Xie Z et al. (2020) Biomed Pharmacother "Magnolol alleviates Alzheimer's disease-like pathology in transgenic C. elegans by promoting microglia phagocytosis and the degradation of beta-amyloid through activation of PPAR-."

Xie Z, Zhang Z, Fu Y, Xu J, Zhao J, Yang Q, Wang H, Holscher C, Jiang Y, Zeng H

[Biomed Pharmacother, 2020]

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (A) and the possible mechanisms involved. MG dose-dependently reduces A deposition, toxicity and memory impairment caused by A in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor- (PPAR-) antagonist. MG is more effective in enhancing PPAR- luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR- (PPAR--LBD). As expected, MG inhibited the luciferase activity of NF-B and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased A-induced reactive oxygen species (ROS). The target gene LXR of PPAR- is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of A, and these effects were also reversed by GW9662. In summary, MG can attenuate A-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of A, which is dependent on PPAR-.

Frandsen J et al. (2020) ACS Chem Neurosci "Neural Glyoxalase Pathway Enhancement by Morin Derivatives in an Alzheimer's Disease Model."

Frandsen J, Narayanasamy P, Choi SR

[ACS Chem Neurosci, 2020]

The gyloxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), glyoxalase I (glo-1), and glyoxalase II (glo-2) convert MG into D-lactate. Spontaneous reactions involving MG alter the structure and function of cellular macromolecules through the formation of inflammatory advanced glycation endproducts (AGEs). Accumulation of MG and AGEs in neural cells contributes to oxidative stress (OS), a state of elevated inflammation commonly found in neurodegenerative diseases including Alzheimer's Disease (AD). Morin is a common plant-produced flavonoid polyphenol that exhibits the ability to enhance the GP-mediated detoxification of MG. We hypothesize that structural modifications to morin will improve its inherent GP enhancing ability. Here we synthesized a morin derivative, dibromo-morin (DBM) and formulated a morin encapsulated nanoparticle (MNP) - and examined their efficacy in enhancing neural GP activity. Cultured mouse primary cerebellar neurons and Caenorhabditis elegans were induced to a state of OS with MG, and treated with morin, DBM, and MNP. Results indicated the morin derivatives were more effective compared to the parent compound in neural GP enhancement and preventing MG-mediated OS.

Hashizume O et al. (2024) Dev Biol "Intestinal Mg2+ accumulation induced by cnnm mutations decreases the body size by suppressing TORC2 signaling in Caenorhabditis elegans."

Hashizume O, Funato Y, Kawabe T, Miki H

[Dev Biol, 2024]

Mg²⁺ is a vital ion involved in diverse cellular functions by forming complexes with ATP. Intracellular Mg²⁺ levels are tightly regulated by the coordinated actions of multiple Mg²⁺ transporters, such as the Mg²⁺ efflux transporter, cyclin M (CNNM). Caenorhabditis elegans (C. elegans) worms with mutations in both cnnm-1 and cnnm-3 exhibit excessive Mg²⁺ accumulation in intestinal cells, leading to various phenotypic abnormalities. In this study, we investigated the mechanism underlying the reduction in body size in cnnm-1; cnnm-3 mutant worms. RNA interference (RNAi) of gtl-1, which encodes a Mg²⁺-intake channel in intestinal cells, restored the worm body size, confirming that this phenotype is due to excessive Mg²⁺ accumulation. Moreover, RNAi experiments targeting body size-related genes and analyses of mutant worms revealed that the suppression of the target of rapamycin complex 2 (TORC2) signaling pathway was involved in body size reduction, resulting in downregulated DAF-7 expression in head ASI neurons. As the DAF-7 signaling pathway suppresses dauer formation under stress, cnnm-1; cnnm-3 mutant worms exhibited a greater tendency to form dauer upon induction. Collectively, our results revealed that excessive accumulation of Mg²⁺ repressed the TORC2 signaling pathway in C. elegans worms and suggest the novel role of the DAF-7 signaling pathway in the regulation of their body size.

Schulz-Key H et al. (1977) Tropenmed Parasitol "Isolation of living adult Onchocerca volvulus from nodules."

Buttner DW, Albiez EJ, Schulz-Key H

[Tropenmed Parasitol, 1977]

A technique for the isolation of adult Onchocerca volvulus from excised onchocercomata is described. The nodules are incubated in medium 199 containing 1-5 mg collagenase and 0.2 mg gentamicin per ml for 6-48 hours in a waterbath at 30-37 degrees C. A proportion of the worms can be isolated alive.

Abuzar S et al. (1986) J Med Chem "Studies in potential filaricides. 18. Synthesis of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds as potential anthelmintics."

Gupta S, Fatma N, Sen AB, Sharma S, Abuzar S, Katiyar JC, Murthy PK, Chatterjee RK

[J Med Chem, 1986]

A series of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds have been synthesized of which 2,2'-bis(carbomethoxyamino)-5,5'-dibenzimidazolyl ketone exhibited a broad spectrum of anthelmintic activity in experimental animals. At doses of 10-50 mg/kg given intraperitoneally, 5 killed 100% of the adult worms of Litomosoides carinii, Dipetalonema viteae, and Brugia malayi. By the oral route the macrofilaricidal efficacy of 5 was 97-100% at 100-200 mg/kg X 5 days. The treated animals showed gradual disappearance of microfilariae and before autopsy they became amicrofilariaemic. Some of the compounds also showed 100% efficacy against the human hookworms and tapeworm, Ancylostoma ceylanicum in hamsters, and Hymenolepis nana in rats at a single oral dose of 50-250 mg/kg. Compound 5 was also effective against Syphacia obvelata in mice at a single oral dose of 100 mg/kg and was found to be well tolerated by mice up to an oral dose of 2500 mg/kg.

Duke BO (1970) Bull World Health Organ "The effects of drugs on Onchocerca volvulus. 4. Trials of melarsonyl potassium."

Duke BO

[Bull World Health Organ, 1970]

The effects of the arsenical drug melarsonyl potassium on Onchocerca volvulus were investigated in patients in Cameroon infected with the Cameroon forest and Sudan savanna strains of the parasite. Two intramuscular dosage schedules were tested: the first comprised 4 consecutive daily doses of 200 mg repeated once after a 10-14 day interval, i.e., 2 (4x200 mg). The second was a single dose schedule at 7.1 mg/kg-10 mg/kg, with a maximum of 500 mg.In most trials the drug had no immediate action on microfilarial concentrations. Only after the 2(4x200 mg) melarsonyl course against the Sudan savanna strain was a slight microfilaricidal action detected.The 2(4x200 mg) course of melarsonyl apparently killed or sterilized most or all of the adult female worms in the patients tested, leaving the residual population of microfilariae to decline gradually, from natural mortality, over the ensuing 2 years. These residual microfilariae could be killed with diethylcarbamazine.Single doses of melarsonyl at 7.1 mg/kg-10 mg/kg were somewhat less effective in killing or sterilizing adult worms, but it is suggested that if doses at the higher end of this range were to be repeated annually patients could be rendered free from microfilariae by the end of 3 years.It is emphasized that the risks of arsenical encephalopathy should at present preclude the use of melarsonyl potassium in the treatment of onchocerciasis, but that if this danger could be avoided the drug might prove to be of considerable use for mass therapy in control campaigns.

Agotegaray M et al. (2020) J Mater Sci Mater Med "-cyclodextrin coating: improving biocompatibility of magnetic nanocomposites for biomedical applications."

Blanco MG, Agotegaray M, Lassalle V, Massheimer V, Campelo A, Garcia E, De Rosa MJ, Zysler R

[J Mater Sci Mater Med, 2020]

The role Beta-cyclodextrin (CD) on improving biocompatibility on healthy cellular and animal models was studied upon a formulation obtained from the development of a simple coating procedure. The obtained nanosystems were thoroughly characterized by FTIR, TGA, atomic absorption spectroscopy, dynamic light scattering and zeta potential, TEM/HR-TEM and magnetic properties. CD might interact with the magnetic core through hosting OA. It is feasible that the nanocomposite is formed by nanoparticles of MG@OA dispersed in a CD matrix. The evaluation of CD role on biocompatibility was performed on two healthy models. To this end, in vivo studies were carried out on Caenorhabditis elegans. Locomotion and progeny were evaluated after exposure animals to MG, MG@OA, and MG@OA-CD (10 to 500g/mL). The influence of CD on cytotoxicity was explored in vitro on healthy rat aortic endothelial cells, avoiding alteration in the results derived from the use of transformed cell lines. Biological studies demonstrated that CD attaching improves MG biocompatibility.

Hans S et al. (2019) J Glob Antimicrob Resist "Magnesium deprivation affects cellular circuitry involved in drug resistance and virulence in Candida albicans."

Hameed S, Fatima Z, Hans S

[J Glob Antimicrob Resist, 2019]

OBJECTIVES: Candida albicans has to struggle for the limited micronutrients present in the hostile niche. One such significant environmental factor that C. albicans must surmount is magnesium (Mg) limitation. Herein, we aimed to study the effect of Mg deprivation on drug resistance mechanisms and virulence traits of C. albicans. METHODS: Drug susceptibilities against C. albicans SC5314was measured by broth microdilution and spot assay. Drug efflux pump activity was measured by substrate R6G efflux. Membrane intactness was studied by propidium iodide influx and ergosterol levels by alcoholic KOH method. Metabolic flexibility was studied by enzymatic activities of glyoxylate cycle. Virulence factors were assessed by yeast to hyphae, biofilm formation and cell adherence. In-vivo study was performed by Caenorhabditis elegans infection model. RESULTS: We found that Mg chelation leads to potentiation of membrane targeting antifungals. We explored the role of Mg on membrane homeostasis and found significant differences in ergosterol levels. Interestingly we also explored that Mg deprivation impedes metabolic flexibility of C. albicans SC5314 by inhibiting glyoxylate cycle enzymes. Furthermore, Mg deprivation inhibited potential virulence traits including morphological transition, biofilm formation and buccal epithelial cell adherence. All the disrupted targets were validated by RT-PCR which corroborates our findings. Lastly, we demonstrated the enhanced survival of C. albicans SC5314 infected Caenorhabditis elegans model under Mg deprivation. CONCLUSION: In view of the restricted growth of C. albicans in Mg deficient environment, approaches could be utilized to boost the effectiveness of existing antifungals thereby improving the management of fungal infections.

Hashizume O et al. (2020) Antioxid Redox Signal "Excessive Mg²⁺ Impairs Intestinal Homeostasis by Enhanced Production of ATP and Reactive Oxygen Species."

Funato Y, Miki H, Yamazaki D, Hashizume O

[Antioxid Redox Signal, 2020]

<b><i>Aims</i></b>: Mg<sup>2+</sup> is fundamental for life and its shortage severely impairs vital functions. However, whether excessive Mg<sup>2+</sup> has beneficial or adverse effects has remained unknown. To clarify this issue, we analyzed the effect of suppressing the functions of Cyclin M (CNNM) Mg<sup>2+</sup> efflux transporters in various experimental systems. <b><i>Results</i></b>: Investigation of short-lived <i>Caenorhabditis elegans</i> worms mutated for CNNM genes revealed reactive oxygen species (ROS) augmentation in intestinal cells, coincidently with high levels of Mg<sup>2+</sup>. Knockdown of <i>gtl-1</i>, encoding Mg<sup>2+</sup>-incorporating channel into intestinal cells, reduced ROS levels and restored lifespan, confirming the causative role of excessive Mg<sup>2+</sup>. Also, inactivation of orthologous CNNM in human cultured cells and mice by RNA interference, expression of CNNM-inhibiting protein, phosphatase of regenerating liver (PRL) 3, or gene knockout resulted in ROS overproduction. Moreover, biochemical analyses revealed that excessive Mg<sup>2+</sup> stimulates ATP overproduction and accelerates mitochondrial electron transport, whose suppression shut down ROS generation. <b><i>Innovation and Conclusion</i></b>: These results provide definitive evidence that excessive Mg<sup>2+</sup> drives overproduction of ROS by affecting energy metabolism, implying the crucial importance of the tight regulation of intracellular Mg<sup>2+</sup> levels.

Novak J et al. (1992) Folia Microbiol (Praha) "Screening for a new generation of anthelminthic compounds. In vitro selection of the nematode Caenorhabditis elegans for ivermectin resistance."

Novak J, Vanek Z

[Folia Microbiol (Praha), 1992]

Development of resistance to ivermectin in vitro is reported for the first time. Two strains of Caenorhabditis elegans D5 and D6 able to grow on agar plates after treating with up to 3 mg ivermectin per L were selected. The parent strain N2 was extremely sensitive to ivermectin, its growth being inhibited by treatment with 0.1-0.2 mg IVM per L.