scholarly journals A Synthetic SOD/Catalase Mimic Compound for the Treatment of ALS

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 827
Author(s):  
Matan Soll ◽  
Hagit Goldshtein ◽  
Ron Rotkopf ◽  
Niva Russek-Blum ◽  
Zeev Gross
Keyword(s):  
Locomotor Activity ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Iron Homeostasis ◽  
Treated Group ◽  
Iron Complex ◽  
Untreated Group ◽  
Sporadic Als ◽  
Familial Als

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson’s disease, Alzheimer’s disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.

scholarly journals In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

2021 ◽  
Author(s):  
Janet Herrada ◽  
Ahmed Gamal ◽  
Lisa Long ◽  
Sonia P. Sanchez ◽  
Thomas S. McCormick ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Kidney Tissue ◽  
Treated Group ◽  
Untreated Group ◽  
Candida Auris ◽  
Fungal Burden ◽  
In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

scholarly journals The novel chaperone protein SRCP1 reduces insoluble SOD1 protein in vivo without extending ALS mouse lifespan

2020 ◽  
Author(s):  
Ian W. Luecke ◽  
Gloria Lin ◽  
Stephanie Santarriaga ◽  
K. Matthew Scaglione ◽  
Allison D. Ebert
Keyword(s):  
Protein Aggregation ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Insoluble Protein ◽  
Chaperone Protein

AbstractProtein misfolding and aggregation are shared features of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and protein quality control disruption contributes to neuronal toxicity. Therefore, reducing protein aggregation could hold therapeutic potential. We previously identified a novel chaperone protein, serine-rich chaperone protein 1 (SRCP1), that effectively prevents protein aggregation in cell culture and zebrafish models of Huntington’s disease. Here we tested whether this benefit extends to aggregated proteins found in ALS. We used viral-mediated expression of SRCP1 in in vitro and in vivo models of ALS. We found that SRCP1 reduced insoluble SOD1 protein levels in HEK293T cells overexpressing either the A4V or G93R mutant SOD1. However, the reduction of insoluble protein was not observed in either mutant C9orf72 or SOD1 ALS iPSC-derived motor neurons infected with a lentivirus expressing SRCP1. SOD1 G93A ALS mice injected with AAV-SRCP1 showed a small but significant reduction in insoluble and soluble SOD1 in both the brain and spinal cord, but SRCP1 expression did not improve mouse survival. These data indicate that SRCP1 likely reduces insoluble protein burden in a protein and/or context-dependent manner indicating a need for additional insight into SRCP1 function and therapeutic potential.

scholarly journals IBD analysis of Australian amyotrophic lateral sclerosis SOD1-mutation carriers identifies five founder events and links sporadic cases to existing ALS families

2019 ◽  
Author(s):  
Lyndal Henden ◽  
Natalie A. Twine ◽  
Piotr Szul ◽  
Emily P. McCann ◽  
Garth A. Nicholson ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Sporadic Case ◽  
Sporadic Als ◽  
Disease Penetrance ◽  
Sporadic Cases ◽  
Familial Als ◽  
Founder Events ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of upper and lower motor neurons resulting in paralysis and eventual death. Approximately 10% of ALS cases have a family history of disease, while the remaining cases present as apparently sporadic. Heritability studies suggest a significant genetic component to sporadic ALS, and although most sporadic cases have an unknown genetic etiology, some familial ALS mutations have also been found in sporadic cases. This suggests that some sporadic cases may be unrecognised familial cases with reduced disease penetrance. Identifying a familial basis of disease in apparently sporadic ALS cases has significant genetic counselling implications for immediate relatives. A powerful strategy to uncover a familial link is identity-by-descent (IBD) analysis which detects genomic regions that have been inherited from a common ancestor. We performed IBD analysis on 90 Australian familial ALS cases from 25 families and three sporadic ALS cases, each of whom carried one of three SOD1 mutations (p.I114T, p.V149G and p.E101G). We identified five unique haplotypes that carry these mutations in our cohort, indicative of five founder events. This included two different haplotypes that carry SOD1 p.I114T, where one haplotype was present in one sporadic case and 20 families, while the second haplotype was found in the remaining two sporadic cases and one family, thus linking these familial and sporadic cases. Furthermore, we linked two families that carry SOD1 p.V149G and found that SOD1 p.E101G arose independently in each family that carries this mutation.

scholarly journals Oocysts Output of Broilers Experimentally Infected with Eimeria tenella And Treated with N- Butanol Leaf Extract of Khaya senegalensis

2021 ◽  
Vol 41 (3) ◽  
pp. 192-213
Author(s):  
M.O Otu ◽  
I.A Lawal ◽  
D George ◽  
M Abubakar ◽  
A.A Sekoni ◽  
...  
Keyword(s):  
Post Infection ◽  
Treated Group ◽  
Eimeria Tenella ◽  
Post Treatment ◽  
Untreated Group ◽  
Alternative Methods ◽  
Phytochemical Analysis ◽  
Orthodox Medicine ◽  
Khaya Senegalensis

A study to determine the anticoccidial efficacy of Khaya senegalensis in relation to oocyst shedding by broilers experimentally infected with Eimeria tenella was conducted. The development of drug- resistant field strains of Eimeria species has prompted the exploitation of alternative methods for controlling coccidiosis and there is an increasing use of medicinal plants as alternatives to orthodox medicine. Fresh leaves of Khaya senegalensis (KS) were collected dried under shade and the extract prepared using the maceration method in 70% methanol. The dried crude extract was partitioned into petroleum ether, chloroform, n-butanol and aqueous portions, dried with phytochemical analysis conducted on them. One hundred and twenty birds reared under standard management practice were divided into six groups (A, B, C, D, E and F). All the groups except group F (uninfected untreated group) were infected at four weeks old with sporulated Eimeria tenella oocysts (1.0 x 105 sporulated oocysts / ml / bird) obtained locally from the intestinal scrapings of experimentally infected broilers. Groups A, B and C were given calculated three dose levels of 11mg/kg, 33mg/kg, 99mg/kg respectively of the prepared n-butanol methanol extract twice daily for 5 days, group D was given Amprolium while E and F were each given 0.2ml water. Faecal samples were collected daily for 4 weeks into clean well labelled polythene bags and analysed in the laboratory for oocyst count using the McMaster counting chamber and were expressed as oocysts count per gramme of faeces. The birds were observed for pathological lesions grossly and histopathologically and the survival rates were determined. Data collected were analysed using analysis of variance and chi square. Results from the Phytochemical studies showed the presence of phenolic compounds in Khaya senegalensis. Post-infection faecal examination revealed oocyst load of +++ in all the infected pens (A-E) on the 6th day. Comparison of the groups with time showed statistical significance (P˂0.05). High mean oocyst production (A; 156060 ± 67020, B; 261590 ± 144310, C; 211620 ± 114280, D; 276930 ± 233650 and E; 159230 ± 100970) among the infected groups one week post infection as well as irregular oocyst production were observed in the course of this study. The higher mean oocysts count obtained in the infected untreated group (1748849 ± 40869) than the extract treated groups in the first week post treatment indicated that the extract had some inhibitory effects on oocyst production. This however, was dose dependent. Among the extract treated group, the 99mg/kg had lower mean oocyst production 2 weeks post treatment (9720 ± 3180) and this was comparable to the group treated with normal dose of the conventional drug Amprolium (8600 ± 40). This was therefore seen as the effective dose. Grossly, the extract had a beneficial effect in alleviating the damages to the caecal epithelium of the infected treated groups compared to the shrunken caeca of the infected untreated groups. The survival percentage was higher in the treated groups compared to the infected un treated group (55%) though Amprolium was more efficacious in the in vivo study with the highest survival rate of 90%. The histopathological lesions observed in the infected birds in this study were consistent with those associated with E tenella infection in which the parasite induced very severe lesions including severe villous atrophy and fusion. The anticoccidial efficacy of Khaya senegalensis promises greater areas for research as it relates to drug development and it is recommended that Khaya senegalensis should be exploited further for its anticoccidial properties using other parts of the plant. Key words: Broiler chickens, Eimeria tenella, oocyst production, Khaya senegalensis, in vivo

scholarly journals Risedronate Attenuates Podocyte Injury in Phosphate Transporter-Overexpressing Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Yohei Asada ◽  
Takeshi Takayanagi ◽  
Tsukasa Kawakami ◽  
Eisuke Tomatsu ◽  
Atsushi Masuda ◽  
...  
Keyword(s):  
Experimental Period ◽  
Treated Group ◽  
Untreated Group ◽  
Wild Type ◽  
Podocyte Injury ◽  
Mineral Bone Disorder ◽  
Phosphorus Accumulation ◽  
Glomerular Barrier ◽  
Microscopy Images

Osteoporosis patients with chronic kidney disease (CKD) are becoming common in our superaging society. Renal dysfunction causes phosphorus accumulation in the circulating plasma and leads to the development of CKD-mineral bone disorder (MBD). We have previously reported that type III Pi transporter-overexpressing transgenic (Pit-1 TG) rats manifest phosphate (Pi)-dependent podocyte injury. In the present study, we explored the effect of risedronate on Pi-induced podocyte injury in vivo. Pit-1 TG rats and wild-type rats at 5 weeks old were divided into a risedronate-treated group and an untreated group. We subcutaneously administered 5 μg/kg body weight of risedronate or saline twice a week during the experimental period. Risedronate did not alter serum creatinine levels at 5, 8, and 12 weeks of age. However, electron microscopy images showed that thickening of the glomerular basement membrane was improved in the risedronate treatment group. Furthermore, immunostaining for podocyte injury markers revealed that both desmin- and connexin43-positive areas were smaller in the risedronate-treated group than in the untreated group, suggesting that bisphosphonates could rescue Pi-induced podocyte injury. In conclusion, our findings suggest that risedronate could maintain glomerular barrier function by rescuing Pi-induced podocyte injury.

scholarly journals Effects of maturation on the conformational free-energy landscape of SOD1

2018 ◽  
Vol 115 (11) ◽  
pp. E2546-E2555 ◽  
Author(s):  
Robert M. Culik ◽  
Ashok Sekhar ◽  
Jayashree Nagesh ◽  
Harmeen Deol ◽  
Jessica A. O. Rumfeldt ◽  
...  
Keyword(s):  
Free Energy ◽  
Motor Neurons ◽  
Disulfide Bond ◽  
Posttranslational Modifications ◽  
Protein Misfolding ◽  
Metal Loss ◽  
Free Energy Surface ◽  
Switch Mechanism ◽  
Misfolded Sod1

Amyotrophic lateral sclerosis (ALS) is a devastating fatal syndrome characterized by very rapid degeneration of motor neurons. A leading hypothesis is that ALS is caused by toxic protein misfolding and aggregation, as also occurs in many other neurodegenerative disorders, such as prion, Alzheimer’s, Parkinson’s, and Huntington’s diseases. A prominent cause of familial ALS is mutations in the protein superoxide dismutase (SOD1), which promote the formation of misfolded SOD1 conformers that are prone to aberrant interactions both with each other and with other cellular components. We have shown previously that immature SOD1, lacking bound Cu and Zn metal ions and the intrasubunit disulfide bond (apoSOD12SH), has a rugged free-energy surface (FES) and exchanges with four other conformations (excited states) that have millisecond lifetimes and sparse populations on the order of a few percent. Here, we examine further states of SOD1 along its maturation pathway, as well as those off-pathway resulting from metal loss that have been observed in proteinaceous inclusions. Metallation and disulfide bond formation lead to structural transformations including local ordering of the electrostatic loop and native dimerization that are observed in rare conformers of apoSOD12SH; thus, SOD1 maturation may occur via a population-switch mechanism whereby posttranslational modifications select for preexisting structures on the FES. Metallation and oxidation of SOD1 stabilize the native, mature conformation and decrease the number of detected excited conformational states, suggesting that it is the immature forms of the protein that contribute to misfolded conformations in vivo rather than the highly stable enzymatically active dimer.

In vivo Experiments of Natural Products Protection of Antagonistic Effects of Lead on Iron

2018 ◽  
Vol 68 (12) ◽  
pp. 2747-2751
Author(s):  
Marioara Nicula ◽  
Nicolae Pacala ◽  
Lavinia Stef ◽  
Ioan Pet ◽  
Dorel Dronca ◽  
...  
Keyword(s):  
Aquatic Environment ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Antagonistic Effect ◽  
Tissue Samples ◽  
Antagonistic Effects ◽  
In Vivo Experiments ◽  
Living Organisms ◽  
Toxic Potential

Living organisms take nutrients from the environment, and together with them, substances with toxic potential � such as heavy metals. Lead is one common metal pollutant especially in aquatic environment, from where the fish can be intoxicated very easily. Bioavailability, distribution, toxic action, synergistic and antagonistic effects are characteristics which can alter the fish health. Our experimental study followed the effects of lead overload in water on iron distribution, in different tissues sample Carassius gibelio Bloch fish. We performed the experiment in four different fish groups: control C; lead � Pb (administration of lead in water 0.075mg/mL of water, as Pb(NO3)2 x � H2O); lead (the same dose) and 2% of freeze-dry garlic incorporated into fishes� food � Pb+garlic; lead (the same dose) and 2% chlorella incorporated into fishes� food � Pb+chlorella, for 21 consecutive days. The iron concentration was analysed with AAS (Atomic Absorption Spectroscopy) from gills, muscle, skin (and scales), intestine, liver, heart, brain, ovary, testicles, and kidney. The obtained data presented a significantly decrease of iron content in all tested tissue samples that demonstrated, alteration of iron homeostasis, explained by a strong antagonistic effect of lead on iron. Our experiment showed that biologic active principles from garlic and chlorella act like natural protectors, and potentiate the iron deficiency even in the case of lead overload in aquatic environment, for fish.

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