25 years of development of Mn porphyrins — from mimics of superoxide dismutase enzymes to thiol signaling to clinical trials: The story of our life in the USA

2019 ◽  
Vol 23 (11n12) ◽  
pp. 1326-1335 ◽  
Author(s):  
Ines Batinic-Haberle ◽  
Ivan Spasojevic
Keyword(s):  
Clinical Trials ◽  
Superoxide Dismutase ◽  
Signaling Proteins ◽  
Phase Ii Clinical Trials ◽  
Protein Thiols ◽  
The Usa ◽  
Thiol Signaling ◽  
Mn Porphyrins ◽  
High Bioavailability

We have developed Mn porphyrins (MnPs) initially as mimics of superoxide dismutase (SOD) enzymes based on structure–activity relationships. Several cationic Mn porphyrins, being substituted with cationic ortho [Formula: see text]-alkyl- or alkoxyalkylpyridyl groups in meso positions of the porphyrin ring, have been identified as potential therapeutics based on their high SOD-like activity and high bioavailability. Two of those [Mn(III) meso-tetrakis([Formula: see text]-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP[Formula: see text] (BMX-010, AEOL10113) and Mn(III) meso-tetrakis(Nn-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP[Formula: see text] (BMX-001)] are now in five Phase II clinical trials. Studies of ours, and those of others, contributed to the understanding of the diverse activities of these compounds. With biologically compatible potentials and four biologically accessible oxidation states, Mn porphyrins interact with numerous reactive species, both as oxidants and reductants. Among those reactions, their abilities to (catalytically) oxidize [Formula: see text]-glutathionylate protein thiols may perhaps be their major in vivo mode of action. Via [Formula: see text]-glutathionylation, MnPs modulate actions of signaling proteins and, in turn, cellular apoptotic and proliferative pathways. During the major part of our stay in the USA, our lives have been dedicated to Mn porphyrins. Our families and especially our son and his three babies have been our inspiration not to give up on a life often burdened with hardship. It is thus our immense pleasure to see our compounds in clinical trials. Above all, we hope that our story will inspire future researchers to persevere — women in particular.

scholarly journals Quantitative proteomic analysis of the tizoxanide effect in vero cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
K. A. Yamamoto ◽  
K. Blackburn ◽  
E. Migowski ◽  
M. B. Goshe ◽  
D. T. Brown ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Rna Processing ◽  
Cell Metabolism ◽  
Antimicrobial Effect ◽  
Vero Cells ◽  
Label Free ◽  
Proteomic Approach ◽  
The Usa

Abstract Nitazoxanide (NTZ) is effective against helminths and numerous microorganisms, including bacteria and viruses. In vivo, NTZ is metabolized into Tizoxanide (TIZ), which is the active circulating metabolite. With the emergence of SARS-Cov-2 as a Pandemic agent, NTZ became one of the molecules already approved for human use to engage clinical trials, due to results in vitro showing that NTZ was highly effective against the SARS-Cov-2, agent of COVID-19. There are currently several ongoing clinical trials mainly in the USA and Brazil involving NTZ due not only to the in vitro results, but also for its long-known safety. Here, we study the response of Vero cells to TIZ treatment and unveil possible mechanisms for its antimicrobial effect, using a label-free proteomic approach (LC/MS/MS) analysis to compare the proteomic profile between untreated- and TIZ-treated cells. Fifteen differentially expressed proteins were observed related to various biological processes, including translation, intracellular trafficking, RNA processing and modification, and signal transduction. The broad antimicrobial range of TIZ points towards its overall effect in lowering cell metabolism and RNA processing and modification. The decreased levels of FASN, HNRNPH and HNRNPK with the treatment appear to be important for antiviral activity.

scholarly journals TheREnantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis

2013 ◽  
Vol 57 (10) ◽  
pp. 4699-4706 ◽  
Author(s):  
Stephen Patterson ◽  
Susan Wyllie ◽  
Laste Stojanovski ◽  
Meghan R. Perry ◽  
Frederick R. C. Simeons ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Visceral Leishmaniasis ◽  
Phase Ii ◽  
Leishmania Donovani ◽  
Oral Treatment ◽  
Parasite Burden ◽  
Content Type ◽  
Phase Ii Clinical Trials

ABSTRACTThe novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity againstMycobacterium tuberculosisin vitroandin vivoand is currently in phase II clinical trials for tuberculosis (TB). In contrast toM. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity againstLeishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although thein vitroandin vivopharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight−1, twice daily for 5 days. InM. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent inLeishmaniaspp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studiesin vitroindicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.

Superoxide, Xanthine Oxidase and Platelet Reactions: Further Studies on Mechanisms by which Oxidants Influence Platelets

1981 ◽  
Vol 45 (03) ◽  
pp. 290-293 ◽  
Author(s):  
Peter H Levine ◽  
Danielle G Sladdin ◽  
Norman I Krinsky
Keyword(s):  
Superoxide Dismutase ◽  
Cytochrome C ◽  
Xanthine Oxidase ◽  
Direct Effect ◽  
Platelet Function ◽  
Experimental Conditions ◽  
Release Reaction

SummaryIn the course of studying the effects on platelets of the oxidant species superoxide (O- 2), Of was generated by the interaction of xanthine oxidase plus xanthine. Surprisingly, gel-filtered platelets, when exposed to xanthine oxidase in the absence of xanthine substrate, were found to generate superoxide (O- 2), as determined by the reduction of added cytochrome c and by the inhibition of this reduction in the presence of superoxide dismutase.In addition to generating Of, the xanthine oxidase-treated platelets display both aggregation and evidence of the release reaction. This xanthine oxidase induced aggreagtion is not inhibited by the addition of either superoxide dismutase or cytochrome c, suggesting that it is due to either a further metabolite of O- 2, or that O- 2 itself exerts no important direct effect on platelet function under these experimental conditions. The ability of Of to modulate platelet reactions in vivo or in vitro remains in doubt, and xanthine oxidase is an unsuitable source of O- 2 in platelet studies because of its own effects on platelets.

ACE-2-Receptors of the Epidermis, Dermal Vascular Walls and Sebaceous Gland Cells: The Way of COVID-19 Entry into the Body?

2020 ◽  
Author(s):  
Stefan Bittmann
Keyword(s):  
Clinical Trials ◽  
Viral Infection ◽  
Sebaceous Gland ◽  
The Body ◽  
Viral Agent ◽  
Therapy Options ◽  
Vascular Walls ◽  
Fish Market ◽  
The World ◽  
The Usa

Since the outbreak near a fish market in Wuhan, China, in December 2019, researchers have been searching for an effective therapy to control the spreading of the new coronavirus SARS-CoV-2 and inhibit COVID-19 infection. Many countries like Italy, Spain, and the USA were ambushed by this viral agent. To date, more than 2.5 million people were infected with SARS-CoV-2. There is no clear answer, why SARS-CoV-2 infects so many people so fast. To date of April 2020, no effective drug has been found to treat this new severe viral infection. There are many therapy options under review and clinical trials were initiated to get clearer information, what kind of drug can help in this devastating and serious situation. The world has no time.

Naphthoquinone Derivatives Isolated from Plants: Recent Advances in Biological Activity

2020 ◽  
Vol 20 (19) ◽  
pp. 2019-2035
Author(s):  
Esmaeil Sheikh Ahmadi ◽  
Amir Tajbakhsh ◽  
Milad Iranshahy ◽  
Javad Asili ◽  
Nadine Kretschmer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biological Activity ◽  
Small Molecules ◽  
Anticancer Activity ◽  
Clinical Significance ◽  
Phase Ii ◽  
Biological Activities ◽  
Phase Ii Clinical Trials ◽  
Naturally Occurring ◽  
The Subject

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals Whither Magnetic Hyperthermia? A Tentative Roadmap

Materials ◽  
2021 ◽  
Vol 14 (4) ◽  
pp. 706
Author(s):  
Irene Rubia-Rodríguez ◽  
Antonio Santana-Otero ◽  
Simo Spassov ◽  
Etelka Tombácz ◽  
Christer Johansson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Nanoparticle Synthesis ◽  
Careful Analysis ◽  
Magnetic Hyperthermia ◽  
Lessons Learned ◽  
In Vivo Testing ◽  
Evolution Of Science ◽  
Made In ◽  
Critical Aspects

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.

scholarly journals Superoxide Dismutase 1 Nanoparticles (Nano-SOD1) as a Potential Drug for the Treatment of Inflammatory Eye Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 396
Author(s):  
Alexander N. Vaneev ◽  
Olga A. Kost ◽  
Nikolay L. Eremeev ◽  
Olga V. Beznos ◽  
Anna V. Alova ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Reproductive Toxicity ◽  
Clinical Problem ◽  
Eye Diseases ◽  
Therapeutic Modality ◽  
Side Reactions ◽  
Copper Zinc Superoxide Dismutase ◽  
Tissue Degeneration ◽  
Endogenous Antioxidant

Inflammatory eye diseases remain the most common clinical problem in ophthalmology. The secondary processes associated with inflammation, such as overproduction of reactive oxygen species (ROS) and exhaustion of the endogenous antioxidant system, frequently lead to tissue degeneration, vision blurring, and even blindness. Antioxidant enzymes, such as copper–zinc superoxide dismutase (SOD1), could serve as potent scavengers of ROS. However, their delivery into the eye compartments represents a major challenge due to the limited ocular penetration. This work presents a new therapeutic modality specifically formulated for the eye on the basis of multilayer polyion complex nanoparticles of SOD1 (Nano-SOD1), which is characterized by appropriate storage stability and pronounced therapeutic effect without side reactions such as eye irritation; acute, chronic, and reproductive toxicity; allergenicity; immunogenicity; mutagenicity even at high doses. The ability of Nano-SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with a model immunogenic uveitis—the inflammation of the inner vascular tract of the eye. It was shown during preclinical studies that topical instillations of Nano-SOD1 were much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as corneal and conjunctival edema, iris hyperemia, and fibrin clots. Moreover, Nano-SOD1 penetrates into interior eye structures more effectively than SOD itself and retains enzyme activity in the eye for a much longer period of time, decreasing inflammation and restoring antioxidant activity in the eye. Thus, the presented Nano-SOD1 can be considered as a potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.

scholarly journals Stable Mn(III) porphyrins mimic superoxide dismutase in vitro and substitute for it in vivo.

1994 ◽  
Vol 269 (38) ◽  
pp. 23471-23476 ◽  
Author(s):  
K.M. Faulkner ◽  
S.I. Liochev ◽  
I. Fridovich
Keyword(s):  
Superoxide Dismutase
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