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Epithelial-mesenchymal transition (EMT) is an important process triggered during cancer metastasis. Regulation of EMT is mostly initiated by outside signalling, including TGF-β, growth factors, Notch ligand, Wnt, and hypoxia. Many signalling pathways have been delineated to explain the molecular mechanisms of EMT. In this review, we will focus on the epigenetic regulation of two critical EMT signalling pathways: hypoxia and TGF-β. For hypoxia, hypoxia-induced EMT is mediated by the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5 coupled with the presence of histone 3 lysine 4 acetylation (H3K4Ac) mark that labels the promoter regions of various traditional EMT marker genes (e.g. CDH1 , VIM ). Recently identified new hypoxia-induced EMT markers belong to transcription factors (e.g. SMO, GLI1) that mediate EMT themselves. For TGF-β-induced ΕΜΤ, global chromatin changes, removal of a histone variant (H2A.Z), and new chromatin modifiers (e.g. UTX, Rad21, PRMT5, RbBP5, etc) are identified to be crucial for the regulation of both EMT transcription factors (EMT-TFs) and EMT markers (EMT-Ms). The epigenetic mechanisms utilized in these two pathways may serve as good model systems for other signalling pathways and also provide new potential therapeutic targets.

Time-restricted feeding (TRF) is known to be an effective strategy for weight loss and metabolic health. TRF’s effect on metabolism is complex and likely acts on various pathways within multiple tissues. Adipose tissue plays a key role in systemic homeostasis of glucose and lipid metabolism. Adipose tissue dysregulation has been causally associated with metabolic disorders in obesity. However, it is largely unknown how TRF impacts metabolic pathways such as lipolysis, lipogenesis, and thermogenesis within different in adipose tissue depots in obesity. To determine this, we conducted a 10-week TRF regimen in male mice, previously on a long-term high fat diet (HFD) and subjected the mice to TRF of a HFD for 10 h per day or ad libitum. The TRF regimen showed reduction in weight gain. TRF restored HFD-induced impairment of adipogenesis and increased lipid storage in white adipose tissues. TRF also showed a depot-dependent effect in lipid metabolism and restored ATP-consuming futile cycle of lipogenesis and lipolysis that is impaired by HFD within epididymal adipose tissue, but not inguinal fat depot. We demonstrate that TRF may be a beneficial option as a dietary and lifestyle intervention in lowering bodyweight and improving adipose tissue metabolism.

Background/objectivesPentraxin 3 (PTX3) has been characterized as a soluble and multifunctional pattern recognition protein in the regulation of innate immune response. However, little is known about its role in adipose tissue inflammation and obesity. Herein, we investigated the role of PTX3 in the regulation of lipopolysaccharide (LPS)-induced inflammation in adipocytes and adipose tissue, as well as high-fat diet (HFD)-induced metabolic inflammation in obesity.MethodsPtx3 knockdown 3T3-L1 Cells were generated using shRNA for Ptx3 gene and treated with different inflammatory stimuli. For the in vivo studies, Ptx3 knockout mice were treated with 0.3 mg/kg of LPS for 6 h. Adipose tissues were collected for gene and protein expression by qPCR and western blotting, respectively. Ptx3 knockout mice were fed with HFD for 12 week since 6 week of age.ResultsWe observed that the expression of PTX3 in adipose tissue and serum PTX3 were markedly increased in response to LPS administration. Knocking down Ptx3 in 3T3-L1 cells reduced adipogenesis and caused a more profound and sustained upregulation of proinflammatory gene expression and signaling pathway activation during LPS-stimulated inflammation in 3T3-L1 adipocytes. In vivo studies showed that PTX3 deficiency significantly exacerbated the LPS-induced upregulation of inflammatory genes and downregulation of adipogeneic genes in visceral and subcutaneous adipose tissue of mice. Accordingly, LPS stimulation elicited increased activation of nuclear factor-κB (NF-κB) and p44/42 MAPK (Erk1/2) signaling pathways in visceral and subcutaneous adipose tissue. The expression of PTX3 in adipose tissue was also induced by HFD, and PTX3 deficiency led to the upregulation of proinflammatory genes in visceral adipose tissue of HFD-induced obese mice.ConclusionsOur results suggest a protective role of PTX3 in LPS- and HFD-induced sustained inflammation in adipose tissue.

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways. Mitochondrial function is essential for energy metabolism in brown adipocytes. Here, the authors show that LCN2 plays a critical role as a phosphatidic acid binding protein in phospholipid acyl chain remodeling and mitochondrial bioenergetics, influencing signaling pathway activation.

Apart from a well-known role in the innate immune system, lipocalin 2 (Lcn2) has been recently characterized as a critical regulator of thermogenesis and lipid metabolism. However, the physiological mechanism through which Lcn2 regulates cellular metabolism and thermogenesis in adipocytes remains unknown. We found that Lcn2 expression and secretion are significantly upregulated by arachidonic acid (AA) and mTORC1 inhibition in differentiated inguinal adipocytes. AA-induced Lcn2 expression and secretion correlate with the inflammatory NFkB activation. Lcn2 deficiency leads to the upregulation of cyclooxygenase-2 (COX2) expression, as well as increased biosynthesis and secretion of prostaglandins (PGs), particularly PGE2 and PGD2, induced by AA in adipocytes. Furthermore, Lcn2 deficiency affects the mTOR signaling regulation of thermogenic gene expression, lipogenesis, and lipolysis. The loss of Lcn2 dismisses the effect of mTORC1 inhibition by rapamycin on COX2, thermogenesis genes, lipogenesis, and lipolysis, but has no impact on p70 S6Kinase-ULK1 activation in Lcn2-deficient adipocytes. We conclude that Lcn2 converges the COX2-PGE2 and mTOR signaling pathways in the regulation of thermogenesis and lipid metabolism in adipocytes.

Extracellular vesicle (EV) secretion and cargo composition are dysregulated in metabolic diseases. This study aimed to investigate how changes in serum EV concentration and protein composition reflect the metabolic effects of a high‐fat diet (HFD) and time‐restricted feeding (TRF), with a particular focus on adipocyte‐derived EVs (Ad‐EVs) in circulation. Mice were fed an HFD for 18 weeks prior to being placed either ad libitum or on a TRF for an additional 10 weeks. Mice on a normal chow ad libitum served as the control. The TRF group had food available for 10 h and fasted for 14 h per day. The serum EV size profile and amount displayed sex‐ and age‐dependent changes in HFD‐induced obesity, with age reducing EV amounts. HFD decreased small EV populations and increased larger EV populations, while TRF reversed these changes. Quantitative proteomic analysis showed that the abundance and composition of EV proteins changed in response to both acute stimulation with lipopolysaccharides (LPS) and HFD. Gene ontology analysis identified specific sets of EV proteins and their involved biological processes, reflecting the effect of LPS and HFD, as well as the reversal effect of TRF on metabolic and inflammatory pathways. EV proteins altered by HFD and those reversed by TRF had low protein overlap but significant functional overlap in biological processes. TRF activated the PPAR signalling pathway and the AKT‐mTOR signalling pathway. The most significant impacts of HFD and TRF were observed on lipoprotein and carbohydrate metabolism, the complement system, and neutrophil degranulation. Additionally, we showed that serum Ad‐EVs respond dynamically to HFD and TRF. Our findings suggest that EVs play a role in diet‐induced metabolic and inflammatory responses, with changes in circulating EVs, particularly Ad‐EVs, reflecting metabolic adaptations to dietary exposures and interventions.

Buddleja davidii Franch. [Scrophulariaceae] commonly found in the mountainous regions of Taiwan, is used as herbal medicine around the world. In spite of this , no research has been conducted on the physiological activities of B. davidii extracts from different parts of the plant and from plants grown at different altitudes. In this study, B . davidii flower, stem, and leaf extracts were prepared using distilled water, methanol, and 60% ethanol as extraction solvents. The total phenolic content of the extracts served as an indicator of their activities. Our results indicated high bioactivity in the water extract of B . davidii flowers grown at 1,500 m, the 60% ethanol extract of B . davidii stems grown at 1,000 m, and the methanol extract of B . davidii leaves grown at 1,500 m. The freeze-dried leaf extract exhibited the highest antioxidant activity, which may be attributed to its abundance of phenylethanoid glycosides and flavonoids. The major bioactive components of the flower extract were crocin, crocetin, quercetin, and rutin. Those in the stem extract were luteolin, naringenin, quercetin, acacetin, and apigenin; and in the leaf extract were verbascoside, isoverbascoside and oleanolic acid. These compounds were potentially responsible for the antiaging and anti-inflammatory activity of the flower extract (IC 50 : 28.6–125.1 mg/L), the antibacterial activity of the stem extract (minimum inhibitory concentration: 60–100 mg/L), and the antityrosinase activity of the leaf extract (IC 50 : 38.17 mg/L). For example, the antiaging activity of B. davidii flower extract was found to be superior to or comparable with that of the positive controls, which include EGCG (IC 50 : 67.2–162.8 mg/L), 1,10-phenanthroline (IC 50 : 46.7 mg/L), gallic acid (IC 50 : 132.6 mg/L), and tannic acid (IC 50 : 140.3 mg/L). Moreover, these extracts can be deemed safe, as they demonstrated no toxic effects on CCD-966SK, HEMn, and RAW264.7 cells at a concentration of 200 mg/L. To our knowledge, this is the first report revealing differences in activities of B. davidii extracts based on plant part and altitudes. The findings provide insights for potential applications of the identified bioactive compounds in health foods, herbal medicines, and cosmetics.

Myofibroblasts have a key role in wound healing by secreting growth factors and chemoattractants to create new substrates and proteins in the extracellular matrix. We have found that galectin-1, a β-galactose-binding lectin involved in many physiological functions, induces myofibroblast activation; however, the mechanism remains unclear. Here, we reveal that galectin-1-null (Lgals1−/−) mice exhibited a delayed cutaneous wound healing response. Galectin-1 induced myofibroblast activation, migration, and proliferation by triggering intracellular reactive oxygen species (ROS) production. A ROS-producing protein, NADPH oxidase 4 (NOX4), was upregulated by galectin-1 through the neuropilin-1/Smad3 signaling pathway in myofibroblasts. Subcutaneous injection of galectin-1 into wound areas accelerated the healing of general and pathological (streptozotocin-induced diabetes mellitus) wounds and decreased the mortality of diabetic mice with skin wounds. These findings indicate that galectin-1 is a key regulator of wound repair that has therapeutic potential for pathological or imperfect wound healing.

This study investigated the feasibility of using Peucedanum ostruthium leaves, typically regarded as waste, as a substitute for the widely used rhizome. To identify the optimal parameters for ultrasound-assisted extraction of P. ostruthium leaves, we used Box–Behnken design in combination with response surface methodology. The optimal parameters were as follows: ethanol, 80%; extraction temperature, 61.0°C; ultrasonication duration, 35.5 min; liquid-to-solid ratio, 20; and ultrasonic power, 249 W. The half-maximal inhibitory concentration for the inhibition of extracellular tyrosinase activity, scavenging of free radicals, and suppression of various aging-related and inflammatory enzymes by P. ostruthium leaf extract (POLE) were 62.30, 20.62, 8.63, 40.82–91.23, and 12.8–126.4 mg/L, respectively. The minimum bactericidal concentration and minimum fungicidal concentration of POLE for the microorganisms tested in this study were 150–350 and 400–500 mg/L, respectively. Therefore, POLE exhibited strong whitening, antiaging, anti-inflammatory, and antimicrobial properties, surpassing those of the rhizome extract. Furthermore, POLE was biologically safe at concentrations of ≤500 mg/L. The extract exhibited remarkable wound healing capacity (92.5%) at 25 mg/L. The average efficiency of transdermal absorption and penetration reached 98%. A total of 34 predominant volatile organic compounds and 19 major nonvolatile organic compounds were identified in POLE. Molecular docking analysis attributed POLE’s whitening effects to both phenolic acids and flavonoids and its antiaging effects to mainly flavonoids. Furthermore, POLE’s anti-inflammatory and antimicrobial effects were attributed to flavonoids and coumarins. Overall, as a viable alternative to imported P. ostruthium rhizome extract, POLE holds promise for applications in cosmeceutical, healthcare, and medical products.

Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer. TNBC does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. Cytotoxic chemotherapy and surgery are the current therapeutic strategies for TNBC patients, but the chemoresistance of TNBC limits the efficiency of this strategy and shortens the lifespan of patients. The exploration of targeted therapy is ongoing in TNBC research. The aim of the present study was to identify the mechanism underlying acquired resistance in TNBC through the exploration of the relationship between the expression of USP7 and of ABCB1. We found that ubiquitin specific protease 7 (USP7) is a potential therapeutic target for overcoming the chemoresistance of TNBC. USP7 overexpression increased the chemoresistance of TNBC, while the knockdown of USP7 effectively increased the chemosensitivity of chemoresistant TNBC. A USP7 inhibitor effectively induced apoptosis and suppressed metastasis in chemoresistant TNBC. We further clarified that USP7 is a specific deubiquitinating enzyme for ABCB1 that plays an essential role in drug resistance. USP7 directly interacted with ABCB1 and regulated its stability. We concluded that USP7 promotes the chemoresistance of TNBC by stabilizing the ABCB1 protein.