Modification of the immune response by bacteriophages alters methicillin-resistant Staphylococcus aureus infection.

There is an urgent need to develop phage therapies for multidrug-resistant bacterial infections. However, although bacteria have been shown to be susceptible to phage therapy, phage therapy is not sufficient in some cases. PhiMR003 is a methicillin-resistant Staphylococcus aureus phage previously isolated from sewage influent, and it has demonstrated high lytic activity and a broad host range to MRSA clinical isolates in vitro. To investigate the potential of phiMR003 for the treatment of MRSA infection, the effects of phiMR003 on immune responses in vivo were analysed using phiMR003-susceptible MRSA strains in a mouse wound infection model. Additionally, we assessed whether phiMR003 could affect the immune response to infection with a nonsusceptible MRSA strain. Interestingly, wounds infected with both susceptible and nonsusceptible MRSA strains treated with phiMR003 demonstrated decreased bacterial load, reduced inflammation and accelerated wound closure. Moreover, the infiltration of inflammatory cells in infected tissue was altered by phiMR003. While the effects of phiMR003 on inflammation and bacterial load disappeared with heat inactivation of phiMR003. Transcripts of proinflammatory cytokines induced by lipopolysaccharide were reduced in mouse peritoneal macrophages. These results show that the immune modulation occurring as a response to the phage itself improves the clinical outcomes of phage therapy.

Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue.

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.

Standardized Extract of Asparagus officinalis Stem Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1ß Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages.

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. A standardized extract of Asparagus officinalis stem (EAS) is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of EAS on pro-inflammatory responses in S1-stimulated macrophages. Murine peritoneal exudate macrophages were co-treated with EAS and S1. Concentrations and mRNA levels of pro-inflammatory cytokines were assessed using enzyme-linked immunosorbent assay and reverse transcription and real-time polymerase chain reaction, respectively. Expression and phosphorylation levels of signaling proteins were analyzed using western blotting and fluorescence immunomicroscopy. EAS significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. EAS also markedly suppressed the S1-induced transcription of IL-6 and IL-1ß. However, among the TLR4 signaling proteins, EAS did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, EAS significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1ß by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that EAS attenuates S1-induced IL-6 and IL-1ß production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, EAS may be beneficial in regulating excessive inflammation in patients with COVID-19.

SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now spread globally. Some patients develop severe complications including multiple organ failure. It has been suggested that excessive inflammation associated with the disease plays major role in the severity and mortality of COVID-19. To elucidate the inflammatory mechanisms involved in COVID-19, we examined the effects of SARS-CoV-2 spike protein S1 subunit (hereafter S1) on the pro-inflammatory responses in murine and human macrophages. Murine peritoneal exudate macrophages produced pro-inflammatory mediators in response to S1 exposure. Exposure to S1 also activated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. Pro-inflammatory cytokine induction by S1 was suppressed by selective inhibitors of NF-κB and JNK pathways. Treatment of murine peritoneal exudate macrophages and human THP-1 cell-derived macrophages with a toll-like receptor 4 (TLR4) antagonist attenuated pro-inflammatory cytokine induction and the activation of intracellular signaling by S1 and lipopolysaccharide. Similar results were obtained in experiments using TLR4 siRNA-transfected murine RAW264.7 macrophages. In contrast, TLR2 neutralizing antibodies could not abrogate the S1-induced pro-inflammatory cytokine induction in either RAW264.7 or THP-1 cell-derived macrophages. These results suggest that SARS-CoV-2 spike protein S1 subunit activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. Therefore, TLR4 signaling in macrophages may be a potential target for regulating excessive inflammation in COVID-19 patients.

Comparative evaluation of methods to determine intra-individual reference ranges in nutrition support team (NST)-related tests.

BACKGROUND: The intra-individual reference range is generally narrower than the commonly used reference range. Consequently, close monitoring of changes in the laboratory test results of individuals based on the inter-individual reference range remains challenging. METHODS: We examined the determination of individual reference ranges using four indicators of nutritional conditions: transferrin (TRF), albumin (ALB), retinol-binding protein (RBP), and transthyretin (TTR). The subjects comprised 20 healthy individuals and blood samples were collected and tested five times at 2-week intervals. We used the measurement results for the four indicators and examined individual reference ranges using four methods, including calculation methods based on the reference change value and Bayesian inference. RESULTS: The resulting intra-individual reference ranges were narrower than the currently used inter-individual reference range for all measurements using four methods. Furthermore, the intra-individual coefficient of variation [CV (intra)] was smaller than the inter-individual coefficient of variation [CV (inter)] for TRF, RBP, and TTR for all 20 subjects. The means CV (intra) for the four indicators were also lower than the corresponding CV (inter). CONCLUSIONS: The intra-individual reference range can be used to validate the standard deviation and coefficient of variation for currently used indicators. Moreover, Bayesian methods are speculated to be the most versatile.

Exercise Training-Enhanced Lipolytic Potency to Catecholamine Depends on the Time of the Day.

Exercise training is well known to enhance adipocyte lipolysis in response to hormone challenge. However, the existence of a relationship between the timing of exercise training and its effect on adipocyte lipolysis is unknown. To clarify this issue, Wistar rats were run on a treadmill for 9 weeks in either the early part (E-EX) or late part of the active phase (L-EX). L-EX rats exhibited greater isoproterenol-stimulated lipolysis expressed as fold induction over basal lipolysis, with greater protein expression levels of hormone-sensitive lipase (HSL) phosphorylated at Ser 660 compared to E-EX rats. Furthermore, we discovered that Brain and muscle Arnt-like (BMAL)1 protein can associate directly with several protein kinase A (PKA) regulatory units (RIα, RIß, and RIIß) of protein kinase, its anchoring protein (AKAP)150, and HSL, and that the association of BMAL1 with the regulatory subunits of PKA, AKAP150, and HSL was greater in L-EX than in E-EX rats. In contrast, comparison between E-EX and their counterpart sedentary control rats showed a greater co-immunoprecipitation only between BMAL1 and ATGL. Thus, both E-EX and L-EX showed an enhanced lipolytic response to isoproterenol, but the mechanisms underlying exercise training-enhanced lipolytic response to isoproterenol were different in each group.

ETAS®50 Attenuates Ultraviolet-B-Induced Interleukin-6 Expression by Suppressing Akt Phosphorylation in Normal Human Dermal Fibroblasts.

We recently reported that ETAS 50, a standardized extract from the Asparagus officinalis stem, exerted anti-inflammatory effects on ultraviolet-B- (UV-B-) irradiated normal human dermal fibroblasts (NHDFs) by inhibiting nuclear factor-κB p65 nuclear import and the resulting interleukin-1ß (IL-1ß) expression. To further elucidate the antiphotoaging potency of ETAS 50, we examined the anti-inflammatory effects on UV-B-irradiated NHDFs by focusing on the stress-activated mitogen-activated protein kinase (MAPK) and Akt signaling pathways. NHDFs were treated with 1 mg/mL of ETAS 50 or dextrin (vehicle control) after UV-B irradiation (20 mJ/cm2) for different time periods. Phosphorylation levels of c-Jun N-terminal kinase (JNK), p38 MAPK, and Akt were analyzed by western blotting. IL-6 mRNA levels were analyzed by real-time polymerase chain reaction. UV-B-irradiated NHDFs showed increased phosphorylation levels of JNK, p38 MAPK, and Akt, as well as increased mRNA levels of IL-6. ETAS 50 treatment after UV-B irradiation suppressed the increased phosphorylation levels of Akt without affecting those of JNK and p38 MAPK. ETAS 50 as well as Akt inhibitor Perifosine repressed UV-B irradiation-induced IL-6 mRNA expression. These results suggest that ETAS 50 treatment represses UV-B irradiation-induced IL-6 expression by suppressing Akt phosphorylation. The present findings demonstrate the potential of ETAS 50 to prevent photoaging by attenuating UV-B irradiation-induced proinflammatory responses in skin fibroblasts.

A standardized extract of Asparagus officinalis stem prevents reduction in heat shock protein 70 expression in ultraviolet-B-irradiated normal human dermal fibroblasts: an in vitro study.

BACKGROUND: Heat shock protein 70 (HSP70) exhibits protective effects against ultraviolet (UV)-induced premature skin aging. A standardized extract of Asparagus officinalis stem (EAS) is produced as a novel and unique functional food that induces HSP70 cellular expression. To elucidate the anti-photoaging potencies of EAS, we examined its effects on HSP70 expression levels in UV-B-irradiated normal human dermal fibroblasts (NHDFs). METHODS: NHDFs were treated with 1 mg/mL of EAS or dextrin (vehicle control) prior to UV-B irradiation (20 mJ/cm2). After culturing NHDFs for different time periods, HSP70 mRNA and protein levels were analyzed using real-time polymerase chain reaction and western blotting, respectively. RESULTS: UV-B-irradiated NHDFs showed reduced HSP70 mRNA levels after 1-6 h of culture, which were recovered after 24 h of culture. Treatment with EAS alone for 24 h increased HSP70 mRNA levels in the NHDFs, but the increase was not reflected in its protein levels. On the other hand, pretreatment with EAS abolished the UV-B irradiation-induced reduction in HSP70 expression at both mRNA and protein levels. These results suggest that EAS is capable to preserve HSP70 quantity in UV-B-irradiated NHDFs. CONCLUSIONS: EAS exhibits anti-photoaging potencies by preventing the reduction in HSP70 expression in UV-irradiated dermal fibroblasts.

Anti-Inflammatory Effect of ETAS®50 by Inhibiting Nuclear Factor-κB p65 Nuclear Import in Ultraviolet-B-Irradiated Normal Human Dermal Fibroblasts.

Ultraviolet (UV) irradiation induces proinflammatory responses in skin cells, including dermal fibroblasts, accelerating premature skin aging (photoaging). ETAS 50, a standardized extract from the Asparagus officinalis stem, is a novel and unique functional food that suppresses proinflammatory responses of hydrogen peroxide-stimulated skin fibroblasts and interleukin- (IL-) 1ß-stimulated hepatocytes. To elucidate its antiphotoaging potencies, we examined whether ETAS 50 treatment after UV-B irradiation attenuates proinflammatory responses of normal human dermal fibroblasts (NHDFs). UV-B-irradiated NHDFs showed reduced levels of the cytosolic inhibitor of nuclear factor-κB α (IκBα) protein and increased levels of nuclear p65 protein. The nuclear factor-κB nuclear translocation inhibitor JSH-23 abolished UV-B irradiation-induced IL-1ß mRNA expression, indicating that p65 regulates transcriptional induction. ETAS 50 also markedly suppressed UV-B irradiation-induced increases in IL-1ß mRNA levels. Immunofluorescence analysis revealed that ETAS 50 retained p65 in the cytosol after UV-B irradiation. Western blotting also showed that ETAS 50 suppressed the UV-B irradiation-induced increases in nuclear p65 protein. Moreover, ETAS 50 clearly suppressed UV-B irradiation-induced distribution of importin-α protein levels in the nucleus without recovering cytosolic IκBα protein levels. These results suggest that ETAS 50 exerts anti-inflammatory effects on UV-B-irradiated NHDFs by suppressing the nuclear import machinery of p65. Therefore, ETAS 50 may prevent photoaging by suppressing UV irradiation-induced proinflammatory responses of dermal fibroblasts.

Exercise Training Attenuates the Dysregulated Expression of Adipokines and Oxidative Stress in White Adipose Tissue.

Obesity-induced inflammatory changes in white adipose tissue (WAT), which caused dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein-1, contribute to the development of insulin resistance. Moreover, current literature reports state that WAT generates reactive oxygen species (ROS), and the enhanced production of ROS in obese WAT has been closely associated with the dysregulated expression of adipokines in WAT. Therefore, the reduction in excess WAT and oxidative stress that results from obesity is thought to be one of the important strategies in preventing and improving lifestyle-related diseases. Exercise training (TR) not only brings about a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the adipokines in WAT. Furthermore, some reports indicate that TR affects the generation of oxidative stress in WAT. This review outlines the impact of TR on the expression of inflammation-related adipokines and oxidative stress in WAT.

Regular Voluntary Exercise Potentiates Interleukin-1ß and Interleukin-18 Secretion by Increasing Caspase-1 Expression in Murine Macrophages.

Moderate-intensity regular exercise improves proinflammatory responses of lipopolysaccharide- (LPS-) stimulated macrophages. However, intracellular events that mediate the beneficial effects of exercise were unclear. This study aimed to clarify the mechanism by which regular voluntary exercise (VE) improves proinflammatory cytokine production by macrophages challenged with LPS. Peritoneal macrophages from VE mice secreted considerably higher amounts of interleukin- (IL-) 1ß and IL-18 than did cells from sedentary control (SC) mice in the presence and absence of LPS, although tumor necrosis factor-α and IL-10 secretion were comparable between both groups. The mRNA levels of these cytokines increased significantly in response to LPS; similar levels were noted in macrophages from both SC and VE mice. Moreover, LPS evoked similar levels of degradation of inhibitor of κB (IκB) α and phosphorylation of IκB kinase ß, c-Jun N-terminal kinase, and p38 in macrophages from SC and VE mice. These results indicate that the increased IL-1ß and IL-18 secretion in VE mice are regulated posttranscriptionally. On the other hand, macrophages from VE mice showed higher amounts of caspase-1 protein than did cells from SC mice. These results suggest that regular VE potentiates IL-1ß and IL-18 secretion in LPS-challenged macrophages by increasing caspase-1 levels.

NEU1 sialidase controls gene expression and secretion of IL-6 and MCP-1 through NF-κB pathway in 3T3-L1 adipocytes.

A sialidase NEU1 that removes sialic acids from glycoconjugates has been implicated in diverse cellular functions. Aberrant NEU1 activity is associated with various pathologies including lysosomal storage disorder sialidosis, autoimmune diseases and the malignancy and metastasis of cancer cells. We recently reported that NEU1 activity increases during 3T3-L1 adipogenesis and that it is higher in the epididymal fat of obese and diabetic mice. However, the precise functions of NEU1 in adipocytes have not been elucidated. Knockdown of NEU1 using siRNA transfection in 3T3-L1 adipocytes significantly decreased the mRNA expression and protein secretion of IL-6 and MCP-1 induced by LPS. The promoter activities of both IL-6 and MCP-1 as well as nuclear factor-kappa B (NF-κB) nuclear translocation were reduced in adipocytes transfected with an siRNA sequence that targets NEU1(siNEU1). NEU1 suppression using siNEU1 affected TLR4 sialylation. These findings suggest that NEU1 is involved in the production of IL-6 and MCP-1 in adipocytes possibly through TLR4/NF-κB signalling.

Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study.

OBJECTIVE: Approximately 8-10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. STUDY DESIGN: The study included 23 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5 days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. RESULTS: The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). CONCLUSIONS: We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders.

Enzyme-Treated Asparagus Extract Attenuates Hydrogen Peroxide-Induced Matrix Metalloproteinase-9 Expression in Murine Skin Fibroblast L929 Cells.

Enzyme-treated asparagus extract (ETAS) exerts a wide variety of beneficial biological actions including facilitating anti-cortisol stress and neurological anti-aging responses. However, the anti-skin aging effects of ETAS remain to be elucidated. Reactive oxygen species (ROS) play pivotal roles in skin aging. Increased ROS levels in fibroblasts in response to ultraviolet irradiation activate c-Jun N-terminal kinase (JNK) and its downstream transcription factor activator protein-1 (AP-1), and the resultant gene expression of matrix metalloproteinase (MMP) isoforms accelerates collagen breakdown in the dermis. Therefore, we explored whether ETAS has anti-skin aging effects by attenuating the oxidative stress responses in fibroblasts. Simultaneous treatment of murine skin L929 fibroblasts with hydrogen peroxide (H2O2) and either ETAS or dextrin showed that ETAS significantly suppressed H2O2-induced expression of MMP-9 mRNA as measured by real-time polymerase chain reaction. ETAS also clearly suppressed H2O2-stimulated phosphorylation of c-Jun (AP-1 subunit) and JNK as determined by Western blot. However, ETAS did not affect the increased amounts of carbonyl proteins in response to H2O2, also as determined by Western blotting. These results suggest that ETAS diminishes cellular responsiveness to ROS but does not scavenge ROS. Thus, ETAS has the potential to prevent skin aging through attenuating the oxidative stress responses in dermal fibroblasts.

Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.

Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders.

Habitual exercise training acts as a physiological stimulator for constant activation of lipolytic enzymes in rat primary white adipocytes.

It is widely accepted that lipolysis in adipocytes are regulated through the enzymatic activation of both hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) via their phosphorylation events. Accumulated evidence shows that habitual exercise training (HE) enhances the lipolytic response in primary white adipocytes with changes in the subcellular localization of lipolytic molecules. However, no study has focused on the effect that HE exerts on the phosphorylation of both HSL and ATGL in primary white adipocytes. It has been shown that the translocation of HSL from the cytosol to lipid droplet surfaces requires its phosphorylation at Ser-563. In primary white adipocytes obtained from HE rats, the level of HSL and ATGL proteins was higher than that in primary white adipocytes obtained from sedentary control (SC) rats. In HE rats, the level of phosphorylated ATGL and HSL was also significantly elevated compared with that in SC rats. These differences were confirmed by Phos-tag SDS-PAGE, a technique used to measure the amount of total phosphorylated proteins. Our results suggest that HE can consistently increase the activity of both lipases, thereby enhancing the lipolysis in white fat cells. Thus, HE helps in the prevention and treatment of obesity-related diseases by enhancing the lipolytic capacity.

The Molecular Mechanism Underlying Continuous Exercise Training-Induced Adaptive Changes of Lipolysis in White Adipose Cells.

Physical exercise accelerates the mobilization of free fatty acids from white adipocytes to provide fuel for energy. This happens in several tissues and helps to regulate a whole-body state of metabolism. Under these conditions, the hydrolysis of triacylglycerol (TG) that is found in white adipocytes is known to be augmented via the activation of these lipolytic events, which is referred to as the "lipolytic cascade." Indeed, evidence has shown that the lipolytic responses in white adipocytes are upregulated by continuous exercise training (ET) through the adaptive changes in molecules that constitute the lipolytic cascade. During the past few decades, many lipolysis-related molecules have been identified. Of note, the discovery of a new lipase, known as adipose triglyceride lipase, has redefined the existing concepts of the hormone-sensitive lipase-dependent hydrolysis of TG in white adipocytes. This review outlines the alterations in the lipolytic molecules of white adipocytes that result from ET, which includes the molecular regulation of TG lipases through the lipolytic cascade.

Effect of Circadian Rhythm on Clinical and Pathophysiological Conditions and Inflammation.

Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging-related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases.

Direct and indirect suppression of interleukin-6 gene expression in murine macrophages by nuclear orphan receptor REV-ERBα.

It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERBα plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBα in the regulation of interleukin-6 (il6) gene expression in murine macrophages. REV-ERBα agonists, or overexpression of rev-erb α in the murine macrophage cell line RAW264 cells, suppressed the induction of il6 mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erb α overexpression decreased LPS-stimulated nuclear factor κB (NFκB) activation in RAW264 cells. We showed that REV-ERBα represses il6 expression not only indirectly through an NFκB binding motif but also directly through a REV-ERBα binding motif in the murine il6 promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erb α increased il6 mRNA expression. These data suggest that REV-ERBα regulates the inflammatory response of macrophages through the suppression of il6 expression. REV-ERBα may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.

ETAS, an enzyme-treated asparagus extract, attenuates amyloid beta-induced cellular disorder in PC12 cells.

One of the pathological characterizations of Alzheimer's disease (AD) is the deposition of amyloid beta peptide (Abeta) in cerebral cortical cells. The deposition of Abeta in neuronal cells leads to an increase in the production of free radicals that are typified by reactive oxygen species (ROS), thereby inducing cell death. A growing body of evidence now suggests that several plant-derived food ingredients are capable of scavenging ROS in mammalian cells. The purpose of the present study was to investigate whether enzyme-treated asparagus extract (ETAS), which is rich in antioxidants, is one of these ingredients. The pre-incubation of differentiated PC 12 cells with ETAS significantly recovered Abeta-induced reduction of cell viability, which was accompanied by reduced levels of ROS. These results suggest that ETAS may be one of the functional food ingredients with anti-oxidative capacity to help prevent AD.