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Cannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1 -/- ) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-17) in serum collected from hCNR1 -/- and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1 -/- mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1 -/- mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.

Simple Summary: The aim of this study was to explore the potential impact of red ginseng (RG) on age-associated cellular senescence through in vitro, ex vivo, and 19-month-old aged mouse models. In addition to enhancing insulin homeostasis, RG supplementation modified the canonical cellular senescence pathway and inhibited apoptotic markers. Moreover, RG significantly reduced the senescence-associated inflammatory pathway in the liver. Finally, the RG treatment mitigated cellular senescence in primary hepatocytes and mouse embryonic fibroblasts. In conclusion, these findings suggest that RG has a positive influence on the aging process by regulating hepatic cellular senescence and age-related phenotypes. Cellular senescence is defined as an irreversible cell cycle arrest accompanied by morphological and physiological alterations during aging. Red ginseng (RG), processed from fresh ginseng (Panax ginseng C.A. Meyer) with a one-time steaming and drying process, is a well-known beneficial herbal medicine showing antioxidant, anti-inflammatory, and anti-aging properties. The current study aimed to investigate the benefits of RG in alleviating hepatic cellular senescence and its adverse effects in 19-month-old aged mice. We applied two different intervention methods and durations to compare RG's effects in a time-dependent manner: (1) oral gavage injection for 4 weeks and (2) ad libitum intervention for 14 weeks. We observed that 4-week RG administration was exerted to maintain insulin homeostasis against developing age-associated insulin insensitivity and suppressed cellular senescence pathway in the liver and primary hepatocytes. Moreover, with remarkable improvement of insulin homeostasis, 14-week RG supplementation downregulated the activation of c-Jun N-terminal kinase (JNK) and its downstream transcriptional factor nuclear factor-κB (NF-κB) in aged mice. Lastly, RG treatment significantly reduced the senescence-associated β-galactosidase (SA-β-gal)-positive cells in primary hepatocytes and ionizing radiation (IR)-exposed mouse embryonic fibroblasts (MEFs). Taken together, we suggest that RG can be a promising candidate for a senolytic substance by preventing hepatic cellular senescence. [ABSTRACT FROM AUTHOR]

Dietary interventions with bioactive compounds have been found to suppress the accumulation of senescent cells and senescence-associated secretory phenotypes (SASPs). One such compound, curcumin (CUR), has beneficial health and biological effects, including antioxidant and anti-inflammatory properties, but its ability to prevent hepatic cellular senescence is unclear. The objective of this study was to investigate the effects of dietary CUR as an antioxidant on hepatic cellular senescence and determine its benefits on aged mice. We screened the hepatic transcriptome and found that CUR supplementation led to the downregulation of senescence-associated hepatic gene expressions in both usually fed and nutritionally challenged aged mice. Our results showed that CUR supplementation enhanced antioxidant properties and suppressed mitogen-activated protein kinase (MAPK) signaling cascades in the liver, particularly c-Jun N-terminal kinase (JNK) in aged mice and p38 in diet-induced obese aged mice. Furthermore, dietary CUR decreased the phosphorylation of nuclear factor-κB (NF-κB), a downstream transcription factor of JNK and p38, and inhibited the mRNA expression of proinflammatory cytokines and SASPs. The potency of CUR administration was demonstrated in aged mice via enhanced insulin homeostasis along with declined body weight. Taken together, these results suggest that CUR supplementation may be a nutritional strategy to prevent hepatic cellular senescence. [ABSTRACT FROM AUTHOR]

Background: Although type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. To date, curcumin (CUR), a natural polyphenol and primary component of turmeric, shows putative therapeutic properties such as reducing the incidence of obesity-related diseases in mice. However, the mechanism by which CUR regulates insulin levels remains unclear. Methods: This study investigates how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the diet-induced obesity (DIO) mouse model. Male C57BL/6 J mice were fed a control, a high fat/high sugar (HFS) or a HFS diet containing 0.4% (w/w) curcumin (HFS + CUR) (N = 16 per group) for 16 weeks. Results: Mice given HFS + CUR had reduced body weight and fat accumulation in the liver and had lower blood insulin levels under fasting conditions compared to mice on HFS alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE). We also observed restoration of phosphoinositide 3-kinase (PI3K), especially class Ia catalytic subunits, p110α and p110β, and class Ib regulatory subunit, p101, and phosphorylated protein kinase B (AKT) expression levels in liver on HFS + CUR diet. Additionally, HFS + CUR fed mice had significantly smaller islets of Langerhans and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas. The expression of thioredoxin interacting protein (TXNIP), a pro-oxidant and pro-apoptotic protein, was significantly elevated in mouse and human islets cultured under HFS mimicking conditions, which was mitigated by CUR treatment. Conclusions: CUR supplementation in obese subjects may alleviate the burden imposed by HFS diets. Our data indicate administration of dietary CUR reinstates PI3K, AKT and IDE levels in obese mice. Additionally, CUR treatment preserves islet integrity by downregulation of TXNIP transcription levels. Therefore, dietary CUR may have the potential to serve as a novel therapeutic agent to address the underlying links of obesity and T2DM. [ABSTRACT FROM AUTHOR]