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The leaves of Metapanax delavayi shrub have been widely used in Chinese traditional diet to prepare tea-like beverages for alleviating inflammation. This study aimed to identify phytochemical components of M. delavayi leaf extract (MDE), and assess their anti-inflammation effects. The results showed that of the 101 compounds identified in the MDE, 96 were assessed as potentially anti-inflammatory based on network pharmacology analysis. The MAPK signaling pathway was surmised as the major anti-inflammatory pathway of action. The MDE enhanced the viability of the RAW264.7 cells, significantly inhibiting the overproduction of inflammatory factors (NO, IL-6, TNF-α, and PGE2), relative mRNA expression of TNF-α, iNOS, and COX-2, as well as several proteins (p-P38, p-ERK, p-JNK, iNOS, and COX-2) in lipopolysaccharide-induced RAW264.7 cells, meanwhile TGF-β1 production was increased. The key residues involved in binding to the top 10 leaf metabolites were Lys53, Thr179, Asp177, Glu147, and Pro174, in p-P38, p-ERK, p-JNK proteins. Molecular dynamic simulations demonstrated that predominantly three phosphorylated proteins formed stable and tightly bound complexes with certain metabolites of MDE.

Background: Although caffeine generally offers benefits to human health, its impact on bone metabolism remains unclear.Aim and Methods: This study aimed to systematically evaluate the long-term effects of caffeine administration on osteoclasts, osteoblasts, and ovariectomy-induced postmenopausal osteoporosis (OP).Results: Our in vitro findings revealed that 3.125 and 12.5 μg/mL caffeine inhibited RANKL-mediated osteoclastogenesis in RAW 264.7 cells through the MAPK and NF-κB pathways, accompanied by the inactivation of nuclear translocation of nuclear factor NFATc1. Similarly, 3.125 and 12.5 μg/mL of caffeine modulated MC3T3-E1 osteogenesis via the AKT, MAPK, and NF-κB pathways. However, 50 μg/mL of caffeine promoted the phosphorylation of IκBα, P65, JNK, P38, and AKT, followed by the activation of NFATc1 and the inactivation of Runx2 and Osterix, ultimately disrupting the balance between osteoblastogenesis and osteoclastogenesis. In vivo studies showed that gavage with 55.44 mg/kg caffeine inhibited osteoclastogenesis, promoted osteogenesis, and ameliorated bone loss in ovariectomized mice.Conclusion: Conversely, long-term intake of high-dose caffeine (110.88 mg/kg) disrupted osteogenesis activity and promoted osteoclastogenesis, thereby disturbing bone homeostasis. Collectively, these findings suggest that a moderate caffeine intake (approximately 400 mg in humans) can regulate bone homeostasis by influencing both osteoclasts and osteoblasts. However, long-term high-dose caffeine consumption (approximately 800 mg in humans) could have detrimental effects on the skeletal system.

Theabrownin (TB) is the main characteristic component and bioactive substance of Pu-erh tea. Our previous studies have demonstrated interactions among the TB, the circadian rhythm, and obesity, but the underlying mechanism remains unclear. In this study, we focused on the mechanism by which TB ameliorates lipid accumulation caused by oleic acid (OA) by modulating circadian rhythm genes in HepG2 cells. The results showed that TB could reduce triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL-C) levels, reactive oxygen species (ROS) overproduction and lipid droplet formation. Additionally, TB could regulate OA-mediated circadian desynchrony by regulating the mRNA and protein expression of circadian genes. Furthermore, as revealed by proteomics results, the PPAR pathway is a potential pathway through which TB ameliorates lipid metabolism disorders. After Bmal1 knockdown, the ameliorative effect of TB on OA-induced PPARγ and plin1 protein expression was decreased, which suggested that TB could ameliorate lipid accumulation in HepG2 cells via a Bmal1-dependent pathway.

The objective of the study is to investigate the effect of theabrownin on the immunohistochemistry of brain tissue in aging mice, screen the differential metabolites and analyze the metabolic pathways involved. A mouse aging model was established by subcutaneous injection of D-galactose in mice. Immunohistochemical and UHPLC-QE-MS metabolomics techniques were used to detect brain samples of normal control mice, D-galactose model mice and theabrownin-treated (pretreatment and treatment) mice. The results showed that the areal density of choline acetyltransferase positive expression was significantly increased (P

Platelet transfusion is frequently applied to control and prevent bleeding under many clinical settings. However, the current storage strategy limits the collected platelets to a shelf life of only 5–7 days due to platelet storage lesion (PSL). To date, mitochondria are reported to play a pivotal role in platelet energy metabolism, platelet activation and platelet apoptosis. In addition, the development of PSL is closely associated with oxidative stress and mitochondrial dysfunction. Hence, efforts to preserve mitochondrial function against oxidative stress may potentially curtail PSL and extend the shelf life of platelet concentrates (PCs). The research summarized in this review shows that many small molecules have a beneficial effect on stored platelets, and we believe that addition of small molecules for mitochondrial targeted intervention may be an effective approach in mitigating PSL and thereby extend the shelf life of PCs.

BackgroundPapillary thyroid carcinoma (PTC) is the most common thyroid malignancy, but little is known regarding PTC metabolic phenotypes and the effects of mitochondrial activity on PTC progression. The great potential of mitochondria-targeting therapy in cancer treatment promoted us to use tool compounds from a family of Mito-Fu derivatives to investigate how the regulation of mitochondrial respiration affected tumor progression characteristics and molecular changes in PTC.MethodsMito-Fu L20, a representative of 12 synthetic derivatives, was chosen for mitochondrial inhibition experiments. Sample sections from PTC patients were collected and processed to explore potential molecular alterations in tumor lymph node metastasis (LNM). In vitro analyses were performed using human PTC cell lines (K1 and TPC-1), with the human normal thyroid follicular cell line (Nthy) as a control. K1 cells were injected into nude mice to generate an animal model. The mice were injected with normal saline or Mito-Fu L20 at 20 or 50 mg/kg every other day; their body weights and tumor volumes were also measured over time. To elucidate the resulting metabolic phenotype, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), cellular adenosine triphosphate (ATP) levels and reactive oxygen species (ROS) production, and mitochondrial membrane potential. Wound healing and Transwell assays, cell cycle assays, real-time fluorescence quantitative PCR, Western blotting, and immunohistochemical staining were performed to explore glycolysis-dominant metabolism in PTC.ResultsCyclin D1 and mitochondrial complex IV were detected in tumor samples from PTC patients with LNM. Mito-Fu L20 showed dose-independent and reversible modulation of mitochondrial respiration in PTC. In addition to mitochondrial dysfunction and early apoptosis, G1/S phase arrest. Notably, reversible mitochondrial inhibition yielded durable suppression of tumor proliferation, migration, and invasion via the PI3K/Akt/FoxO1/Cyclin D1 pathway. In vivo experiments demonstrated that Mito-Fu L20 has a good safety profile and specific restorative effect on mitochondrial activity in the liver. In addition, Mito-Fu L20 showed antitumor effects, alleviated tumor angiogenesis, and improved thyroid function.ConclusionReversible inhibition of ATP production and durable suppression of PTC growth indicates that the downregulation of mitochondrial function has a negative impact on tumor progression and LNM via the PI3K/Akt/FoxO1/Cyclin D1 pathway. The results provide new insights into the antitumor potential and clinical translation of mitochondrial inhibitors.

Theabrownin (TB) is a complex oxidized polyphenol formed during the microbial fermentation of Pu-erh tea. It offers some health benefits such as weight loss, blood glucose reduction, and oxidation resistance; however, the anti-aging effect and the related mechanism have not yet been explored. In this study, symptoms of aging were induced in mice using D-galactose. Morris water maze test, hematoxylin-eosin staining, 16S rDNA high-throughput sequencing, and UHPLC-QE-MS metabolomics were used to reveal the anti-aging effects and potential mechanism of TB. TB improved the learning and memory ability, the liver oxidative stress (SOD, GSH-Px, and MDA), inflammation (IL-2, IL-6, and TNF-α), and degeneration of the small intestine in the aging mice. Further analysis showed that TB pretreatment increased the relative abundance of Lactobacillus_murinus and Bacteroides_acidifaciens, and regulated 19 metabolites in the serum. In addition, TB treatment increased the relative abundance of Akkermansia_muciniphila, and regulated 12 metabolites. In conclusion, the anti-aging effect of TB is exerted by the targeted regulation of intestinal microorganisms, which could prevent and delay aging.

Neurodegeneration is a pathological condition in which nervous system or neuron losses its structure, function, or both leading to progressive neural degeneration. Growing evidence strongly suggests that reduction of plasmalogens (Pls), one of the key brain lipids, might be associated with multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Plasmalogens are abundant members of ether-phospholipids. Approximately 1 in 5 phospholipids are plasmalogens in human tissue where they are particularly enriched in brain, heart and immune cells. In this study, we employed a scheme of 2-months Pls intragastric administration to aged female C57BL/6J mice, starting at the age of 16 months old. Noticeably, the aged Pls-fed mice exhibited a better cognitive performance, thicker and glossier body hair in appearance than that of aged control mice. The transmission electron microscopic (TEM) data showed that 2-months Pls supplementations surprisingly alleviate age-associated hippocampal synaptic loss and also promote synaptogenesis and synaptic vesicles formation in aged murine brain. Further RNA-sequencing, immunoblotting and immunofluorescence analyses confirmed that plasmalogens remarkably enhanced both the synaptic plasticity and neurogenesis in aged murine hippocampus. In addition, we have demonstrated that Pls treatment inhibited the age-related microglia activation and attenuated the neuroinflammation in the murine brain. These findings suggest for the first time that Pls administration might be a potential intervention strategy for halting neurodegeneration and promoting neuroregeneration.