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Article ; Online: Mitochondrial Effects of Hydromethylthionine, Rivastigmine and Memantine in Tau-Transgenic Mice.

Kondak, Constantin / Leith, Michael / Baddeley, Thomas C / Santos, Renato X / Harrington, Charles R / Wischik, Claude M / Riedel, Gernot / Klein, Jochen

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT ... ...

Abstract	Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2-4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug.
MeSH term(s)	Mice ; Animals ; Rivastigmine/pharmacology ; Memantine/pharmacology ; Memantine/therapeutic use ; tau Proteins/genetics ; tau Proteins/metabolism ; Mice, Transgenic ; Cholinesterase Inhibitors/pharmacology ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/chemically induced ; Mitochondria/metabolism
Chemical Substances	Rivastigmine (PKI06M3IW0) ; Memantine (W8O17SJF3T) ; tau Proteins ; hydromethylthionine (IHU4GYZ2R3) ; Cholinesterase Inhibitors
Language	English
Publishing date	2023-06-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241310810
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mitochondrial Effects of Hydromethylthionine, Rivastigmine and Memantine in Tau-Transgenic Mice

Constantin Kondak / Michael Leith / Thomas C. Baddeley / Renato X. Santos / Charles R. Harrington / Claude M. Wischik / Gernot Riedel / Jochen Klein

International Journal of Molecular Sciences, Vol 24, Iss 10810, p

2023 Volume 10810

Abstract: Tau protein aggregations are important contributors to the etiology of Alzheimer’s disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT ... ...

Abstract	Tau protein aggregations are important contributors to the etiology of Alzheimer’s disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2–4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug.
Keywords	microdialysis ; Alzheimer’s disease ; rivastigmine ; memantine ; complex I ; cytochrome c oxidase ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Human impacts as the main driver of tropical forest carbon.

Pyles, Marcela Venelli / Magnago, Luiz Fernando Silva / Maia, Vinícius Andrade / Pinho, Bruno X / Pitta, Gregory / de Gasper, André L / Vibrans, Alexander C / Dos Santos, Rubens Manoel / van den Berg, Eduardo / Lima, Renato A F

Science advances

2022 Volume 8, Issue 24, Page(s) eabl7968

Abstract: Understanding the mechanisms controlling forest carbon storage is crucial to support "nature-based" solutions for climate change mitigation. We used a dataset of 892 Atlantic Forest inventories to assess the direct and indirect effects of environmental ... ...

Abstract	Understanding the mechanisms controlling forest carbon storage is crucial to support "nature-based" solutions for climate change mitigation. We used a dataset of 892 Atlantic Forest inventories to assess the direct and indirect effects of environmental conditions, human impacts, tree community proprieties, and sampling methods on tree above-ground carbon stocks. We showed that the widely accepted drivers of carbon stocks, such as climate, soil, topography, and forest fragmentation, have a much smaller role than the forest disturbance history and functional proprieties of the Atlantic Forest. Specifically, within-forest disturbance level was the most important driver, with effect at least 30% higher than any of the environmental conditions individually. Thus, our findings suggest that the conservation of tropical carbon stocks may be dependable on, principally, avoiding forest degradation and that conservation policies focusing only on carbon may fail to protect tropical biodiversity.
Language	English
Publishing date	2022-06-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abl7968
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Article: HMTM-Mediated Enhancement of Brain Bioenergetics in a Mouse Tauopathy Model Is Blocked by Chronic Administration of Rivastigmine.

Santos, Renato X / Melis, Valeria / Goatman, Elizabeth A / Leith, Michael / Baddeley, Thomas C / Storey, John M D / Riedel, Gernot / Wischik, Claude M / Harrington, Charles R

Biomedicines

2022 Volume 10, Issue 4

Abstract: The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer's disease (AD) clinical trials; the ...

Abstract	The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer's disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiety has been reported to increase the clearance of pathological tau and to enhance mitochondrial activity, which is impaired in AD patients. In line 1 (L1) mice (a model of AD), HMTM (5/15 mg/kg) was administered either as a monotherapy or as an add-on to a chronic administration with the cholinesterase inhibitor rivastigmine (0.1/0.5 mg/kg) to explore mitochondrial function and energy substrate utilization as potential targets of drug interference. Compared with wild-type NMRI mice, the L1 mice accumulated greater levels of l-lactate and of the LDH-A subunit responsible for the conversion of pyruvate into l-lactate. In contrast, the levels of LDH-B and mitochondrial ETC subunits and the activity of complexes I and IV was not altered in the L1 mice. The activity of complex I and complex IV tended to increase with the HMTM dosing, in turn decreasing l-lactate accumulation in the brains of the L1 mice, despite increasing the levels of LDH-A. The chronic pre-dosing of the L1 mice with rivastigmine partially prevented the enhancement of the activity of complexes I and IV by HMTM and the increase in the levels of LDH-A while further reducing the levels of l-lactate. Thus, HMTM in combination with rivastigmine leads to a depletion in the energy substrate l-lactate, despite bioenergetic production not being favoured. In this study, the changes in l-lactate appear to be regulated by LDH-A, since neither of the experimental conditions affected the levels of LDH-B. The data show that HMTM monotherapy facilitates the use of substrates for energy production, particularly l-lactate, which is provided by astrocytes, additionally demonstrating that a chronic pre-treatment with rivastigmine prevented most of the HMTM-associated effects.
Language	English
Publishing date	2022-04-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10040867
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Article ; Online: HMTM-Mediated Enhancement of Brain Bioenergetics in a Mouse Tauopathy Model Is Blocked by Chronic Administration of Rivastigmine

Renato X. Santos / Valeria Melis / Elizabeth A. Goatman / Michael Leith / Thomas C. Baddeley / John M. D. Storey / Gernot Riedel / Claude M. Wischik / Charles R. Harrington

Biomedicines, Vol 10, Iss 867, p

2022 Volume 867

Abstract	The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer’s disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiety has been reported to increase the clearance of pathological tau and to enhance mitochondrial activity, which is impaired in AD patients. In line 1 (L1) mice (a model of AD), HMTM (5/15 mg/kg) was administered either as a monotherapy or as an add-on to a chronic administration with the cholinesterase inhibitor rivastigmine (0.1/0.5 mg/kg) to explore mitochondrial function and energy substrate utilization as potential targets of drug interference. Compared with wild-type NMRI mice, the L1 mice accumulated greater levels of l -lactate and of the LDH-A subunit responsible for the conversion of pyruvate into l -lactate. In contrast, the levels of LDH-B and mitochondrial ETC subunits and the activity of complexes I and IV was not altered in the L1 mice. The activity of complex I and complex IV tended to increase with the HMTM dosing, in turn decreasing l -lactate accumulation in the brains of the L1 mice, despite increasing the levels of LDH-A. The chronic pre-dosing of the L1 mice with rivastigmine partially prevented the enhancement of the activity of complexes I and IV by HMTM and the increase in the levels of LDH-A while further reducing the levels of l -lactate. Thus, HMTM in combination with rivastigmine leads to a depletion in the energy substrate l -lactate, despite bioenergetic production not being favoured. In this study, the changes in l -lactate appear to be regulated by LDH-A, since neither of the experimental conditions affected the levels of LDH-B. The data show that HMTM monotherapy facilitates the use of substrates for energy production, particularly l -lactate, which is provided by astrocytes, additionally demonstrating that a chronic pre-treatment with ...
Keywords	Alzheimer’s disease ; bioenergetics ; hydromethylthionine ; lactate ; HMTM ; mitochondria ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Effects of two intensities of treadmill exercise on neuromuscular recovery after median nerve crush injury in Wistar rats.

Ferreira, Marcílio Coelho / Oliveira, Murilo X / Souza, Josiane I / Souza, Renato A / Machado, Thaís P G / Santos, Ana Paula

Journal of exercise rehabilitation

2019 Volume 15, Issue 3, Page(s) 392–400

Abstract: Considering the potential action of exercise on neuroplasticity and the need to adapt protocols to enhance functional recovery after nerve injury, this study evaluated the effects of two intensities of treadmill exercise on nervous and muscular tissues ... ...

Abstract	Considering the potential action of exercise on neuroplasticity and the need to adapt protocols to enhance functional recovery after nerve injury, this study evaluated the effects of two intensities of treadmill exercise on nervous and muscular tissues and functional recovery after nerve crush injury.
Language	English
Publishing date	2019-06-30
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2756291-8
ISSN	2288-1778 ; 2288-176X
ISSN (online)	2288-1778
ISSN	2288-176X
DOI	10.12965/jer.19.328126.063
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Article ; Online: Study on radiation dosimetry and radioprotection applied to Seaport Cargo Inspection Activity.

Gomes, Renato G / Braga, Kelmo L / Silva, Ademir X / Correa, Samanda C A / Stenders, Ricardo M / Rebello, Wilson F / Berdeguez, Mirta B T / Santos, Raphael F G / Andrade, Edson R

Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine

2020 Volume 160, Page(s) 109130

MeSH term(s)	Calibration ; Radiation Protection/methods ; Radiometry/methods
Language	English
Publishing date	2020-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	1142596-9
ISSN	1872-9800 ; 0883-2889 ; 0969-8043
ISSN (online)	1872-9800
ISSN	0883-2889 ; 0969-8043
DOI	10.1016/j.apradiso.2020.109130
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Article ; Online: THC inhibits the expression of ethanol-induced locomotor sensitization in mice.

Filev, Renato / Engelke, Douglas S / Da Silveira, Dartiu X / Mello, Luiz E / Santos-Junior, Jair G

Alcohol (Fayetteville, N.Y.)

2017 Volume 65, Page(s) 31–35

Abstract: The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans. Here, ...

Abstract	The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans. Here, we verified the effects of the two main phytocannabinoid compounds of Cannabis sp., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), in the expression of ethanol-induced locomotor sensitization in mice. Male adult DBA/2 mice were exposed to locomotor sensitization by daily intraperitoneal injections of ethanol (2.5 g/kg) for 12 days; control groups received saline. After the acquisition phase, animals were treated with cannabinoids: CBD (2.5 mg/kg); THC (2.5 mg/kg); CBD + THC (1:1 ratio), or vehicle for 4 days with no access to ethanol during this period. One day after the last cannabinoid injection, all animals were challenged with ethanol (2.0 g/kg) to evaluate the expression of the locomotor sensitization. Mice treated with THC alone or THC + CBD showed reduced expression of locomotor sensitization, compared to the vehicle control group. No effects were observed with CBD treatment alone. Our findings showing that phytocannabinoid treatment prevents the expression of behavioral sensitization in mice provide insight into the potential therapeutic use of phytocannabinoids in alcohol-related problems.
MeSH term(s)	Animals ; Cannabinoid Receptor Agonists/pharmacology ; Dronabinol/pharmacology ; Ethanol/administration & dosage ; Injections, Intraperitoneal ; Locomotion/drug effects ; Locomotion/physiology ; Male ; Mice ; Mice, Inbred DBA
Chemical Substances	Cannabinoid Receptor Agonists ; Ethanol (3K9958V90M) ; Dronabinol (7J8897W37S)
Language	English
Publishing date	2017-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	605912-0
ISSN	1873-6823 ; 0741-8329
ISSN (online)	1873-6823
ISSN	0741-8329
DOI	10.1016/j.alcohol.2017.06.004
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Article ; Online: Brazilian regulatory authority contribution to the shielding dimensioning model of radiotherapy rooms proposed by the NCRP 151.

L Braga, Kelmo / G Gomes, Renato / Terra, André M B P T / Silva, Ademir X / Medeiros, Marcos P C / Stenders, Ricardo M / Rebello, Wilson F / Salata, Camila / Santos, Raphael F G / R Andrade, Edson

Biomedical physics & engineering express

2020 Volume 6, Issue 6

Abstract: The National Council on Radiation Protection and Measurements (NCRP) Report No. 151 is an essential document for bunker design commonly applied for radiotherapy treatment rooms. This document is used as a reference by several countries, including Brazil. ...

Abstract	The National Council on Radiation Protection and Measurements (NCRP) Report No. 151 is an essential document for bunker design commonly applied for radiotherapy treatment rooms. This document is used as a reference by several countries, including Brazil. The objective of this study is to evaluate the shielding dimensioning methodology recommended by NCRP 151, and compare it with the one adopted by the Brazilian regulatory authority. Radiotherapy rooms and respective doors were designed to use linear accelerators operating at 6, 10, 15, and 18 MeV under two different ways: (a) applying exclusively the methodology recommended by the NCRP 151, and (b) taking into consideration the complementary recommendations from the Brazilian authorities. The results suggest that designers in Brazil can count on at least 4 and 11% safety margin for dimensioning primary barriers in controlled and free areas respectively. Also 8% for secondary barriers in controlled areas, 9.7% for secondary barriers adjacent to the primary belt of free areas, and 6.6% for the lead of the doors.
MeSH term(s)	Brazil ; Particle Accelerators ; Protective Devices ; Radiation Protection/methods
Language	English
Publishing date	2020-09-30
Publishing country	England
Document type	Journal Article
ISSN	2057-1976
ISSN (online)	2057-1976
DOI	10.1088/2057-1976/abbabe
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Article ; Online: Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.

Zhu, Wenhan / Miyata, Naoteru / Winter, Maria G / Arenales, Alexandre / Hughes, Elizabeth R / Spiga, Luisella / Kim, Jiwoong / Sifuentes-Dominguez, Luis / Starokadomskyy, Petro / Gopal, Purva / Byndloss, Mariana X / Santos, Renato L / Burstein, Ezra / Winter, Sebastian E

The Journal of experimental medicine

2019 Volume 216, Issue 10, Page(s) 2378–2393

Abstract: Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin- ... ...

Abstract	Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing
MeSH term(s)	Animals ; Colitis/chemically induced ; Colitis/genetics ; Colitis/microbiology ; Colitis/pathology ; Colorectal Neoplasms/chemically induced ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/microbiology ; Dextran Sulfate/toxicity ; Dysbiosis/chemically induced ; Dysbiosis/genetics ; Dysbiosis/microbiology ; Escherichia coli/growth & development ; Gastrointestinal Microbiome ; Interleukin-10/deficiency ; Mice ; Neoplasms, Experimental/chemically induced ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/microbiology
Chemical Substances	IL10 protein, mouse ; Interleukin-10 (130068-27-8) ; Dextran Sulfate (9042-14-2)
Language	English
Publishing date	2019-07-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20181939
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