Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.

Abstract:This study provides the scientific basis for the anti-inflammatory effects of licorice extract in a t-BHP (tert-butyl hydrogen peroxide)-induced liver damage model and the effects of its ingredients, glycyrrhizic acid (GA), liquiritin (LQ) and liquiritigenin (LG), in a lipopolysaccharide (LPS)-stimulated microglial cell model. The GA, LQ and LG inhibited the LPS-stimulated elevation of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and interleukin (IL)-6 in BV2 (mouse brain microglia) cells. Furthermore, licorice extract inhibited the expression levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the livers of t-BHP-treated mice models. This result suggested that mechanistic-based evidence substantiating the traditional claims of licorice extract and its three bioactive components can be applied for the treatment of inflammation-related disorders, such as oxidative liver damage and inflammation diseases.

Nonalcoholic fatty liver is involved in the development of nonalcoholic steatohepatitis and chronic liver injury. Impairment of hepatic transsulfuration reactions is suggested to be critically linked with alcoholic liver injury, but its role in nonalcoholic fatty liver remains unknown. We examined the early changes in sulfur-amino acid metabolism and their implication in nonalcoholic fatty liver disease (NAFLD). Male rats were provided with a standard liquid diet or a high-fat liquid diet (HF) for 3 wk. An additional group of rats received the HF diet supplemented with betaine (1%). HF diet intake elevated hepatic triglyceride and serum tumor necrosis factor-alpha (TNFalpha) concentrations. Antioxidant capacity of liver cytosol against hydroxyl and peroxyl radicals was reduced significantly. Hepatic S-adenosylmethionine (SAM) and glutathione (GSH) decreased, but hypotaurine and taurine concentrations increased. Methionine adenosyltransferase (MAT) activity, not its concentration, was depressed, whereas both activity and concentration of cysteine dioxygenase and GSH S-transferase were elevated. Betaine supplementation of the HF diet inhibited hepatic fat accumulation and serum TNFalpha elevation. The decrease in cytosolic antioxidant capacity was also prevented. MAT activity and its concentration were induced significantly. Hepatic SAM and GSH increased and elevation of hypotaurine and taurine was depressed. The results indicate that the metabolism of S-containing substances is significantly disturbed by the HF diet, suggesting a causal role of impairment of hepatic transsulfuration reactions in NAFLD. Betaine supplementation protects the liver from nonalcoholic steatosis and oxidative stress most probably via its effects on the transsulfuration reactions.

BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0121-7) contains supplementary material, which is available to authorized users.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent ingredient of red pepper, is reported to have antimutagenic and anticarcinogenic properties. However, the mechanisms underlying its chemoprotective effects remain largely unresolved. In the present study, we found that capsaicin induced expression of heme oxygenase-1 (HO-1) in HepG2 cells. Capsaicin treatment resulted in a transient increase in the phosphorylation of Akt and subsequently nuclear translocation of NF-E2-related factor 2 (Nrf2), enhancing its binding to antioxidant response element (ARE). HepG2 cells treated with capsaicin exhibited increased production of reactive oxygen species (ROS). Prior exposure of cells to N-acetyl-L -cysteine blocked not only the ROS production but also the nuclear translocation of Nrf2 and its ARE binding, as well as HO-1 induction by capsaicin. Immunoblot analysis showed that whereas the level of HO-1 protein was elevated, that of NAD(P)H:quinone oxidoreductase (NQO1) was decreased after the treatment with capsaicin or the inhibitor of NQO1, dicumarol. We hypothesize that quinone metabolites or other reactive forms of capsaicin may bind covalently to NQO1 and thereby inhibit its activity, leading to production of ROS. This, in turn, would trigger the activation of Akt via phosphorylation, increase the nuclear translocation and ARE binding of Nrf2, and upregulate the expression of HO-1.