggest that individuals who are exposed to different SARS-CoV-2 variants might not acquire sufficiently protective immunity through natural infection and emphasize the necessity of their vaccination and the regular follow-up of their immune status both in quantitative and qualitative terms., Competing Interests: Declaration of Competing Interest All authors declare no competing interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nanotechnology is one of the emerging fields of the 21st Century. Many new devices and patentable technology is based on nanomaterials (NMs). One of the dominant factors in the use of nanomaterials and their applications in various fields is the synthesis and growth mechanism of nanostructures and nanomaterials. A nanostructured material may have been a good candidate in one application but could be more useful in a different application if synthesized by a different mechanism and technique. Similarly, the structure and morphology of a nanomaterial also depend upon the method of growth and synthesis. For example, it is easy to grow and synthesize amorphous nanostructured thin film using the plasma magnetron sputtering technique, but it may be difficult to obtain a similar structure using the thermal evaporation process due to the nature of the technique itself. In this study, the Top-down and Bottom-up methods and techniques of synthesizing nanostructured materials are reviewed, compared, and analyzed. Both approaches are critically analyzed, and the influencing factors on the synthesis of different nanomaterials, the advantages, and disadvantages of each technique are reported. This review also provides a step-by-step analysis of the choice of method for the synthesis of namomaterials for specific applications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Prostate cancer is the most highly diagnosed cancer in men worldwide. It is characterized by high proliferation, great invasion and metastatic potential. Sodium channel subtypes have been identified as highly expressed in different prostate cancer cell lines. In this study, we have screened the negatively charged fractions of Androctonus australis (Aa) scorpion venom to identify active peptides on DU145 prostate cancer cells proliferation. The most active compound was identified to be the sodium channel peptide AaHIV with an IC 50 value of 15 μM. At this concentration, AaHIV had low effect on the adhesion of DU145 cells to fibronectin. When compared to other Na + channel Aa toxins, AaHIV was found to be 2 times more active than AaHI and AaHII on DU145 cells proliferation and slightly less active than AaHII on their adhesion. The three peptides are inactive on DU145 cells migration. AaHIV was found to be 16 times more active than veratridine, asteroidal alkaloid from plants of the lily family widely used as a sodium channel activator. Electrophysiological experiments showed that the AaHIV toxin activates Nav1.6 channel, suggesting that this sodium channel subtype is implicated in the proliferation of DU145 prostate cancer cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primitive intimal sarcoma is a rare malignant cardiac tumor. Through the observation of a 41-year-old man who presented with an acute heart failure revealing a left atrial intimal sarcoma, we discuss different diagnostic and therapeutic modalities., (Published by Elsevier Masson SAS.)

Galloway-Mowat syndrome (GAMOS [MIM 251300]) is a rare autosomal recessive disorder that manifests as a combination of nephrotic syndrome, brain abnormalities and developmental delay. It is a clinically and genetically heterogeneous disease. The WDR73 variations are associated with GAMOS1. Here we report two consanguineous families affected by GAMOS1. In the first family, three sisters are affected and in the second family, only one index case is identified. They all show a nephrotic syndrome, a neurological involvement and a collapsing glomerulopathy. The analysis of mutations of WDR73 revealed a new homozygous missense mutation NM_032856.3 c.293T > C; p.(Leu98Pro) in two patients from the first family, and a new homozygous missense mutation NM_032856.3: c.767G > A; p.(Arg256Gln) in the second one. This study extended the clinical and molecular spectrum of GAMOS1 with other cases associated with collapsing glomerulopathy and two novel WDR73 variations that are most likely pathogenic., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We previously reported that immunoreactivity of recombinant CFP32 (Rv0577), a virulence factor of Mycobacterium tuberculosis, was higher when produced in transformed Pichia pastoris as compared to transformed E. coli. In this study, we show that this difference is partly due to the N-glycosylation of the recombinant CFP32 (rCFP32) by the yeast Pichia pastoris. In addition, SDS-PAGE and western blotting analysis of Mycobacterium bovis BCG and yeast-produced rCFP32 showed the presence of a band corresponding to a homodimeric state of the protein, unlike that of rCFP32 produced in E. coli. Computational modeling indicates that a single cysteine residue at position 193 of each monomer might bond to stabilize the homodimeric state of CFP32. Computational study showed that this residue is buried inside the protein core of E. coli-produced rCFP32 suggesting that rCFP32 may adopt a different folding in P. pastoris and BCG, in which C193 is solvent exposed. Surprisingly, an enzyme-linked immunosorbent assay using a generated monoclonal antibody (14D4) reveals the presence of a differential epitope that appears to be the consequence of the protein dimerization of the yeast- and BCG-, but not E.coli- produced, CFP32 recombinant form. We conclude that, in addition to N-glycosylation, homodimeric folding significantly enhances the immunoreactivity of rCFP32 and may these post-translational modifications may factor into the structure and function of native M. tuberculosis CFP32., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Scorpion toxins have been the subject of many studies exploring their pharmacological potential. The high affinity and the overall selectivity to various types of ionic channels endowed scorpion toxins with a potential therapeutic effect against many channelopathies. These are diseases in which ionic channels play an important role in their development. Cancer is considered as a channelopathy since overexpression of some ionic channels was highlighted in many tumor cells and was linked to the pathology progression. Interestingly, an increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth in vitro and in vivo. Furthermore through their ability to penetrate the cell plasma membrane, certain scorpion toxins are able to enhance the efficiency of some clinical chemotherapies. These observations back-up the applicability of scorpion toxins as potential cancer therapeutics. In this review, we focused on the anti-cancer activity of scorpion toxins and their effect on the multiple hallmarks of cancer. We also shed light on effectors and receptors involved in signaling pathways in response to scorpion toxins effect. Until now, the anticancer mechanisms described for scorpion peptides consist on targeting ion channels to (i) inhibit cell proliferation and metastasis; and (ii) induce cell cycle arrest and/or apoptosis through membrane depolarization leading to hemostasis deregulation and caspase activation. Putative targets such as metalloproteinases, integrins and/or growth factor receptors, beside ion channels, have been unveiled to be affected by scorpion peptides., (Copyright © 2019. Published by Elsevier Ltd.)

Scorpion peptides are well known for their pharmaceutical potential on different targets. These include mainly the ion channels which were found to be highly expressed in many diseases, including cancer, auto-immune pathologies and Alzheimer. So far, however, the disintegrin activity had only been characterized for snake venom molecules. Herein, we present the first short peptide, purified from the venom of Buthus occitanus tunetanus, (termed RK) able to inhibit the cell adhesion of Glioblastoma, Melanoma and Rat pheochromocytoma to different extracellular matrix (ECM) receptors. Anti-integrin antibody assay suggests that RK interacts with both α 1 β 1 and α v β 3 with a more pronounced effect for the former. The examination of the primary structure of RK suggests the involvement of two motifs: KSS, analogue to KTS which was characterized for α 1 β 1 Snake venom disintegrins, and ECD, analogue to RGD which was found to be active on α v β 3 . To assess their roles in the disintegrin activity of RK, we conducted a computational analysis. The molecular docking study shows that RK involves mainly two segments to interact with the α 1 β 1 integrin, but the peptide does not implicate the KSS motif in the interaction. The molecular modeling study, suggests the key contribution of the ECD segment in the interaction with α v β 3 integrin., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Voltage-gated potassium (Kv) channels are known to play a pivotal role in the progression of various cancer types and considered as new targets for designing anti-cancer therapy. However, the fact that many Kv channels are expressed in different cell lines makes it difficult to ascribe a functional role for a given Kv channel on a specific aspect of the tumorogenesis. In this work, we showed that although both Kv1.1 and Kv1.3 channels are expressed in U87 (glioblastoma), MDA-MB-231 (breast cancer) and LS174 (colon adenocarcinoma) cells, these respond differently to KAaH1 or KAaH2, two homologous Kv1 blockers from scorpion venom. KAaH1 is active on Kv1.1 and Kv1.3 and was found to inhibit migration and adhesion of U87 cells whereas KAaH2 which is slightly active only on Kv1.1 channel, inhibits their proliferation via the EGFR signaling pathway. The correlation between the electro-physiological activity of the scorpion peptides and their anti-migratory effects suggests the involvement of the Kv1.1 and Kv1.3 channels in the mobility of the three cancer cell lines. Our results showed that besides they can elucidate the implication of Kv1.1 and Kv1.3 channels in molecular mechanisms of neoplastic progression, KAaH1 and KAaH2 may be used as therapeutic tools against glioblastoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The resistance of melanoma cells to cisplatin restricts its clinical use. Therefore, the search for novel tumor inhibitors and effective combination treatments that sensitize tumor cells to this drug are still needed. We purified macrovipecetin, a novel heterodimeric C-type lectin, from Macrovipera lebetina snake venom and investigated its anti-tumoral effect on its own or combined with cisplatin, in human melanoma cells., Methods: Biochemical characterization, in vitro cells assays such as viability, apoptosis, adhesion, migration, invasion, Western blotting and in silico analysis were used in this study., Results: Macrovipecetin decreased melanoma cell viability 100 times more than cisplatin. Interestingly, when combined with the drug, macrovipecetin enhanced the sensitivity of SK-MEL-28 cells by augmenting their apoptosis through increased expression of the apoptosis inducing factor (AIF) and activation of ERK 1/2 , p38, AKT and NF-κB. Moreover, macrovipecetin alone or combined with cisplatin induced the expression of TRADD, p53, Bax, Bim and Bad and down-regulated the Bcl-2 expression and ROS levels in SK-MEL-28 cells. Interestingly, these treatments impaired SK-MEL-28 cell adhesion, migration and invasion through modulating the function and expression of αvβ3 integrin along with regulating E-cadherin, vimentin, β-catenin, c-Src and RhoA expression. In silico study suggested that only the α chain of macrovipecetin interacts with a region overlapping the RGD motif binding site on this integrin., Conclusions: We validated the antitumor effect of macrovipecetin when combined, or not, with cisplatin on SK-MEL-28 cells., General Significance: The presented work proposes the potential use of macrovipecetin and cisplatin in combination as an effective anti-melanoma treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The present study investigated the kinetic and interfacial properties of two secreted phospholipases isolated from Tunisian vipers'venoms: Cerastes cerastes (CC-PLA2) and Macrovipera lebetina transmediterranea (MVL-PLA2). Results show that these enzymes have great different abilities to bind and hydrolyse phospholipids. Using egg-yolk emulsions as substrate at pH 8, we found that MVL-PLA2 has a specific activity of 1473U/mg at 37°C in presence of 1mM CaCl2. Furthermore the interfacial kinetic and binding data indicate that MVL-PLA2 has a preference to the zwitterionic phosphatidylcholine monolayers (PC). Conversely, CC-PLA2 was found to be able to hydrolyse preferentially negatively charged head group phospholipids (PG and PS) and exhibits a specific activity 9 times more important (13333U/mg at 60°C in presence of 3mM CaCl2). Molecular models of both CC-PLA2 and MVL-PLA2 3D structures have been built and their electrostatic potentials surfaces have been calculated. A marked anisotropy of the overall electrostatic charge distribution leads to a significantly difference in the dipole moment intensity between the two enzymes explaining the great differences in catalytic and binding properties, which seems to be governed by the electrostatic and hydrophobic forces operative at the surface of the two phospholipases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Angiogenesis constitutes a fundamental step in tumor progression. Thus, targeting tumour angiogenesis has been identified to be promising in cancer treatment. In this work, CC5 and CC8, two highly homologous disintegrins isolated from the venom Cerastes cerastes viper from the south of Tunisia, were assessed for their anti-angiogenic effect by testing their ability to interfere with viability, adhesion, migration and angiogenesis of Human Microvascular Endothelial Cells, HMEC-1 and HBMEC. We found that CC5 and CC8 displayed pro-apoptotic potential in HMEC-1 cells. Anoïkis like induced by these two disintegrins was evidenced by cell detachment, down regulation of FAK/AKT/PI3K axis and caspase activation. In addition, both CC5 and CC8 exhibited in vitro anti-adhesive, anti-migratory and anti-proliferative effects on endothelial cells HBMEC. These effects appeared to require RGD and/or WGD loops disintegrin. CC5 and CC8 also inhibited tube-formation on matrigel and displayed potent anti-angiogenic activities as assessed ex vivo, using both the embryo chick chorioallantoic membrane model (CAM) and rat aortic ring assay. Altogether our results demonstrate that CC5 and CC8, are potent inhibitors of angiogenesis, by disrupting αvβ3 and α5β1 binding. The use of CC5 and/or CC8 could provide a beneficial tool to inhibit abnormal angiogenesis and to induce cancer regression., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Snake venom l-amino acid oxidases are multifunctional enzymes that exhibited a wide range of pharmacological activities. Although it has been established that these activities are primarily caused by the H2O2 generated in the enzymatic reaction, the molecular mechanism, however, has not been fully investigated. In this work, LAAO interaction with cytoplasmic membranes using different cell types and Langmuir interfacial monolayers was evaluated. The Cerastes cerastes venom LAAO (CC-LAAO) did not exhibit cytotoxic activities against erythrocytes and peripheral blood mononuclear cells (PBMC). However, CC-LAAO caused cytotoxicity on several cancer cell lines and induced platelet aggregation in dose-dependent manner. Furthermore, the enzyme showed remarkable effect against Gram-positive and Gram-negative bacteria. These activities were inhibited on the addition of catalase or substrate analogs, suggesting that H2O2 liberation× is required for these effects. Binding studies revealed that CC-LAAO binds to the cell surface and enables the production of highly localized concentration of H2O2 in or near the binding interfaces. On another hand, the interaction of CC-LAAO with a mimetic phospholipid film was evaluated, for the first time, using a monomolecular film technique. Results indicated that phospholipid/CC-LAAO interactions are not involved in their binding to membrane and in their pharmacological activities., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel Kunitz-type serine proteinase inhibitor, termed PIVL, was purified to homogeneity from the venom of the Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric polypeptide chain cross-linked by three disulfide linkages with an isotope-averaged molecular mass of 7691.7 Da. The 67-residue full-length PIVL sequence was deduced from a venom gland cDNA clone. Structurally, PIVL is built by a single Kunitz/BPTI-like domain. Functionally, it is able to specifically inhibit trypsin activity. Interestingly, PIVL exhibits an anti-tumor effect and displays integrin inhibitory activity without being cytotoxic. Here we show that PIVL is able to dose-dependently inhibit the adhesion, migration and invasion of human glioblastoma U87 cells. Our results also show that PIVL impairs the function of αvβ3 and to a lesser extent, the activity of αvβ6, αvβ5, α1β1 and α5β1 integrins. Interestingly, we demonstrate that the (41)RGN(43) motif of PIVL is likely responsible for its anti-cancer effect. By using time lapse videomicroscopy, we found that PIVL significantly reduced U87 cells motility and affected cell directionality persistence by 68%. These findings reveal novel pharmacological effects for a Kunitz-type serine proteinase inhibitor., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Pakistan and Afghanistan are two of the three remaining countries yet to interrupt wild-type poliovirus transmission. The increasing incidence of poliomyelitis in these countries during 2010-11 led the Executive Board of WHO in January, 2012, to declare polio eradication a "programmatic emergency for global public health". We aimed to establish why incidence is rising in these countries despite programme innovations including the introduction of new vaccines., Methods: We did a matched case-control analysis based on a database of 46,977 children aged 0-14 years with onset of acute flaccid paralysis between Jan 1, 2001, and Dec 31, 2011. The vaccination history of children with poliomyelitis was compared with that of children with acute flaccid paralysis due to other causes to estimate the clinical effectiveness of oral poliovirus vaccines (OPVs) in Afghanistan and Pakistan by conditional logistic regression. We estimated vaccine coverage and serotype-specific vaccine-induced population immunity in children aged 0-2 years and assessed their association with the incidence of poliomyelitis over time in seven regions of Afghanistan and Pakistan., Findings: Between Jan 1, 2001, and Dec 31, 2011, there were 883 cases of serotype 1 poliomyelitis (710 in Pakistan and 173 in Afghanistan) and 272 cases of poliomyelitis serotype 3 (216 in Pakistan and 56 in Afghanistan). The estimated clinical effectiveness of a dose of trivalent OPV against serotype 1 poliomyelitis was 12·5% (95% CI 5·6-18·8) compared with 34·5% (16·1-48·9) for monovalent OPV (p=0·007) and 23·4% (10·4-34·6) for bivalent OPV (p=0·067). Bivalent OPV was non-inferior compared with monovalent OPV (p=0·21). Vaccination coverage decreased during 2006-11 in the Federally Administered Tribal Areas (FATA), Balochistan, and Khyber Pakhtunkhwa in Pakistan and in southern Afghanistan. Although partially mitigated by the use of more effective vaccines, these decreases in coverage resulted in lower vaccine-induced population immunity to poliovirus serotype 1 in FATA and Balochistan and associated increases in the incidence of poliomyelitis., Interpretation: The effectiveness of bivalent OPV is comparable with monovalent OPV and can therefore be used in eradicating serotype 1 poliomyelitis whilst minimising the risks of serotype 3 outbreaks. However, decreases in vaccination coverage in parts of Pakistan and southern Afghanistan have severely limited the effect of this vaccine., Funding: Poliovirus Research subcommittee of WHO, Royal Society, and Medical Research Council., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Cardiac hydaticyst is a rare condition and accounts for only 0.5 to 2% of all visceral locations of hydatid disease. The objective of this study was to point out the main clinical, radiological, and disease-course characteristics of this rare and serious pathology. We report a 13-year-old patient with a hydatid pulmonary embolism caused by a hydatid cyst of the interauricular septum. The diagnosis was established by transthoracic echocardiography, thoracic CT scan, and hydatid serology. Surgery was performed without delay and the outcome was good after 15 months of follow-up. This case underlines the need for rapid diagnosis and surgery before complications of cardiac hydatid cyst., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Leberagin-C, a new member of the disintegrin-like/cysteine-rich (D/C) family, was purified to homogeneity from the venom of Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric protein with a molecular mass of 25,787 Da. Its complete sequence of 205 amino acid residues was established by cDNA cloning. The leberagin-C shows many conserved sequences with other known D/C proteins, like the SECD binding sites and a pattern of 28 cysteines. It is the first purified protein from M. lebetina transmediterranea with only two disintegrin-like/cysteine-rich domains. Leberagin-C is able to inhibit platelet aggregation induced by thrombin and arachidonic acid with IC(50) of 40 and 50 nM respectively. It was also able to inhibit the adhesion of melanoma tumour cells on fibrinogen and fibronectin, by interfering with the function of alphavbeta3 and, to a lesser extent, with alphavbeta6 and alpha5beta1 integrins. To our knowledge, leberagin-C is the sole described D/C protein that does not specifically interact with the alpha2beta1 integrin. Structure-activity relationship study of leberagin-C suggested that there are some important amino acid differences with jararhagin, the most studied PIII metalloprotease from Bothrops jararaca, notably around the SECD motif in its disintegrin-like domain. Other regions implicated in leberagin-C specificities could not be excluded., (2009 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Here, we report the purification and characterization of an acidic Asp49 phospholipase A2, named MVL-PLA2, with a molecular mass of 13,626.64 Da. The complete MVL-PLA2 cDNA was cloned from Macrovipera lebetina transmediterranea venom gland cDNA library. MVL-PLA2 possesses 122 amino acid residues, including 14 cysteines, and belongs to group II snake venom phospholipase A2 enzymes. MVL-PLA2 was not cytotoxic up to 2 muM and completely abolished cell adhesion and migration of various human tumor cells. Chemical modification with p-bromophenacyl bromide abolished the enzymatic activity of MVL-PLA2 without affecting its anti-tumor effect, suggesting the presence of 'pharmacological sites' distinct from the catalytic site in snake venom phospholipase A2. We demonstrated for the first time that the anti-tumor effect of MVL-PLA2 was mediated by alpha5beta1 and alphav-containing integrins. This finding may serve as starting point for structure-function relationship studies leading to design a new generation of specific anti-cancer drugs.

Objective: To do a critical systematic review regarding effects of prone positioning (PP) in patients with acute respiratory distress syndrome (ARDS)., Methods: A systematic review (Highwire, Medline, Cochrane Library from 1976 to 2004), using the keywords: prone position, acute respiratory distress syndrome, allowed us to include the human studies on PP in ARDS patients, independantly of their objectives or their type of protocol. To appreciate the studies validity, we scored the quality evidence of the studies in order to grade our conclusions., Results and Conclusion: The qualitative analysis of the 58 included studies (1,500 patients returned prone, 4,000 episodes of PP) led to the following main conclusions: 1) the PP improves oxygenation in the majority of ARDS patients (level of evidence I); 2) the PP improves the pulmonary haemodynamics without altering the systemic haemodynamics (level of evidence III); 3) the PP enhances the recruitment maneuvers (level of evidence III); 4) because there are no formal predictive criteria for response to the PP, a "trial of PP" or better two PP trials are necessary to look for the responders; 5) the PP should be performed as early as possible in the course of severe ARDS; 6) the optimal duration of PP is 18 to 23 hours daily, and it should be continued until improvement of arterial oxygenation, or loss of the positive effect of PP on arterial oxygenation or evidently patient's death.

Background and Aim: Type 2 diabetes mellitus is associated with atherosclerosis, which has been, in part, ascribed to abnormalities in the reverse cholesterol transport system. Among the key actors involved in this pathway is cholesteryl ester transfer protein (CETP) which mediates the transfer of cholesteryl esters (CE) from HDL to apoB-containing lipoproteins., Methods and Results: The purpose of this study was to examine CETP activity in 220 patients with type 2 diabetes mellitus (type 2 DM) treated with diet alone or diet and sulphonylurea drugs and to identify the factors that may regulate it in the diabetic state. We also examined the effect of diet on the activity of plasma CETP in a subgroup of type 2 DM women. CETP activity was assessed by measuring plasma-mediated cholesteryl ester transfer (CET) between pooled exogenous HDL and apoB-containing lipoproteins. In 220 patients with type 2 DM, CET was significantly higher in conjunction with higher plasma triglycerides and lower HDL-cholesterol compared to 100 matched healthy controls. Correlation analysis showed that CETP activity was significantly correlated with the HDL-C to apoA1 ratio (r = -0.205, P = 0.003) and to LDL-C to HDL-C ratio in diabetic women (P = 0.010). Furthermore, CETP activity was correlated marginally with total energy intake (P = 0.052) but to a statistically significant extent with the amount of fat consumed daily (P = 0.008). A significant negative correlation was found between plasma CETP activity and MUFA of plasma phospholipids or free PUFA (P = 0.032), especially with omega3-fatty acids (P = 0.001)., Conclusion: Our findings indicate that CET is accelerated in patients with type 2 DM and that this may be regulated by dietary fatty acids in the diabetic state.