Energy Metabolism Dysfunction Research Articles

Passion fruit seed extract protects hydrogen peroxide-induced cell damage in human retinal pigment epithelium ARPE-19 cells

Age-related macular degeneration (AMD) is a major cause of vision loss among adults. We investigated the protective effects of passion fruit seed extract (PFSE) and its rich polyphenol piceatannol in an AMD cell model in which human retinal pigment epithelial ARPE-19 cells were exposed to hydrogen peroxide (H2O2). Using a cell viability WST-8 assay, we revealed that PFSE and piceatannol increased the cellular viability of ARPE-19 cells by 130% and 133%, respectively. Moreover, PFSE and piceatannol recovered the cell viability of ARPE-19 cells, which had decreased to 60% owing to H2O2-induced damage, to approximately 84% and 89%, respectively. In addition, we found that the treatment of ARPE-19 cells with H2O2 decreased the mitochondrial and glycolytic ATP production rate to approximately 54% that of healthy control ARPE-19 cells using a Seahorse extracellular flux analyzer. Furthermore, pretreatment with PFSE and piceatannol restored the oxidative stress-induced decrease in the mitochondrial and glycolytic ATP production rate to approximately 97% and 82%, respectively. These results indicated the cytoprotective effects of PFSE and piceatannol against oxidative stress in human ARPE-19 cells by resolving the dysfunction of mitochondrial and glycolytic energy metabolism.

Oxidative stress and energy metabolism abnormalities in polycystic ovary syndrome: from mechanisms to therapeutic strategies.

Polycystic ovary syndrome (PCOS), as a common endocrine and metabolic disorder, is often regarded as a primary cause of anovulatory infertility in women. The pathogenesis of PCOS is complex and influenced by multiple factors. Emerging evidence highlights that energy metabolism dysfunction and oxidative stress in granulosa cells (GCs) are pivotal contributors to aberrant follicular development and impaired fertility in PCOS patients. Mitochondrial dysfunction, increased oxidative stress, and disrupted glucose metabolism are frequently observed in individuals with PCOS, collectively leading to compromised oocyte quality. This review delves into the mechanisms linking oxidative stress and energy metabolism abnormalities in PCOS, analyzing their adverse effects on reproductive function. Furthermore, potential therapeutic strategies to mitigate oxidative stress and metabolic disturbances are proposed, providing a theoretical basis for advancing clinical management of PCOS.

Sex and Age Differences in the Impact of Metabolic Syndrome on Heart Failure Development.

Metabolic syndrome (MetS), a cluster of metabolic dysregulations, is recognized as a significant risk factor for the development of heart failure (HF). The pathophysiological mechanisms linking MetS to HF are complex and multifaceted, with the components of MetS contributing to cardiac deterioration through impaired myocardial energy metabolism, increased inflammation, and endothelial dysfunction. Numerous clinical studies have confirmed the relationship between MetS and HF. Multiple studies have demonstrated that the impact of MetS on HF varies by sex and age. Metabolic disorders, including MetS, have a greater impact on HF incidence in younger adults compared to the elderly population and in women compared to men. Although the reasons for these differences are not yet fully understood, recognizing the sex- and age-related variations is crucial for developing targeted strategies to prevent HF in individuals with MetS. Future research should continue to investigate the underlying mechanisms behind these variations and identify optimal management approaches that account for both sex and age in reducing HF risk.

The mechanism of paclitaxel induced damage on placental trophoblast cells

ObjectiveChemotherapy during pregnancy has a certain risk of causing a series of complications, such as miscarriage, premature birth, or fetal growth restriction, although the relationship between these complications and chemotherapy is currently unclear. This experiment focuses on the possible damage mechanism of the chemotherapeutic drug paclitaxel on placental trophoblast cells, and explores whether chemotherapy can affect pregnancy outcomes by directly damaging placental tissue.MethodsThis study explored the mechanism of paclitaxel induced damage on placental trophoblast cell lines JEG-3 and BEWO through immunofluorescence staining, Western blot experiments, cell flow cytometry, Seahorese cell metabolism experiments, and mouse modeling verification.ResultsThe experiment found that paclitaxel could induce JEG-3 and BEWO cells to produce reactive oxygen species (ROS), and elevate the ratio of Bax/Bcl-2 expression. Besides, paclitaxel mediated the reduction of mitochondrial membrane potential in JEG-3 and BEWO cells, causing damage and leading to mitochondrial autophagy and the occurrence of unfolded protein response. Paclitaxel inhibited the glycolysis rate of JEG-3 and BEWO cells, and leaded to impaired mitochondrial function, including decreased basal respiratory values, decreased respiratory reserve capacity, and proton leakage. In pregnant mice with tumor modeling, paclitaxel could cause DNA damage in placental tissue cells, and might lead to apoptosis of chemotherapy mice placental tissue cells and impairment of normal physiological functions.ConclusionPaclitaxel may directly or indirectly affect the normal physiological functions of placental trophoblast cells, including energy metabolism and protein synthesis dysfunction, which may be related to the adverse pregnancy outcomes caused by paclitaxel chemotherapy.

Role of glia in delirium: proposed mechanisms and translational implications.

Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.

Identification of energy metabolism anomalies and serum biomarkers in the progression of premature ovarian failure via extracellular vesicles’ proteomic and metabolomic profiles

BackgroundPremature ovarian failure (POF) is a clinical condition characterized by the cessation of ovarian function, leading to infertility. The underlying molecular mechanisms remain unclear, and no predictable biomarkers have been identified. This study aimed to investigate the protein and metabolite contents of serum extracellular vesicles to investigate underlying molecular mechanisms and explore potential biomarkers.MethodsThis study was conducted on a cohort consisting of 14 POF patients and 16 healthy controls. The extracellular vesicles extracted from the serum of each group were subjected to label-free proteomic and unbiased metabolomic analysis. Differentially expressed proteins and metabolites were annotated. Pathway network clustering was conducted with further correlation analysis. The biomarkers were confirmed by ROC analysis and random forest machine learning.ResultsThe proteomic and metabolomic profiles of POF patients and healthy controls were compared. Two subgroups of POF patients, Pre-POF and Pro-POF, were identified based on the proteomic profile, while all patients displayed a distinguishable metabolomic profile. Proteomic analysis suggested that inflammation serves as an early factor contributing to the infertility of POF patients. For the metabolomic analysis, despite the dysfunction of metabolism, oxidative stress and hormone imbalance were other key factors appearing in POF patients. Signaling pathway clustering of proteomic and metabolomic profiles revealed the progression of dysfunctional energy metabolism during the development of POF. Moreover, correlation analysis identified that differentially expressed proteins and metabolites were highly associated, with six of them being selected as potential biomarkers. ROC curve analysis, together with random forest machine learning, suggested that AFM combined with 2-oxoarginine was the best diagnostic biomarker for POF.ConclusionsOmics analysis revealed that inflammation, oxidative stress, and hormone imbalance are factors that damage ovarian tissue, but the progressive dysfunction of energy metabolism might be the critical pathogenic pathway contributing to the development of POF. AFM combined with 2-oxoarginine serves as a precise biomarker for clinical POF diagnosis.

Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.

Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival. Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate. Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029). We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Mitochondria-Associated Organelle Crosstalk in Myocardial Ischemia/Reperfusion Injury.

Organelle damage is a significant contributor to myocardial ischemia/reperfusion (I/R) injury. This damage often leads to disruption of endoplasmic reticulum protein regulatory programs and dysfunction of mitochondrial energy metabolism. Mitochondria and endoplasmic reticulum are seamlessly connected through the mitochondrial-associated endoplasmic reticulummembrane (MAM), which serves as a crucial site for the exchange of organelles and metabolites. However, there is a lack of reports regarding the communication of information and metabolites between mitochondria and related organelles, which is a crucial factor in triggering myocardial I/R damage. To address this research gap, this review described the role of crosstalk between mitochondria and the correlative organelles such as endoplasmic reticulum, lysosomal and nuclei involved in reperfusion injury of the heart. In summary, this review aims to provide a comprehensive understanding of the crosstalk between organelles in myocardial I/R injury, with the ultimate goal of facilitating the development of targeted therapies based on this knowledge.

Altered Serum Proteins Suggest Inflammation, Fibrogenesis and Angiogenesis in Adult Patients with a Fontan Circulation.

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.

Trauma patients with type O blood exhibit unique multiomics signature with decreased lectin pathway of complement levels.

Patients with type O blood may have an increased risk of hemorrhagic complications because of lower baseline levels of von Willebrand factor and factor VIII, but the transition to a mortality difference in trauma is less clear. We hypothesized that type O trauma patients will have differential proteomic and metabolomic signatures in response to trauma beyond von Willebrand factor and factor VIII alone. Patients meeting the highest level of trauma activation criteria were prospectively enrolled. Blood samples were collected upon arrival to the emergency department. Proteomic and metabolomic (multiomics) analyses of these samples were performed using liquid chromatography-mass spectrometry. Demographic, clinical, and multiomics data were compared between patients with type O blood versus all other patients. There were 288 patients with multiomics data; 146 (51%) had type O blood. Demographics, injury patterns, and initial vital signs and laboratory measurements were not different between groups. Type O patients had increased lengths of stay (7 vs. 6 days, p = 0.041) and a trend toward decreased mortality secondary to traumatic brain injury compared with other causes (traumatic brain injury, 44.4% vs. 87.5%; p = 0.055). Type O patients had decreased levels of mannose-binding lectin and mannose-binding lectin-associated serine proteases 1 and 2, which are required for the initiation of the lectin pathway of complement activation. Type O patients also had metabolite differences signifying energy metabolism and mitochondrial dysfunction. Blood type O patients have a unique multiomics signature, including decreased levels of proteins required to activate the lectin complement pathway. This may lead to overall decreased levels of complement activation and decreased systemic inflammation in the acute phase, possibly leading to a survival advantage, especially in traumatic brain injury. However, this may later impair healing. Future work will need to confirm these associations, and animal studies are needed to test therapeutic targets. Prognostic and Epidemiological; Level IV.

Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

Low-dose BPA-induced neuronal energy metabolism dysfunction and apoptosis mediated by PINK1/parkin mitophagy pathway in juvenile rats

Bisphenol A (BPA) is related to neurological disorders involving mitochondrial dysfunction, while the mechanism remains elusive. Therefore, we explored it through in vitro and in vivo experiments. In vitro, hippocampal neurons derived from neonatal rats of different genders were exposed to 1–100 nM and 100 μM BPA, autophagy activator Rapa and inhibitor 3-MA for 7 d. The results suggested that even nanomolar BPA (1–100 nM) disturbed Ca2+ homeostasis and damaged the integrity of mitochondrial cristae in neurons (p < 0.05). Furthermore, BPA increased the number of autophagic lysosomes, LC3II/LC3I ratio, and p62 expression, and decreased parkin expression (p < 0.05), suggesting that the entry of damaged mitochondria into autophagic pathway was prompted, while the autophagic degradation pathway was blocked. This further disrupts neuronal energy metabolism and promotes neuronal apoptosis. However, Rapa attenuated the adverse effects caused by BPA, while 3-MA exacerbated these reactions. In vivo, exposure of juvenile rats to 0.5, 50, 5000 μg/kg‧bw/day BPA during PND 7–21 markedly impaired the structure of hippocampal mitochondria, increased the number of autophagosomes, the rate of neuronal apoptosis, and the expression levels of pro-apoptotic proteins Cyt C, Bax, Bak1, and Caspase3, and decreased the expression of anti-apoptotic protein Bcl2 (p < 0.05). Particularly, male rats are more sensitive to low-dose BPA than females. Overall, environmental-doses BPA can induce the imbalance of energy metabolism in hippocampal neurons via PINK1/parkin mitophagy, thereby inducing their apoptosis. Importantly, this study provides a theoretical basis for attenuating BPA-related neurological diseases.

Neural Processing without O2 and Glucose Delivery: Lessons from the Pond to the Clinic.

Neuronal activity requires a large amount of ATP, leading to a rapid collapse of brain function when aerobic respiration fails. Here, we summarize how rhythmic motor circuits in the brain stem of adult frogs, which normally have high metabolic demands, transform to produce proper output during severe hypoxia associated with emergence from hibernation. We suggest that general principles underlying plasticity in brain bioenergetics may be uncovered by studying nonmammalian models that face extreme environments, yielding new insights to combat neurological disorders involving dysfunctional energy metabolism.

Rhodiola crenulata alleviates hypobaric hypoxia-induced brain injury by maintaining BBB integrity and balancing energy metabolism dysfunction

Background/Purpose: Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (R. crenulate), a famous and characteristic Tibetan medicine, has been demonstrated to exert an outstanding brain protection role in the treatment of high-altitude hypoxia disease. However, the metabolic effects of R. crenulate on high-altitude hypoxic brain injury (HHBI) are still incompletely understood. Herein, the anti-hypoxic effect and associated mechanisms of R. crenulate were explored through both in vivo and in vitro experiments. Study design/MethodsThe mice model of HHBI was established using an animal hypobaric and hypoxic chamber. R. crenulate extract (RCE, 0.5, 1.0 and 2.0 g/kg) and salidroside (Sal, 25, 50 and 100 mg/kg) was given by gavage for 7 days. Pathological changes and neuronal apoptosis of mice hippocampus and cortex were evaluated using H&E and TUNEL staining, respectively. The effects of RCE and Sal on the permeability of blood brain barrier (BBB) were detected by Evans blue staining and NIR-II fluorescence imaging. Meanwhile, the ultrastructural BBB and cerebrovascular damages were observed using a transmission electron microscope (TEM). The levels of tight junction proteins Claudin-1, ZO-1 and occludin were detected by immunofluorescence. Additionally, the metabolites in mice serum and brain were determined using UHPLC-MS and MALDI-MSI analysis. The cell viability of Sal on hypoxic HT22 cells induced by CoCl2 was investigated by cell counting kit-8. The contents of LDH, MDA, SOD, GSH-PX and SDH were detected by using commercial biochemical kits. Meanwhile, intracellular ROS, Ca2+ and mitochondrial membrane potential were determined by corresponding specific labeled probes. The intracellular metabolites of HT22 cells were performed by the targeted metabolomics analysis of the Q300 kit. The cell apoptosis and necrosis were examined by YO-PRO-1/PI, Annexin V/PI and TUNEL staining. In addition, mitochondrial morphology was tested by Mito-tracker red with confocal microscopy and TEM. Real-time ATP production, oxygen consumption rate, and proton efflux rate were measured using a Seahorse analyzer. Subsequently, MCU, OPA1, p-Drp1ser616, p-AMPKα, p-AMPKβ and Sirt1 were determined by immunofluorescent and western blot analyses. ResultsThe results demonstrated that R. crenulate and Sal exert anti-hypoxic brain protection from inhibiting neuronal apoptosis, maintaining BBB integrity, increasing tight junction protein Claudin-1, ZO-1 and occludin and improving mitochondrial morphology and function. Mechanistically, R. crenulate and Sal alleviated HHBI by enhancing the tricarboxylic acid cycle to meet the demand of energy of brain. Additionally, experiments in vitro confirmed that Sal could ameliorate the apoptosis of HT22 cells, improve mitochondrial morphology and energy metabolism by enhancing mitochondrial respiration and glycolysis. Meanwhile, Sal-mediated MCU inhibited the activation of Drp1 and enhanced the expression of OPA1 to maintain mitochondrial homeostasis, as well as activation of AMPK and Sirt1 to enhance ATP production. ConclusionCollectively, the findings suggested that RCE and Sal may afford a protective intervention in HHBI through maintaining BBB integrity and improving energy metabolism via balancing MCU-mediated mitochondrial homeostasis by activating the AMPK/Sirt1 signaling pathway.

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.

Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases.

Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains of patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer's disease (AD) and autism may be attributed to mitochondrial dysfunction and changes in energy metabolism. While neuronal activity is associated with reduction in brain pH, astrocytes are responsible for rebalancing the pH to maintain the equilibrium. As lactate level is the main determinant of brain pH, neuronal activities are impacted by pH changes due to the binding of protons (H+) to various types of proteins, altering their structure and function in the neuronal and non-neuronal cells of the brain. Lactate and pH could affect diverse types of epigenetic modifications, including histone lactylation, which is linked to histone acetylation and DNA methylation. In this review, we discuss the importance of pH homeostasis in normal brain function, the role of lactate as an essential epigenetic regulatory molecule and its contributions to brain pH abnormalities in neuropsychiatric diseases, and shed light on lactate-based and pH-modulating therapies in neuropsychiatric diseases by targeting epigenetic modifications. In conclusion, we attempt to highlight the potentials and challenges of translating lactate-pH-modulating therapies to clinics for the treatment of neuropsychiatric diseases.

Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation

ABSTRACT Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems.

Depression is the most disabling neuropsychiatric disorder, causing difficulties in daily life activities and social interactions. The exact mechanisms of depression remain largely unclear. However, some studies have shown that mitochondrial dysfunction would play a crucial role in the occurrence and development of depression. To summarize the known knowledge about the role of mitochondrial dysfunction in the pathogenesis of depression. We review the recent literature， including 105 articles, to summarize the mitochondrial energy metabolism and quality control systems in the occurrence and development of depression. Some antidepressants which may exert their effects by improving mitochondrial function are also discussed. Impaired brain energy metabolism and (or) damaged mitochondrial quality control systems have been reported not only in depression patients but in animal models of depression. Although the classical antidepressants have not been specially designed to target mitochondria, the evidence suggests that many antidepressants may exert their effects by improving mitochondrial function. This brief review focuses on the findings that implicate mitochondrial dysfunction and the quality control systems as important etiological factors in the context of depressive disorders. It will help us to understand the various concepts of mitochondrial dysfunction in the pathogenesis of depression, and to explore novel and more targeted therapeutic approaches for depression.

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases.

This narrative review was conducted due to uncertainty in predicting the beneficial impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors on a dip of estimated glomerular filtration rate (eGFR), regardless of albuminuria presence, with the aim of elucidating plausible predictors of kidney function outcome among patients treated with SGLT2 inhibitors. The PubMed and Web of Science databases were searched in May 2023 for relevant articles published in English between 2013 and 2023. A total of 25 full-length scientific publications (comprising 11 large randomized trials and two cohort studies) were included for analysis. The majority of studies demonstrated a limited value of conventional biomarkers, such as initial decline in eGFR, a trajectory of eGFR during SGLT2 inhibitor administration, and urine albumin-to-creatinine ratio (UACR), in prediction of renoprotection. Included studies showed that the tendency to decreased eGFR, UACR, hemoglobin, glycosylated hemoglobin, lipid profile, serum uric acid, inflammatory biomarkers and natriuretic peptides did not predict clinical outcomes in groups without heart failure (HF) treated with SGLT2 inhibitors. In HF groups, biomarkers of inflammation, kidney injury, oxidative stress, mitochondrial dysfunction, ketogenesis, energy metabolism, and adipose tissue dysfunction (adropin and irisin), were detected with the aim of finding potential biomarkers. Biomarkers of adipose tissue dysfunction and inflammation may be promising for predicting SGLT2 inhibitor benefit compared with N-terminal pro-B-type natriuretic peptide and energy metabolism indicators.