Benedek G et al. (2020) PLoS Negl Trop Dis "Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove."

Benedek G, Edvardson S, Alon SA, Galun E, Lako R, Rivkin M, Riek LP, Ramadhan Lasu AA, Levite M, Miller K, Abed El Latif M

[PLoS Negl Trop Dis, 2020]

Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an 'Autoimmune Epilepsy' since: 1. ~50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently-published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B-peptide autoimmune-antibodies that bind, induce Reactive-Oxygen-Species, and kill both neural cells and T cells. Furthermore, NS patient's IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not.

Matencio A et al. (2020) Int J Pharm "Lifespan extension in caenorhabditis elegans by oxyresveratrol supplementation in hyper-branched cyclodextrin-based nanosponges."

Cecone C, Caldera F, Matencio A, Manuel Lopez-Nicolas J, Trotta F, Alejandra Guerrero-Rubio M, Garcia-Carmona F

[Int J Pharm, 2020]

In this work, the increase of the Caenorhabditis elegans (C.elegans) lifespan extension using hyper-branched cyclodextrin-based nanosponges (CD-NS) complexing oxyresveratrol (OXY), and the possible inhibition of C.elegans phosphodiesterase type 4 (PDE4) were evaluated. The titration displacement of fluorescein was used to calculate the apparent complexation constant (K_F) between CD-NS and OXY. Moreover, PDE4 was expressed in E.coli, purified and refolded in presence of cyclodextrins (CDs) to study its possible inhibition as pharmacological target of OXY. The apparent activity was characterized and the inhibitory effect of OXY on PDE4 displayed a competitive in vitro inhibition corroborated in silico. A maximum increase of the in vivo life expectancy of about 9.6% of using OXY/CD-NS complexes in comparison with the control was obtained, in contrast to the 6.5 % obtained with free OXY. No effect on lifespan or toxicity with CD-NS alone was found. These results as a whole represent new opportunities to use OXY and CD-NS in lifespan products.

Lagoro DK et al. (2017) Pan Afr Med J "Nodding syndrome (NS) and Onchocerca Volvulus (OV) in Northern Uganda."

Arony DA, Lagoro DK

[Pan Afr Med J, 2017]

Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction, wasting and stunted growth. There are recent published information suggesting associations between Nodding Syndrome (NS) with cerebrospinal fluid (CSF) VGKC antibodies and serum leiomidin-1 antibody cross reacting with Onchocerca Volvulus (OV). These findings suggest a neuro-inflammatory cause of NS and they are important findings in the search for the cause of Nodding Syndrome. These observations perhaps provide further, the unique explanation for the association between Nodding Syndrome and Onchocerca Volvulus. Many clinical and epidemiological studies had shown a significant correlation between NS and infestation with a nematode, Onchocerca volvulus which causes a disease, Onchocerciasis, some of which when left untreated can develop visual defect ("River Blindness"). While these studies conducted in Northern Uganda and Southern Sudan indicate a statistically significant association with (OV infection (using positive skin snips), we observe that (OV is generally endemic in many parts of Sub Saharan Africa and Latin America and that to date, no NS cases have been recorded in those regions. This letter to the Editor is to provide additional information on the current view about the relationship between Nodding Syndrome and Onchocerca Volvulus as seen in Northern Uganda.

Campion R et al. (2023) Int J Pharm "Zein-based nanospheres and nanocapsules for the encapsulation and oral delivery of quercetin."

Irache JM, Campion R, Cristina Martinez-Oharriz M, Luisa Martnez Lopez A, Collantes M, Gonzalez-Navarro CJ, Saiz-Abajo MJ, Matias C, Penuelas I

[Int J Pharm, 2023]

In this study, the ability of zein nanospheres (NS) and zein nanocapsules containing wheat germ oil (NC) to enhance the bioavailability and efficacy of quercetin was evaluated. Both types of nanocarriers had similar physico-chemical properties, including size (between 230 and 250 nm), spherical shape, negative zeta potential, and surface hydrophobicity. However, NS displayed a higher ability than NC to interact with the intestinal epithelium, as evidenced by an oral biodistribution study in rats. Moreover, both types of nanocarriers offered similar loading efficiencies and release profiles in simulated fluids. In C. elegans, the encapsulation of quercetin in nanospheres (Q-NS) was found to be two twice more effective than the free form of quercetin in reducing lipid accumulation. For nanocapsules, the presence of wheat germ oil significantly increased the storage of lipids in C. elegans; although the incorporation of quercetin (Q-NC) significantly counteracted the presence of the oil. Finally, nanoparticles improved the oral absorption of quercetin in Wistar rats, offering a relative oral bioavailability of 26% and 57% for Q-NS and Q-NC, respectively, compared to a 5% for the control formulation. Overall, the study suggests that zein nanocarriers, particularly nanospheres, could be useful in improving the bioavailability and efficacy of quercetin.

Rao GN et al. (2008) Opt Express "In vivo nanosecond laser axotomy: cavitation dynamics and vesicle transport."

Kulkarni SS, Rao GN, Rau KR, Koushika SP

[Opt Express, 2008]

Nanosecond laser pulses (lambda = 355 nm) were used to cut mechanosensory neurons in Caenorhabditis elegans and motorneurons in Drosophila melanogaster larvae. A pulse energy range of 0.8-1.2 microJ and < 20 pulses in single shot mode were sufficient to generate axonal cuts. Viability post-surgery was >95% for C. elegans and 60% for Drosophila. Cavitation bubble dynamics generated due to laser-induced plasma formation were observed in vivo by time-resolved imaging in both organisms. Bubble oscillations were severely damped in vivo and cavitation dynamics were complete within 100 ns in C. elegans and 800 ns in Drosophila. We report the use of this system to study axonal transport for the first time and discuss advantages of nanosecond lasers compared to femtosecond sources for such procedures.

Schollen E et al. (2003) Eur J Hum Genet "PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning."

Matthijs G, Gewillig M, Schollen E, Legius E, Fryns JP

[Eur J Hum Genet, 2003]

Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.European Journal of Human Genetics (2002) 11, 85-88. doi:10.1038/sj.ejhg.5200915

Eijkelkamp BA et al. (2013) Infect Immun "H-NS plays a role in expression of Acinetobacter baumannii virulence features."

Brown MH, Eijkelkamp BA, Elbourne LD, Stroeher UH, Hassan KA, Paulsen IT

[Infect Immun, 2013]

Acinetobacter baumannii has become a major problem in the clinical setting with the prevalence of infections caused by multidrug-resistant strains on the increase. Nevertheless, only a limited number of molecular mechanisms involved in the success of A. baumannii as a human pathogen have been described. In this study, we examined the virulence features of a hypermotile derivative of A. baumannii strain ATCC 17978, which was found to display enhanced adherence to human pneumocytes and elevated levels of lethality toward Caenorhabditis elegans nematodes. Analysis of cellular lipids revealed modifications to the fatty acid composition, providing a possible explanation for the observed changes in hydrophobicity and subsequent alteration in adherence and motility. Comparison of the genome sequences of the hypermotile variant and parental strain revealed that an insertion sequence had disrupted an hns-like gene in the variant. This gene encodes a homologue of the histone-like nucleoid structuring (H-NS) protein, a known global transcriptional repressor. Transcriptome analysis identified the global effects of this mutation on gene expression, with major changes seen in the autotransporter Ata, a type VI secretion system, and a type I pilus cluster. Interestingly, isolation and analysis of a second independent hypermotile ATCC 17978 variant revealed a mutation to a residue within the DNA binding region of H-NS. Taken together, these mutants indicate that the phenotypic and transcriptomic differences seen are due to loss of regulatory control effected by H-NS.

Bhoj PS et al. (2020) Acta Parasitol "Role of Glutathione in Chalcone Derivative Induced Apoptosis of Brugia malayi and its Possible Therapeutic Implication."

Bahekar S, Singh N, Dash D, Togre NS, Khatri V, Bhoj PS, Chandak HS, Goswami K

[Acta Parasitol, 2020]

PURPOSE: Oxidative stress is an essential component of innate response against microbes. The oxidative impact has a very subtle connection with apoptosis. Our previous work indicated presumptive evidence of apoptosis by the chalcone derivatives against the human lymphatic filarial parasite. Evidence suggests the involvement of glutathione-S-transferase (GST) in the mechanism of action of chalcone drugs. In the present study, we explored the implications of redox status in apoptosis of the parasite by this drug. RESULTS: Treatment with the representative drug, 4t, significantly decreased GSH level and increased GST activity in the Brugia malayi microfilariae (Mf) in comparison to Mf without 4t treatment. Drug-induced loss of motility of the parasites was reversed by the treatment with GSH (41%) and NAC (19%). A significant fall in rGST activity was observed due to drug addition, which could be reversed by the addition of GSH co-substrate, but not with the re-addition of rGST, indicating a vital role of GSH. In silico study demonstrated a favorable drug-GST enzyme interaction. Oxidative stress was reflected by increased protein carbonylation and intracellular reactive oxygen species level, in the drug-treated parasite. Mitochondrial oxygen consumption was reduced by the drug, which was reversed on the addition of GSH. Mitochondrial dysfunction was confirmed by MTT and cytochrome c assay. Apoptosis was confirmed by the inhibition in PARP activity. CONCLUSION: We conclude that the depletion of GSH by chalcone with concomitant mitochondrial dysfunction revealed a novel rationale of apoptosis in the parasite. Such a mechanism might have wide therapeutic implications.

Bhoj PS et al. (2019) Parasitol Res "In vitro apoptotic effect on human lymphatic filarial parasite by piperidine derivatives and thymidine reversal study."

Goswami K, Togre NS, Rao S, Patil MB, Sharma R, Agrawal NR, Chandak HS, Bahekar SP, Bhoj PS

[Parasitol Res, 2019]

A novel library of synthetic piperidine derivatives was used to screen against human lymphatic filarial parasite Brugia malayi. Piperidine has earlier been reported to have effect against parasites including rodent filarial nematodes. Compounds with hydroxyl substitutions (4Q and 4H) showed marked antifilarial effect. Molecular docking of 4H derivative showed more favorable thermodynamic parameters against thymidylate synthase of B. malayi than human counterpart. A wide difference between IC₅₀ and LD₅₀ ensured the therapeutic safety of the candidates against the filarial parasites. Addition of thymidine to the treatment regimen led to a significant reversal of antifilarial effect of 4H that confirmed inhibition of thymidylate synthase as pharmacological rationale. Apoptosis induced in the parasite as a consequence of probable inhibition of thymidylate synthase was studied by acridine orange/ethidium bromide fluorescent staining and poly (ADP-ribose) polymerase activity inhibition. Involvement of mitochondria was confirmed by decreased 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) conversion and increased cytosolic cytochrome c level in 4H treated microfilariae, compared with the untreated microfilariae. Moreover, Michael adduct of chalcone targeting dihydrofolate reductase and piperidine targeting thymidylate synthase demonstrated synergistic effect on the parasite, indicating the importance of inhibition of DNA synthesis by combined effect. In conclusion, piperidine derivatives with hydroxyl substitution have a great therapeutic potential with an apoptotic rationale involving mitochondrial pathway, due to possible inhibition of parasitic thymidylate synthase.

Sangaletti R et al. (2014) Am J Physiol Cell Physiol "Mechanosensitive unpaired innexin channels in C. elegans touch neurons."

Sangaletti R, Bianchi L, Dahl G

[Am J Physiol Cell Physiol, 2014]

Invertebrate innexin proteins share sequence homology with vertebrate pannexins and general membrane topology with both pannexins and connexins. While connexins form gap junctions that mediate intercellular communication, pannexins are thought to function exclusively as plasma membrane channels permeable to both ions and small molecules. Undoubtedly, certain innexins function as gap junction proteins. However, due to sequence similarity to pannexins, it was postulated that innexins also function as plasma membrane channels. Indeed, some of the leech innexins were found to mediate ATP release as unpaired membrane channels with shared pharmacology to pannexin channels. We show here that Caenorhabditis elegans touch-sensing neurons express a mechanically gated innexin channel with a conductance of 1 nS and voltage-dependent and K(+)-selective subconductance state. We also show that C. elegans touch neurons take up ethidium bromide through a mechanism that is activated and blocked by innexin activating stimuli and inhibitors, respectively. Finally, we present evidence that touch neurons' innexins are required for cell death induced by chemical ischemia. Our work demonstrates that innexins function as plasma membrane channels in native C. elegans neurons, where they may play a role in pathological cell death.