Hepatic ischemia/reperfusion injury (IRI) is an unavoidable course in liver transplantation, during which the immune response of inflammation plays a leading part. MicroRNA-450b-5p (miR-450b-5p), which has been reported to participate in several inflammatory diseases, was investigated in this study. The purpose of this study is to identify the potential function of miR-450b-5p toward remission of hepatic IRI and elucidate the specific mechanism. Herein we found that expression of miR-450b-5p, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 was stimulated in hepatic IRI. Inhibition of miR-450b-5p could remarkably alleviate mouse hepatic IRI and improve liver function measured by hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA). We further assessed protein expression undergoing Western blot and immunofluorescence, and discovered that miR-450b-5p suppressed alpha B-crystallin (CRYAB), thus restraining the inhibitory κB kinase (IKK) β-mediated canonical nuclear factor-κB (NF-κB) signaling, instead of the noncanonical path guided by IKKα in hepatic IRI. In addition, we demonstrated CRYAB as an activator of M2 polarization through protein kinase B (Akt) 1/mammalian target of rapamycin (mTOR), thus resulting in relief of liver IRI. Combination treatment containing both paths revealed a better antidamage efficacy than adjusting either path alone, suggesting that the joint therapy might be a promising solution in hepatic IRI.

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NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP−/− (thioredoxin-interacting protein) and NLRP3−/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3−/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP−/− but not NLRP3−/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3.

Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a “Trojan horse” system is used for substantia nigra‐targeted delivery of a blood brain barrier‐penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4′‐dimethoxychalcone (DMC) (designated as RVG‐nDMC). Here, the neuroprotective effects of DMC are demonstrated in PD. Specifically, RVG‐nDMC penetrates the blood brain barrier with enhanced brain‐targeted delivery efficiency and is internalized by DA neurons and microglia. In vivo studies demonstrate that RVG‐nDMC ameliorates motor deficits and nigral DA neuron death in PD mice without causing overt adverse effects in the brain or other major organs. Moreover, RVG‐nDMC reverses tyrosine hydroxylase ubiquitination and degradation, alleviates oxidative stress in DA neurons, and exerts antiinflammatory effects in microglia. The “Trojan horse” strategy for targeted delivery of DMC thus provides a potentially powerful and clinically feasible approach for PD intervention.

Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in tumorigenesis. MiR-25 was previously reported to act as tumor suppressor or oncogene in diverse cancers. However, their expression, function, and mechanism in gastric cancer (GC) are not well known. Here, we show that miR-25 was overexpressed in primary tumor tissues of GC patients and was significantly correlated with a more aggressive phenotype of GC in patients. MiR-25 inhibition significantly decreased the proliferation, invasion, and migration of GC cells in vitro. Furthermore, miR-25 repressed F-box and WD-40 domain protein 7 (FBXW7) expression by directly binding to 3-untranslated region (UTR) of FBXW7, and the inverse correlation was observed between the expressions of miR-25 and FBXW7 mRNA in primary GC tissues. Moreover, the restoration of FBXW7 led to suppressed proliferation, invasion, and migration of GC cells. In vivo, miR-25 promotes tumor growth of GC. Taken together, miR-25 promotes GC progression by directly downregulating FBXW7 expression and may be employed as a novel prognostic marker and therapeutic target of GC.

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Inflammation and oxidative stress serve an important role in the development of lipopolysaccharide/D-galactosamine (LPS/GalN)‑induced acute liver injury. Nobiletin, which is found in high quantities in the peel of citrus fruits, is able to modulate immune responses, including inflammatory response and oxidative stress. The present study aimed to evaluate the protective effects of nobiletin on LPS/GalN‑induced acute liver injury. Male C57BL/6 mice were intraperitoneally treated with nobiletin (50, 100 and 200 mg/kg) 2 h prior to LPS/GalN injection. Liver injury was observed in the LPS/GalN group, as demonstrated by increased levels of serum hepatic enzymes and hepatic inflammatory mediators, as well as by histopathological alterations. Treatment with nobiletin reduced serum alanine aminotransferase and aspartate aminotransferase levels, improved hepatic structure, and suppressed hepatic interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α production 24 h after LPS/GalN exposure. Western blot analysis revealed that nobiletin treatment inhibited inducible nitric oxide synthase and cyclooxygenase‑2 liver expression. In addition, nobiletin suppressed LPS/GalN‑induced phosphorylation and degradation of inhibitor of nuclear factor (NF)‑κB (IκB)α, as well as NF‑κB p65 translocation into the nucleus. Nobiletin also upregulated the expression of nuclear NF‑E2‑related factor 2 (Nrf2) and cytoplasmic heme oxygenase‑1. In conclusion, these results indicate that nobiletin serves a protective role in LPS/GalN‑induced acute liver injury via activation of the Nrf2 antioxidant pathway and subsequent inhibition of NF‑κB‑mediated cytokine production. These findings support the potential for nobiletin as a therapeutic agent for the treatment of acute liver injury.