Chronic stress causes duodenal damage, in which iron death is likely to play an important role. Chlorogenic acid (CGA), one of the most widely consumed dietary polyphenols, has been shown to protect the intestine. However, it is unclear whether CGA exerts a duodenoprotective effect in chronic stress by inhibiting ferroptosis. In this work, rats were daily exposed to restraint stress for 6 h over 21 consecutive days, with/without CGA (100 mg/kg, gavage). CGA reduced blood hepcidin, iron, reactive oxygen species (ROS), and ferroportin 1 (FPN1) levels and upregulated the levels of ferroptosis-related biomarkers (GPX4, GSH, NADPH, etc.). These results confirmed that CGA inhibited ferroptosis in the duodenum. Furthermore, the use of S3I-201 (STAT3 inhibitor) helped to further clarify the mechanism of action of CGA. Overall, CGA could reduce hepcidin production by inhibiting the IL-6/JAK2/STAT3 pathway in the liver to increase the expression of FPN1 in the duodenum, which restored iron homeostasis and inhibited ferroptosis, alleviating chronic stress-induced duodenal injury.
Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis.Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1β, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.
Chronic stress can cause chronic inflammatory injury
to the liver.
Chlorogenic acid (CGA) is known to have a wide range of biological
activities and anti-inflammatory effects. Resolvin D1 (RvD1) is a
polyunsaturated fatty acid derivative that has inhibitory effects
on a variety of inflammatory diseases. However, whether CGA can inhibit
liver inflammation in chronic stress through RvD1 remains unclear.
In this work, male rats were subjected to restraint stress for 6 h
every day and built a chronic stress model for 21 days. CGA (100 mg/kg)
was administered intragastrically 1 h before restraint, with intraperitoneal
injection of RvD1 inhibitor WRW4 (antagonist of FPR2, 0.1 mg/kg) or
WRW4 solution every 2 days for 30 min before CGA administration. CGA
reduced hepatic hemorrhage and inflammatory cell infiltration, alleviated
hepatic injury, decreased the activation of the NF-κB pathway
and the expression of interleukin 1β, interleukin 6, and tumor
necrosis factor α in the liver, and increased RvD1 in the serum
and liver. The therapeutic effect of CGA was blocked after WRW4 intervention.
These results suggest that the protective effects of CGA mediate the
NF-κB pathway by upregulating the generation of RvD1. Above
all, this research demonstrates the liver protective effect of CGA
and provides a potential treatment strategy for chronic inflammatory
disease.
The
liver is the major organ of metabolism and is extremely vulnerable
to chronic stress. Lycopene (LYC) is a natural carotenoid with potent
antioxidant and chronic disease potential. However, whether LYC protects
against chronic restraint stress (CRS)-induced liver injury and the
underlying mechanisms remain unclear. In this study, rats were restrained
for 21 days for 6 h per day, with or without gavage of LYC (10 mg/kg).
Serum ALT (85.99 ± 4.07 U/L) and AST (181.78 ± 7.35 U/L)
and scores of liver injury were significantly increased in the CRS
group. LYC significantly promoted the nuclear translocation of Nrf2,
elevated the expression of antioxidant genes, and attenuated reactive
oxygen radicals (ROS) levels within the liver. Cellular thermal shift
assay (CETSA) and molecular docking results indicated that LYC competitively
binds to Keap1 with the lowest molecule affinity of −9.0 kcal/mol.
Moreover, LYC significantly relieved the hepatic endoplasmic reticulum
swelling and decreased the expression of endoplasmic reticulum stress
(ERS) hallmarks like GRP78, CHOP, and cleaved caspase-12. Meanwhile,
LYC also mitigated CRS-induced hepatocyte apoptosis. Interestingly,
every other day, the intraperitoneal injection of the Nrf2 inhibitor
brusatol (0.4 mg/kg) significantly counteracted the protective effect
of LYC. In conclusion, LYC protects against CRS-induced liver injury
by activating the Nrf2 signaling pathway, scavenging ROS, and further
attenuating ERS-associated apoptosis pathways.
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