Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H2S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted H2S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H2S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H2S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H2S delivery compounds has potential as a therapeutic approach to DMD treatment.

Acute, Sublethal, and Developmental Toxicity of Kratom (Mitragyna speciosa Korth.) Leaf Preparations on Caenorhabditis elegans as an Invertebrate Model for Human Exposure.

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with stimulant and opioid-like effects which has seen increased use in Europe and North America in recent years. Its safety and pharmacological effects remain under investigation, especially in regard to developmental and generational toxicity. In the current study, we investigated commercial kratom preparations using the nematode Caenorhabditis elegans as a translational model for toxicity and pharmacological effects. The pure alkaloids mitragynine and 7-hydroxymitragynine as well as aqueous, ethanolic, and methanolic extracts of three commercial kratom products were evaluated using a battery of developmental, genotoxic, and opioid-related experiments. As determined previously, the mitragynine and 7-hydroxymitragynine content in kratom samples was higher in the alcoholic extracts than the aqueous extracts. Above the human consumption range equivalent of 15-70 µg/mL, kratom dose-dependently reduced brood size and health of parent worms and their progeny. 7-hydroxymitragynine, but not mitragynine, presented with toxic and developmental effects at very high concentrations, while the positive control, morphine, displayed toxic effects at 0.5 mM. Kratom and its alkaloids did not affect pumping rate or interpump interval in the same way as morphine, suggesting that kratom is unlikely to act primarily via the opioid-signalling pathway. Only at very high doses did kratom cause developmental and genotoxic effects in nematodes, indicating its relative safety.

Using a Caenorhabditis elegans Parkinson's Disease Model to Assess Disease Progression and Therapy Efficiency.

Despite Parkinson's Disease (PD) being the second most common neurodegenerative disease, treatment options are limited. Consequently, there is an urgent need to identify and screen new therapeutic compounds that slow or reverse the pathology of PD. Unfortunately, few new therapeutics are being produced, partly due to the low throughput and/or poor predictability of the currently used model organisms and in vivo screening methods. Our objective was to develop a simple and affordable platform for drug screening utilizing the nematode Caenorhabditis elegans. The effect of Levodopa, the "Gold standard" of PD treatment, was explored in nematodes expressing the disease-causing α-synuclein protein. We focused on two key hallmarks of PD: plaque formation and mobility. Exposure to Levodopa ameliorated the mobility defect in C. elegans, similar to people living with PD who take the drug. Further, long-term Levodopa exposure was not detrimental to lifespan. This C. elegans-based method was used to screen a selection of small-molecule drugs for an impact on α-synuclein aggregation and mobility, identifying several promising compounds worthy of further investigation, most notably Ambroxol. The simple methodology means it can be adopted in many labs to pre-screen candidate compounds for a positive impact on disease progression.

An extract of Rosaceae, Solanaceae and Zingiberaceae increases health span and mobility in Caenorhabditis elegans.

BACKGROUND: Members of the Rosaceae, Solanaceae and Zingiberaceae families which include fruits such as cherries, tomatoes and ginger are known to have health promoting effects. There is growing interest in consuming these "functional foods" as a means to increase health and healthy ageing. However, many studies explore the effect of these foods in isolation, not as a blend of multiple functional foods. METHODS: In this study, an extract containing the dried berries, fruits, and roots of members of these families was prepared, which we called Bioact®180. The nematode Caenorhabditis elegans was used to evaluate the effects of Bioact®180 on lifespan and health endpoints, including muscle and mitochondria structure and locomotion. RESULTS: Exposure to the 1000 µg/mL of Bioact®180 extract, containing 4% total phenols, were healthier, as observed by an increase in mean lifespan with and small but significant increase in maximal lifespan. Nematodes exposed to Bioact®180 displayed better mobility in mid-life stages as well as enhanced mitochondrial morphology, which was more comparable to younger animals, suggesting that these worms are protected to some degree from sarcopenia. CONCLUSIONS: Together, our findings reveal that Bioact®180, a blend of fruits and roots from Rosaceae, Solanaceae and Zingiberaceae family members has anti-aging effects. Bioact®180 promotes health and lifespan extension in C. elegans, corresponding to functional improvements in mobility.