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.
Extracellular vesicles (EVs) have emerged as a key regulator of intercellular and inter‐organ communications, playing an important role in mediating metabolic responses. Dysregulation of exosome ...secretion and exosome cargo composition has been associated with metabolic diseases. However, how EVs reflect diet‐induced metabolic responses remains unexplored. The objective of the study is to identify changes in the size profile and protein cargoes of circulating exosomes in diet‐induced obesity upon intermittent fasting, as well as to establish EV biomarkers for obesity‐related dietary responses.
Male mice (8‐10 weeks of age) were all fed a high‐fat diet (HFD) for 18 weeks prior to being placed either in ad libitum group (HFD‐AL) or intermittent fasting group (HFD‐IF) for an additional 10 weeks. Mice on the normal chow ad libitum (NC‐AL) served as control. The IF group had food available for 10 hours and fasted for 14 hours per day. EVs were isolated from serum and size was measured using Nanoparticle Tracking Analysis. Additionally, quantitative proteomics was conducted to identify EV protein markers and FunRich Analysis Tool was used to identify pathways related to the identified proteins.
On a long‐term HFD, the IF significantly altered the size profile of serum exosomes. The HFD‐AL mice had an increasing trend in mean diameter of serum EVs by 24nm compared to the NC‐AL mice. The 10 weeks of IF caused a significant decrease in mean diameter of serum EVs by 47.9nm (P= 0.03) when compared to the HFD‐AL mice. However, neither the HFD nor IF altered the overall particle amount per unit of serum. This suggests that the population composition of EVs may be changed in response to the HFD feeding or IF. To address this question, we analyzed the specific populations of EVs with different ranges of sizes. Intriguingly, we found the HFD altered the population composition of EVs (decreased small EVs and increased large EVs) and the IF was able to reverse these changes. The mean population of EVs/exosomes (30‐150nm in size) were increased in the HFD‐IF group by ~30% (P= 0.02), whereas the populations of larger EVs (200‐350nm) were decreased by ~15% (P= 0.02) when compared to the HFD‐AL mice. Proteomic Analysis of the protein abundance within the isolated EVs showed variance between the experimental groups. Compared to the NC‐AL, the HFD‐AL group had 15 upregulated proteins (involved in pathways such as blood coagulation, immune response, and others) and 18 downregulated proteins (involved in pathways such as cytolysis, classical and alternative pathway complement activation, and others). Between the HFD‐IF and HFD‐AL groups, 43 proteins were found to be significantly different in abundance. Of those 43 proteins, 10 proteins altered by HFD‐AL were reversed by implementing IF. FunRich analysis showed that these 10 proteins belonged to the pathways involving NADP metabolism, immune responses, lipoprotein metabolism, and cholesterol homeostasis.
Together, this data suggests intermittent fasting significantly alters the profile and protein cargoes of circulating EVs which may serve as an important mechanism for the metabolic benefits of intermittent fasting in obesity as well as biomarkers for obesity‐related metabolic responses.
Pentraxin 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.
Ptx3 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.
We 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.
Our results suggest a protective role of PTX3 in LPS- and HFD-induced sustained inflammation in adipose tissue.
Pentraxin 3 (PTX3) is a soluble pattern recognition receptor playing an important role in immune response and inflammation. Lipopolysaccharide (LPS) stimulation can significantly induce PTX3 ...expression and secretion in adipocytes. Appropriate regulation of PTX3 secretion is critical for inflammatory homeostasis. Using chemical inhibitors of conventional and unconventional protein secretion, we explored the mechanisms that control LPS-stimulated PTX3 secretion in 3T3-L1 adipocytes. Inhibiting the conventional protein secretion blocked LPS-stimulated PTX3 secretion, resulting in cellular PTX3 accumulation in adipocytes. We also detected PTX3 in exosomes from LPS-treated adipocytes; inhibiting exosome trafficking attenuated PTX3 secretion. However, only 4.3% of secreted PTX3 was detected in exosomes compared to 95.7% in the non-exosomal fractions. The fractionation of isolated exosomes by the iodixanol density gradient centrifugation confirmed that a small portion of secreted PTX3 overlapped with exosomal markers in small extracellular-vesicle fractions. We conclude that PTX3 is secreted mainly through conventional protein secretion, and a small percentage of PTX3 is released in exosomes from LPS-stimulated adipocytes.
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.
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.
Perioperative optimization of Crohn's disease Lin, Chun‐Chi; Lin, Hung‐Hsin; Chen, Hui‐Chuen ...
Annals of gastroenterological surgery,
January 2023, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Crohn's disease (CD) is a chronic inflammatory disease mainly affecting the gastrointestinal tract. With the increased availability of modalities in the last two decades, the treatment of CD has ...advanced remarkably. Although medical treatment is the mainstay of therapy, most patients require surgery during the course of their illness, especially those who experience complications. Nutritional optimization and ERAS implementation are crucial for patients with CD who require surgical intervention to reduce postoperative complications. The increased surgical risk was found to be associated with the use of corticosteroids, but the association of surgical risk with immunomodulators, biologic therapy, such as anti‐TNF mediations, anti‐integrin medications, and anti‐IL 12/23 was low in certainty. Decisions about preoperative medication must be made on an individual case‐dependent basis. Preoperative imaging studies can assist in the planning of appropriate surgical strategies and approaches. However, patients must be informed of any alterations to their treatment. In summary, the management of perioperative medications and surgery‐related decision‐making should be individualized and patient‐centered based on a multidisciplinary approach.
Most Crohn's disease patients require surgery during the course of their illness, especially those who experience complications. The management of perioperative medications and surgery‐related decision‐making should be individualized and patient‐centered based on a multidisciplinary approach.
Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal ...complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque‐Dawley rats with common bile duct ligation–induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6‐cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice‐weekly for 8 weeks)‐induced cirrhotic rats. Caffeine down‐regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho‐VEGFR2, and phospho–Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH‐related complications in cirrhosis. (Hepatology 2015;61:1672‐1684)
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.
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