History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia

Colucci, Anna Clara Machado; Tassinari, Isadora D’Ávila; Loss, Eloisa da Silveira; Fraga, Luciano Stürmer de

doi:10.1016/j.neuroscience.2023.06.022

Cited by 8 publications

(5 citation statements)

References 172 publications

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“… 53 In addition, it has been shown to play various neuroprotective roles by modulating energy metabolism and synaptic activity. 54 In our findings, along with an elevated lactate level in the serum, GPR81 increased after MkD, particularly in AD mice, and angiogenesis pathway was mildly upregulated in the hippocampal area. Furthermore, lactate administration ameliorated LPS-induced neuroinflammation by blocking the transport function of monocarboxylate transporter 1 (MCT1) in microglia, leading to improvements in sickness behavior, such as enhancements in total distance in the OFT and performance on the rotarod.…”

Section: Discussionsupporting

confidence: 62%

A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms

Park,

Kadyan,

Hochuli

et al. 2024

Gut Microbes

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Alzheimer’s disease (AD) is a debilitating brain disorder with rapidly mounting prevalence worldwide, yet no proven AD cure has been discovered. Using a multi-omics approach in a transgenic AD mouse model, the current study demonstrated the efficacy of a modified Mediterranean-ketogenic diet (MkD) on AD-related neurocognitive pathophysiology and underlying mechanisms related to the gut-microbiome-brain axis. The findings revealed that MkD induces profound shifts in the gut microbiome community and microbial metabolites. Most notably, MkD promoted growth of the Lactobacillus population, resulting in increased bacteria-derived lactate production. We discovered elevated levels of microbiome- and diet-derived metabolites in the serum as well, signaling their influence on the brain. Importantly, these changes in serum metabolites upregulated specific receptors that have neuroprotective effects and induced alternations in neuroinflammatory-associated pathway profiles in hippocampus. Additionally, these metabolites displayed strong favorable co-regulation relationship with gut-brain integrity and inflammatory markers, as well as neurobehavioral outcomes. The findings underscore the ameliorative effects of MkD on AD-related neurological function and the underlying gut-brain communication via modulation of the gut microbiome-metabolome arrays.

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Section: Discussionsupporting

confidence: 62%

A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms

Park,

Kadyan,

Hochuli

et al. 2024

Gut Microbes

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“…From this approach, the WE would be caused by the same homeostatic mechanisms that operate in healthy cells under normal circumstances. In fact, normal cells continuously produce lactate even under fully aerobic conditions [13,33,61,[82][83][84]. Both glucose uptake and lactate production increase in normal cells when they are stimulated to proliferate, a behavior that closely resembles the WE described in tumors [25].…”

Section: B)mentioning

confidence: 83%

“…hypoxia, as observed in HeLa cells [20]; ii) an increase in glucose supply should raise HIF-α expression and cause the accumulation of NADH (pseudohypoxia) [41,[50][51][52][53]; iii) cancer cells should upregulate HIF-α and aerobic glycolysis, even in normoxia (WE) [26,56,[63][64][65]78]; and iv) healthy cells should normally produce lactate in fully aerobic conditions, and much more so in hypoxia (Reverse WE) [13,33,61,[82][83][84].…”

Section: Discussionmentioning

confidence: 99%

Redefining the role of Hypoxia-inducible factors (HIFs) in oxygen homeostasis

Arias,

Acosta,

Bertocchini

et al. 2024

Preprint

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Hypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell's metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs' activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs' function and underscores the need to explicitly consider the cell's metabolic activity in understanding its responses to changes in oxygen availability.

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“…Additionally, further exploration of the specific production of D-lactate by gut microbiota was valuable for developing D-lactate into a new type of food nutrient factor. Furthermore, mechanistic investigations at the molecular level have elucidated that lactate exerted its effects through specific binding to its receptor GPR81 [41]. Using flow cytometry to subtype lymphocytes might be advantageous for investigating the involvement of GPR81 in immune responses at a more advanced scientific level.…”

Section: Discussionmentioning

confidence: 99%

Yogurt Alleviates Cyclophosphamide-Induced Immunosuppression in Mice through D-Lactate

Du,

Yan,

Dai

et al. 2024

Nutrients

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Numerous studies have investigated the immunomodulatory effects of yogurt, but the underlying mechanism remained elusive. This study aimed to elucidate the alleviating properties of yogurt on immunosuppression and proposed the underlying mechanism was related to the metabolite D-lactate. In the healthy mice, we validated the safety of daily yogurt consumption (600 μL) or D-lactate (300 mg/kg). In immunosuppressed mice induced by cyclophosphamide (CTX), we evaluated the immune regulation of yogurt and D-lactate. The result showed that yogurt restored body weight, boosted immune organ index, repaired splenic tissue, recovered the severity of delayed-type hypersensitivity reactions and increased serum cytokines (IgA, IgG, IL-6, IFN-γ). Additionally, yogurt enhanced intestinal immune function by restoring the intestinal barrier and upregulating the abundance of Bifidobacterium and Lactobacillus. Further studies showed that D-lactate alleviated immunosuppression in mice mainly by promoting cellular immunity. D-lactate recovered body weight and organ development, elevated serum cytokines (IgA, IgG, IL-6, IFN-γ), enhanced splenic lymphocyte proliferation and increased the mRNA level of T-bet in splenic lymphocyte to bolster Th1 differentiation. Finally, CTX is a chemotherapeutic drug, thus, the application of yogurt and D-lactate in the tumor-bearing mouse model was initially explored. The results showed that both yogurt (600 μL) and D-lactate (300 mg/kg) reduced cyclophosphamide-induced immunosuppression without promoting tumor growth. Overall, this study evaluated the safety, immune efficacy and applicability of yogurt and D-lactate in regulating immunosuppression. It emphasized the potential of yogurt as a functional food for immune regulation, with D-lactate playing a crucial role in its immunomodulatory effects.

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History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia

Cited by 8 publications

References 172 publications

A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms

A modified Mediterranean-style diet enhances brain function via specific gut-microbiome-brain mechanisms

Redefining the role of Hypoxia-inducible factors (HIFs) in oxygen homeostasis

Yogurt Alleviates Cyclophosphamide-Induced Immunosuppression in Mice through D-Lactate

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