Lactate is an important metabolite in cellular metabolism and fluctuates in certain disease conditions including cancer and immune diseases. It was hypothesized that a decrease in lactate would modulate the inflammatory response elicited by lipopolysaccharides (LPS) in macrophages. When RAW 264.7 macrophages were treated with FX11, a specific lactate dehydrogenase (LDHA) inhibitor, the expression of the cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) was downregulated due to reduced cellular lactate levels. Genetic suppression of LDHA by small interfering RNA (siRNA) downregulated the LPS-activated expression of interleukin (IL)-6, iNOS, and COX-2, and reduced the production of IL-6 and nitrites. Pharmacological and genetic suppression of LDHA inhibited the phosphorylation of p38 mitogen-activated protein kinase. Microarray gene expression profile demonstrated that the genes involved in cell proliferation and inflammation were mainly altered by siRNA-mediated LDHA suppression. Collectively, the present observations suggest that lactate may be an important metabolite and implicated in regulation of inflammatory response.

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The aims of this study were to determine bioactive components of Graviola leaf extracts and to examine the radical scavenging capacity, gene expression of antioxidant enzymes and transcription factors.

Annona muricata, commonly known as Graviola, has been utilized as a traditional medicine to treat various human diseases. The aim of this study was to examine the immune-enhancing activity of Graviola leaf extracts in RAW 264.7 macrophage cells. Active ingredients in Graviola leaf extracts (GE) were identified as kaempferol-3-O-rutinoside and quercetin-3-O-rutinoside by LC-MS/MS. When treated with steam or 50% ethanol GE, cell morphology was altered due to initiation of cell differentiation. While the cell viability was not altered by the steam GE, it was reduced by the ethanol GE. Both steam and ethanol GE induced the transcriptional expression of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β, but only the steam extract upregulated inducible nitric oxide synthase (iNOS). In consistence with mRNA expression, the production of TNF-α and nitrite was elevated by both steam and ethanol extracts of Graviola leaves. This is mainly due to activation of mitogen-activated protein (MAP) kinase signaling pathways. These results suggest that Graviola leaves enhance immunity by activation of the MAP kinase pathways. These bioactive properties of Graviola indicate its potential as a health-promoting ingredient to boost the immune system.

Ceramides are the major sphingolipid metabolites involved in cell survival and apoptosis. When HepG2 hepatoma cells were treated with celecoxib, the expression of the genes in de novo sphingolipid biosynthesis and sphingomyelinase pathway was upregulated and cellular ceramide was elevated. In addition, celecoxib induced endoplasmic reticulum (ER) stress in a time-dependent manner. SPTLC2, a subunit of serine palmitoyltransferase, was overexpressed by adenovirus. Adenoviral overexpression of SPTLC2 (AdSPTLC2) decreased cell viability of HEK293 and HepG2 cells. In addition, AdSPTLC2 induced apoptosis via the caspase-dependent apoptotic pathway and elevated cellular ceramide, sphingoid bases, and dihydroceramide. However, overexpression of SPTLC2 did not induce ER stress. Collectively, celecoxib activates de novo sphingolipid biosynthesis and the combined effects of elevated ceramide and transcriptional activation of ER stress induce apoptosis. However, activation of de novo sphingolipid biosynthesis does not activate ER stress in hepatoma cells and is distinct from the celecoxib-mediated activation of ER stress.

Nonalcoholic fatty liver diseases (NAFLD) is characterized by accumulation of lipid droplets in the liver. The objective of this study was to evaluate protective effects of fermented Cordyceps militaris extract by Pediococcus pentosaceus ON188 (ONE) against hepatosteatosis and obesity in mice fed a high-fat diet (HFD). Eight-week-old male C57BL/6J mice were fed HFD mixed with ONE for four weeks and its effects on hepatosteatosis and obesity were examined. Although ONE did not change food intake, it reduced body weights of mice at administration dose of 200 mg/kg/day. Activities of lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine transaminase (ALT) as plasma parameters were reduced by ONE in a dose-dependent manner. Hepatic lipid droplets and triglyceride (TG) levels were also reduced by ONE due to upregulation of fatty acid oxidizing genes such as carnithine palmitoyltransferase (CPT1) and peroxisomal proliferator activated receptor α(PPARα) mediated by induction of sphingosine kinase 2 (SPHK2). In epididymal fat tissue, sizes of adipocytes were significantly reduced by ONE in a dose-dependent manner. This is mainly due to suppression of lipogenesis and upregulation of adipocyte browning genes. Collectively, these results suggest that fermented ONE can activate fatty acid oxidation via SPHK2 in the liver. It can also suppress lipogenesis and activate browning in adipose tissue. Thus, ONE might have potential to be used for the development of functional foods against liver dysfunction and obesity.

Atherosclerosis is the deposition of plaque in the main arteries. It is an inflammatory condition involving the accumulation of macrophages and various lipids (low-density lipoprotein [LDL] cholesterol, ceramide, S1P). Moreover, endothelial cells, macrophages, leukocytes, and smooth muscle cells are the major players in the atherogenic process. Sphingolipids are now emerging as important regulators in various pathophysiological processes, including the atherogenic process. Various sphingolipids exist, such as the ceramides, ceramide-1-phosphate, sphingosine, sphinganine, sphingosine-1-phosphate (S1P), sphingomyelin, and hundreds of glycosphingolipids. Among these, ceramides, glycosphingolipids, and S1P play important roles in the atherogenic processes. The atherosclerotic plaque consists of higher amounts of ceramide, glycosphingolipids, and sphingomyelin. The inhibition of the de novo ceramide biosynthesis reduces the development of atherosclerosis. S1P regulates atherogenesis via binding to the S1P receptor (S1PR). Among the five S1PRs (S1PR1-5), S1PR1 and S1PR3 mainly exert anti-atherosclerotic properties. This review mainly focuses on the effects of ceramide and S1P via the S1PR in the development of atherosclerosis. Moreover, it discusses the recent findings and potential therapeutic implications in atherosclerosis.

Research efforts towards developing near-infrared (NIR) therapeutics to activate the proliferation of human keratinocytes and collagen synthesis in the skin microenvironment have been minimal, and the subject has not been fully explored. Herein, we describe the novel synthesis Ag 2 S nanoparticles (NPs) by using a sonochemical method and reveal the effects of NIR irradiation on the enhancement of the production of collagen through NIR-emitting Ag 2 S NPs. We also synthesized Li-doped Ag 2 S nps that exhibited significantly increased emission intensity because of their enhanced absorption ability in the UV-NIR region. Both Ag 2 S and Li-doped Ag 2 S NPs activated the proliferation of HaCaT (human keratinocyte) and HDF (human dermal fibroblast) cells with no effect on cell morphology. While Ag 2 S NPs upregulated TIMP1 by only twofold in HaCaT cells and TGF-β1 by only fourfold in HDF cells, Li-doped Ag 2 S NPs upregulated TGF-β1 by tenfold, TIMP1 by 26-fold, and COL1A1 by 18-fold in HaCaT cells and upregulated TGF-β1 by fivefold and COL1A1 by fourfold in HDF cells. Furthermore, Ag 2 S nps activated TGF-β1 signaling by increasing the phosphorylation of Smad2 and Smad3. The degree of activation was notably higher in cells treated with Li-doped Ag 2 S nps, mainly caused by the higher pL intensity from Li-doped Ag 2 S NPs. Ag 2 S nps niR activates cell proliferation and collagen synthesis in skin keratinocytes and HDF cells, which can be applied to clinical light therapy and the development of anti-wrinkle agents for cosmetics. Near-infrared (NIR) irradiation has shown great potential for clinical light therapy as well as for cosmetic purposes 1-3 and successfully been applied to photorejuvenation, photoprotection, and treatment for acne and vitiligo 4-9 because of its long optical penetration depth of tissue. Moreover, the uniquely high NIR irradiation penetration efficiency has enabled its extensive application in therapeutic approaches to treating hypertrophic scars, including those resulting from skin aging due to skin wrinkling and skin laxity 10-18. Clinical results have shown improvement in skin texture because NIR irradiation activates collagen synthesis and increases the amount of collagen in human dermal fibroblasts (HDF) 19,20. Changes in collagen have been considered as a leading cause of aging and wrinkle formation because the human dermis is comprised of 90% collagen 21. Schieke et al. 22 reported that the skin temperature increased because the epidermal layers absorbed most of mid-IR (1.5-5.6 μm) and far-IR (5.6-10,000 μm), whereas NIR (0.8-1.5 μm) penetrated deeper to the subcutaneous tissues without causing an increase in skin temperature. However, many studies have reported that NIR irradiation using artificial light sources may be deleterious to human skin because it raises the concentration of matrix metalloproteinase 1 (MMP-1) that damage the skin collagen. Although type I procollagen expression increases with a single NIR irradiation, it should be noted that multiple irradiations can reduce its ex...