The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats

Vogelaar, P.; Roorda, Maurits; Vrij, Edwin L de; Houwertjes, M. C.; Goris, Maaike; Bouma, Hjalmar R.; Graaf, Adrianus Cornelis van der; Krenning, Guido; Henning, Robert H.

doi:10.1093/ndt/gfy080

Cited by 18 publications

(22 citation statements)

References 39 publications

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“…As depletion of GSH leads to increased lipid oxidation, it plays a critical role in activating ferroptosis [34,35]. In line with the added importance of mitochondrial function in hypothermia besides ferroptosis alone, the mitochondrial protector Sul-109 has shown to stabilize ATP levels during hypothermia, leading to increased cell survival [36]. In contrast to this, neutralizing excessive ROS formation with anti-oxidant did not affect cell survival.…”

Section: Cell Death In Non-hibernator Cellsmentioning

confidence: 98%

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells

Hendriks

Joschko

Hoogstra-Berends

et al. 2020

IJMS

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Mitochondrial failure is recognized to play an important role in a variety of diseases. We previously showed hibernating species to have cell-autonomous protective mechanisms to resist cellular stress and sustain mitochondrial function. Here, we set out to detail these mitochondrial features of hibernators. We compared two hibernator-derived cell lines (HaK and DDT1MF2) with two non-hibernating cell lines (HEK293 and NRK) during hypothermia (4 °C) and rewarming (37 °C). Although all cell lines showed a strong decrease in oxygen consumption upon cooling, hibernator cells maintained functional mitochondria during hypothermia, without mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential decline or decreased adenosine triphosphate (ATP) levels, which were all observed in both non-hibernator cell lines. In addition, hibernator cells survived hypothermia in the absence of extracellular energy sources, suggesting their use of an endogenous substrate to maintain ATP levels. Moreover, hibernator-derived cells did not accumulate reactive oxygen species (ROS) damage and showed normal cell viability even after 48 h of cold-exposure. In contrast, non-hibernator cells accumulated ROS and showed extensive cell death through ferroptosis. Understanding the mechanisms that hibernators use to sustain mitochondrial activity and counteract damage in hypothermic circumstances may help to define novel preservation techniques with relevance to a variety of fields, such as organ transplantation and cardiac arrest.

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Section: Cell Death In Non-hibernator Cellsmentioning

confidence: 98%

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells

Hendriks

Joschko

Hoogstra-Berends

et al. 2020

IJMS

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“…ROS production by mitochondria is a well-known early effect of IRI [13] and preventing this would be a valuable target for diminishing IRI. SUL compounds have shown to be protective against cold-induced ischemia and mitochondrial dysfunction [18,19]. Both SUL compounds 109 and 121 have shown to increase ATP levels after hypothermic preservation followed by a period of rewarming of adipose-derived stem cells and in rat kidneys [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we combined HMP with SUL-138, a compound in the group of 6chromanols, which are shown to have a mitochondrial protective effect on cells during hypothermia [16]. SUL-138 is the (S)-enantiomer of SUL-109, an agent that has shown to maintain mitochondrial function of cells during hypothermia and rewarming through the activation of complexes I and IV of the electron transport chain [17,18]. In cold stored porcine kidneys, the addition of SUL-121 resulted in α1-adrenoceptor mediated vasodilation upon warm reperfusion which could be attributed to the (R)-enantiomers of SUL-121 (SUL-150) [19].…”

Section: Introductionmentioning

confidence: 99%

The Effects of 6-Chromanol SUL-138 during Hypothermic Machine Perfusion on Porcine Deceased Donor Kidneys

et al. 2021

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Diminishing ischemia-reperfusion injury (IRI) by improving kidney preservation techniques offers great beneficial value for kidney transplant recipients. Mitochondria play an important role in the pathogenesis of IRI and are therefore interesting targets for pharmacological interventions. Hypothermic machine perfusion (HMP), as a preservation strategy, offers the possibility to provide mitochondrial–targeted therapies. This study focuses on the addition of a mitochondrial protective agent SUL—138 during HMP and assesses its effect on kidney function and injury during normothermic reperfusion. In this case, 30 min of warm ischemia was applied to porcine slaughterhouse kidneys before 24 h of non–oxygenated HMP with or without the addition of SUL—138. Functional assessment was performed by 4 h normothermic autologous blood reperfusion. No differences in renal function or perfusion parameters were found between both groups. ATP levels were lower after 30 min of warm ischemia in the SUL–138 group (n.s, p = 0.067) but restored significantly during 24 h of HMP in combination with SUL—138. Aspartate aminotransferase (ASAT) levels were significantly lower for the SUL—138 group. SUL—138 does not influence renal function in this model. Restoration of ATP levels during 24 h of HMP with the addition of SUL in combination with lower ASAT levels could be an indication of improved mitochondrial function.

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“…Alkaline phosphatase-conjugated secondary antibodies and NBT/BCIP (Bio-Rad, VA, USA) were used for detection. Densitometric analysis was performed using Totallab 120 (Nonlinear Dynamics, Newcastle upon Tyne, England) [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

Wang

Pelgrim

Swart³

et al. 2021

IJMS

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Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.

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The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats

Cited by 18 publications

References 39 publications

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells

Hibernator-Derived Cells Show Superior Protection and Survival in Hypothermia Compared to Non-Hibernator Cells

The Effects of 6-Chromanol SUL-138 during Hypothermic Machine Perfusion on Porcine Deceased Donor Kidneys

SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

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