UNASSIGNED: Medium-chain fatty acids (MCFAs) and docosahexaenoic acid (DHA) could affect the occurrence of mild cognitive impairment (MCI). β-hydroxybutyrate (BHB), mitochondrial DNA copy number (mtDNAcn) and mitochondrial DNA (mtDNA) deletions might be their potential mechanisms. This study aimed to explore the relationship between MCFAs, DHA and MCI, and potential mechanisms.
UNASSIGNED: This study used data from Tianjin Elderly Nutrition and Cognition (TENC) cohort study, 120 individuals were identified with new onset MCI during follow-up, 120 individuals without MCI were selected by 1:1 matching sex, age, and education levels as the control group from TENC. Conditional logistic regression analysis and mediation effect analysis were used to explore their relationship.
UNASSIGNED: Higher serum octanoic acid levels (OR: 0.633, 95% CI: 0.520, 0.769), higher serum DHA levels (OR: 0.962, 95% CI: 0.942, 0.981), and more mtDNAcn (OR: 0.436, 95% CI: 0.240, 0.794) were associated with lower MCI risk, while more mtDNA deletions was associated with higher MCI risk (OR: 8.833, 95% CI: 3.909, 19.960). Mediation analysis suggested that BHB and mtDNAcn, in series, have mediation roles in the association between octanoic acid and MCI risk, and mtDNA deletions have mediation roles in the association between DHA and MCI risk.
UNASSIGNED: Higher serum octanoic acid and DHA levels were associated with lower MCI risk. Octanoic acid could affect the incidence of MCI through BHB, then mitochondria function, or through mitochondria function, or directly. Serum DHA level could affect the incidence of MCI through mitochondria function, or directly.

UNASSIGNED: This study investigated the role of Mzb1 in puerarin protection against heart injury and dysfunction in acute myocardial infarction (AMI) mice.
UNASSIGNED: C57BL/6 mice were pretreated with and without puerarin at doses of 50 mg/kg and 100 mg/kg for 14 days before establishing the AMI model. An AMI model was induced by ligating the left descending anterior coronary artery, and AC16 cardiomyocytes were treated with H2O2 in vitro. Echocardiography was performed to measure cardiac function. DHE staining, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, and DCFH-DA oxidative fluorescence staining were used to determine reactive oxygen species (ROS) production in vivo and in vitro. Bioinformatics analysis was used to predict potential upstream transcription factors of Mzb1.
UNASSIGNED: Puerarin dose-dependently reduced myocardial infarction area and injury, accompanied by the improvement of cardiac function in AMI mice. AMI mice manifested an increase in myocardial oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and mitochondrial biogenesis dysfunction, which were inhibited by pretreatment with puerarin. Puerarin also prevented Mzb1 downregulation in the hearts of AMI mice or H2O2-treated AC16 cells. Consistent with the in vivo findings, puerarin inhibited H2O2-induced cardiomyocyte apoptosis, ER stress, and mitochondrial dysfunction, which were attenuated by siRNA Mzb1. Furthermore, the JASPAR website predicted that KLF4 may be a transcription factor for Mzb1. The expression of KLF4 was partially reversed by puerarin in the cardiomyocyte injury model, and KLF4 inhibitor (kenpaullone) inhibited Mzb1 expression and affected its function.
UNASSIGNED: These results suggest that puerarin can protect against cardiac injury by attenuating oxidative stress and endoplasmic reticulum stress through upregulating the KLF4/Mzb1 pathway and that puerarin may expand our armamentarium for the prevention and treatment of ischemic heart diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious health problem, and recent evidence indicates that gut microbiota plays a key role in its development. It is known that 2-oleoyl glycerol (2-OG) produced by the gut microbiota is associated with hepatic fibrosis, but it is not known whether this metabolite is involved in the development of hepatic steatosis. The aim of this study was to evaluate how a high-fat-sucrose diet (HFS) increases 2-OG production through gut microbiota dysbiosis and to identify whether this metabolite modifies hepatic lipogenesis and mitochondrial activity for the development of hepatic steatosis as well as whether a combination of functional foods can reverse this process. Wistar rats were fed the HFS diet for 7 months. At the end of the study, body composition, biochemical parameters, gut microbiota, protein abundance, lipogenic and antioxidant enzymes, hepatic 2-OG measurement, and mitochondrial function of the rats were evaluated. Also, the effect of the consumption of functional food with an HFS diet was assessed. In humans with MASLD, we analyzed gut microbiota and serum 2-OG. Consumption of the HFS diet in Wistar rats caused oxidative stress, hepatic steatosis, and gut microbiota dysbiosis, decreasing α-diversity and increased Blautia producta abundance, which increased 2-OG. This metabolite increased de novo lipogenesis through ChREBP and SREBP-1. 2-OG significantly increased mitochondrial dysfunction. The addition of functional foods to the diet modified the gut microbiota, reducing Blautia producta and 2-OG levels, leading to a decrease in body weight gain, body fat mass, serum glucose, insulin, cholesterol, triglycerides, fatty liver formation, and increased mitochondrial function. To use 2-OG as a biomarker, this metabolite was measured in healthy subjects or with MASLD, and it was observed that subjects with hepatic steatosis II and III had significantly higher 2-OG than healthy subjects, suggesting that the abundance of this circulating metabolite could be a predictor marker of hepatic steatosis.

Medium-chain chlorinated paraffins (MCCPs, C14-C17) are frequently detected in diverse environmental media. It has been proposed to be listed in Annex A of the Convention on Persistent Organic Pollutants in 2023. Although MCCPs are a crucial health concern, their toxicity remains unclear. This study investigated the toxic effects of MCCPs (0.1-50 mg/kg body weight/day) on the thyroid gland of female Sprague-Dawley rats and characterized the potential toxic pathways via transcriptomics and metabolomics approaches. MCCPs exposure caused histopathological changes to the endoplasmic reticula and mitochondria in thyroid follicular cells at a dose of 50 mg/kg bw/d and increased serum thyrotropin-releasing hormone, thyroid-stimulating hormones, and thyroxine when exposed to a higher dose of MCCPs. Transcriptomic analysis indicated the excessive expression of key genes related to thyroid hormone synthesis induced by MCCPs. Integrating the dual-omics analysis revealed mitochondrial dysfunction of the thyroid by mediating fatty acid oxidation, Kreb\'s cycle, and oxidative phosphorylation. Significant metabolic toxicity on the thyroid might be linked to the characteristics of the chlorine content of MCCPs. This study revealed the toxicity of MCCPs to the thyroid gland via triggering thyroid hormone synthesis and interfering with mitochondrial function, which can provide new insights into the modes of action and mechanism-based risk assessment of MCCPs.

Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac hypertrophy in fetal (ED18.5), postnatal day 7 (PD7), postnatal day 21 (PD21) and postnatal day 90 (PD90) offspring by upregulation of BRD4 and mitochondrial dysfunction. Pregnant mice were divided into control and GDM groups. Hearts were isolated from ED18.5, PD7, PD21 and PD90. GDM increased the body weight (BW) and heart weight (HW) in ED18.5 and PD7, but not PD21 and PD90 offspring. However, HW/BW ratio was increased in all ages of GDM offspring compared to control group. Electron microscopy showed disorganized myofibrils, mitochondrial swelling, vacuolization, and cristae disorder in GDM offspring. GDM resulted in myocardial hypertrophy in offspring, which persisted from fetus to adult in a sex-independent manner. Echocardiography analysis revealed that GDM caused diastolic dysfunction, but had no effect on systolic function. Meanwhile, myocardial BRD4 was significantly upregulated in GDM offspring and BRD4 inhibition by JQ1 alleviated GDM-induced myocardial hypertrophy in offspring. Co-immunoprecipitation showed that BRD4 interacted with DRP1 and there was an increase of BRD4 and DRP1 interaction in GDM offspring. Furthermore, GDM caused the accumulation of damaged mitochondria in hearts from all ages of offspring, including mitochondrial fusion fission imbalance (upregulation of DRP1, and downregulation of MFN1, MFN2 and OPA1) and myocardial mitochondrial ROS accumulation, which was reversed by JQ1. These results suggested that the upregulation of BRD4 is involved in GDM-induced myocardial hypertrophy in the offspring through promoting mitochondrial damage in a gender-independent manner.

Skin aging is an unavoidable natural phenomenon caused by intrinsic and extrinsic factors. In modern society, the pursuit of a wrinkle-free and aesthetically appealing face has gained considerable prominence. Numerous studies have aimed at mitigating the appearance of facial wrinkles. Antiaging research focused on regulating the function of mitochondria, the main reactive oxygen species-generating organelles, has been extensively conducted. In this study, we investigated the correlation between facial wrinkles and the expression of PPARGC1B, considering the association of this gene with mitochondrial function, to identify its potential as a target for exploring antiaging cosmetic materials. We elucidated the role of PPARGC1B in the skin and identified five bioactive materials that modulated its expression. The effectiveness of these materials was verified through in vitro experiments on human dermal fibroblasts. We prepared cosmetic formulations incorporating the five materials and confirmed their ability to enhance dermal collagen in three-dimensional skin models and reduce facial wrinkles under the eyes and nasolabial fold areas in human subjects. The study findings have significant implications for developing novel antiaging cosmetic formulations by reinforcing mitochondrial functions.

Unlike classical protein kinase A, with separate catalytic and regulatory subunits, EPACs are single chain multi-domain proteins containing both catalytic and regulatory elements. The importance of cAMP-Epac-signaling as an energy provider has emerged over the last years. However, little is known about Epac1 signaling in chronic kidney disease. Here, we examined the role of Epac1 during the progression of glomerulonephritis (GN). We first observed that total genetic deletion of Epac1 in mice accelerated the progression of nephrotoxic serum (NTS)-induced GN. Next, mice with podocyte-specific conditional deletion of Epac1 were generated and showed that NTS-induced GN was exacerbated in these mice. Gene expression analysis in glomeruli at the early and late phases of GN showed that deletion of Epac1 in podocytes was associated with major alterations in mitochondrial and metabolic processes and significant dysregulation of the glycolysis pathway. In vitro, Epac1 activation in a human podocyte cell line increased mitochondrial function to cope with the extra energy demand under conditions of stress. Furthermore, Epac1-induced glycolysis and lactate production improved podocyte viability. To verify the in vivo therapeutic potential of Epac1 activation, the Epac1 selective cAMP mimetic 8-pCPT was administered in wild type mice after induction of GN. 8-pCPT alleviated the progression of GN by improving kidney function with decreased structural injury with decreased crescent formation and kidney inflammation. Importantly, 8-pCPT had no beneficial effect in mice with Epac1 deletion in podocytes. Thus, our data suggest that Epac1 activation is an essential protective mechanism in GN by reprogramming podocyte metabolism. Hence, targeting Epac1 activation could represent a potential therapeutic approach.

Kaempferol is a natural flavonoid with reported bioactivities found in many fruits, vegetables, and medicinal herbs. However, its effects on exercise performance and muscle metabolism remain inconclusive. The present study investigated kaempferol\'s effects on improving exercise performance and potential mechanisms in vivo and in vitro. The grip strength, exhaustive running time, and distance of mice were increased in the high-dose kaempferol group (p < 0.01). Also, kaempferol reduced fatigue-related biochemical markers and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) related to antioxidant capacity. Kaempferol also increased the glycogen and adenosine triphosphate (ATP) content in the liver and skeletal muscle, as well as glucose in the blood. In vitro, kaempferol promoted glucose uptake, protein synthesis, and mitochondrial function and decreased oxidative stress in both 2D and 3D C2C12 myotube cultures. Moreover, kaempferol activated the PI3K/AKT and MAPK signaling pathways in the C2C12 cells. It also upregulated the key targets of glucose uptake, mitochondrial function, and protein synthesis. These findings suggest that kaempferol improves exercise performance and alleviates physical fatigue by increasing glucose uptake, mitochondrial biogenesis, and protein synthesis and by decreasing ROS. Kaempferol\'s molecular mechanism may be related to the regulation of the PI3K/AKT and MAPK signaling pathways.

OBJECTIVE: The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions.
METHODS: A literature search was performed in the PubMed and Google Scholar databases.
RESULTS: Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics.
CONCLUSIONS: The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development.

BACKGROUND: Type 2 diabetes is often linked with osteoporosis (T2DOP), a condition that accelerates bone degeneration and increases the risk of fractures. Unlike conventional menopausal osteoporosis, the diabetic milieu exacerbates the likelihood of fractures and osteonecrosis. In particular poliumoside (Pol), derived from Callicarpa kwangtungensis Chun, has shown promising anti-oxidant and anti-inflammatory effects. Yet, its influence on T2DOP remains to be elucidated.
OBJECTIVE: The focus of this study was to elucidate the influence of Pol in HGHF-associated ferroptosis and its implications in T2DOP.
METHODS: A murine model of T2DOP was established using a minimal dosage of streptozotocin (STZ) through intraperitoneal infusion combined with a diet high in fat and sugar. Concurrently, to mimic the diabetic condition in a lab environment, bone mesenchymal stem cells (BMSCs) were maintained in a high-glucose and high-fat (HGHF) setting.
METHODS: The impact of Pol on BMSCs in an HGHF setting was determined using methods, such as BODIPY-C11, FerroOrange staining, mitochondrial functionality evaluations, and Western blot methodologies, coupled with immunoblotting and immunofluorescence techniques. To understand the role of Pol in a murine T2DOP model, techniques including micro-CT, hematoxylin and eosin (H&E) staining, dual-labeling with calcein-alizarin red, and immunohistochemistry were employed for detailed imaging and histological insights.
RESULTS: Our findings suggest that Pol acts against HGHF-induced bone degradation and ferroptosis, as evidenced by an elevation in glutathione (GSH) and a decline in malondialdehyde (MDA) levels, lipid peroxidation, and mitochondrial reactive oxygen species (ROS). Furthermore, Pol treatment led to increased bone density, enhanced GPX4 markers, and reduced ROS in the distal femur region. On investigating the underlying mechanism of action, it was observed that Pol triggers the Nrf2/GPX4 pathway, and the introduction of lentivirus-Nrf2 negates the beneficial effects of Pol in HGHF-treated BMSCs.
CONCLUSIONS: Pol is effective in treating T2DOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.