Tiliroside attenuates acute kidney injury by inhibiting ferroptosis through the disruption of NRF2-KEAP1 interaction.

BACKGROUND: Ferroptosis, an iron-dependent process that regulates cell death. Emerging evidences suggest that ferroptosis induces acute kidney injury (AKI) progression, and inhibiting ferroptosis provides an effect strategy for AKI treatment. The disruption of the NRF2-KEAP1 protein to protein interaction (PPI) induces NRF2 activation, which provides a promising strategy that can identify new ferroptosis inhibitors. A previous study revealed that tiliroside, a glycosidic flavonoid extracted from Edgeworthia chrysantha Lindl (buds), has anti-neuroinflammatory and neuroprotective effects via NRF2 activation. However, the mechanism through which tiliroside activates NRF2 is unknown, and it remains unclear whether it has protective effects against AKI. PURPOSE: To investigate whether tiliroside has protective effects against AKI in mice and the associated mechanisms. METHODS: Possible tiliroside substrates were analyzed using molecular docking. Cisplatin- and ischemia-reperfusion injury (IRI)-induced AKI mouse models and HK2 cells model were constructed to evaluate the protective effects of tiliroside. CRISPR/Cas9 mediated NRF2 knockout HK2 cells were used to verify whether NRF2 mediates tiliroside protective effects. RESULTS: In vivo, our results showed that tiliroside treatment preserved kidney functions in AKI mice models, as showed by lower levels of serum creatinine (SCr), blood urea nitrogen (BUN), and renal injury markers, including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1), compared with the mice in control groups. In vitro, tiliroside treatment greatly ameliorated cisplatin-induced ferroptosis through NRF2 activation in cultured HK2 cells, as evidenced by the protective effects of tiliroside being greatly blunted after the knockout of NRF2 in HK2 cells. Mechanistic studies indicated that tiliroside promoted NRF2/GPX4 pathway activation and ferroptosis inhibition, perhaps via the disruption of the NRF2-KEAP1 PPI. CONCLUSION: Together, our results demonstrate that tiliroside may serve as a NRF2-KEAP1 PPI inhibitor and prevents ferroptosis-induced AKI, indicating its potential for clinical AKI treatment.

Sulfide:quinone oxidoreductase alleviates ferroptosis in acute kidney injury via ameliorating mitochondrial dysfunction of renal tubular epithelial cells.

Ferroptosis is iron-dependent and regulates necrosis caused by lipid peroxidation and mitochondrial damage. Recent evidence has revealed an emerging role for ferroptosis in the pathophysiology of acute kidney injury (AKI). Sulfide:quinone oxidoreductase (SQOR) is a mitochondrial inner membrane protein highly expressed in the renal cortex. However, the effects of SQOR on ferroptosis and AKI have not been elucidated. In this study, we evaluated the effects of SQOR in several AKI models. We observed a rapid decrease in SQOR expression after cisplatin stimulation in both in vivo and in vitro models. SQOR-deletion mice exhibit exacerbated kidney impairment and ferroptosis in renal tubular epithelial cells following cisplatin injury. Additionally, our results showed that the overexpression of SQOR or ADT-OH (the slow-releasing H2S donor) preserved renal function in the three AKI mouse models. These effects were evidenced by lower levels of serum creatinine (SCr), blood urea nitrogen (BUN), renal neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1). Importantly, SQOR knockout significantly aggravates cisplatin-induced ferroptosis by promoting mitochondrial dysfunction in renal tubular epithelial cells (RTECs). Moreover, online database analysis combined with our study revealed that SYVN1, an upregulated E3 ubiquitin ligase, may mediate the ubiquitin-mediated degradation of SQOR in AKI. Consequently, our results suggest that SYVN1-mediated ubiquitination degradation of SQOR may induce mitochondrial dysfunction in RTECs, exacerbating ferroptosis and thereby promoting the occurrence and development of AKI. Hence, targeting the SYVN1-SQOR axis could be a potential therapeutic strategy for AKI treatment.

Long non-coding RNAs and tyrosine kinase-mediated drug resistance in pancreatic cancer.

Pancreatic cancer (PC) is one of the most malignant tumors with a dismal survival rate, this is primarily due to inevitable chemoresistance. Dysfunctional tyrosine kinases (TKs) and long non-coding RNAs (lncRNAs) affect the drug resistance and prognosis of PC. Here, we summarize the mechanisms by which TKs or lncRNAs mediate drug resistance and other malignant phenotypes. We also discuss that lncRNAs play oncogenic or tumor suppressor roles and different mechanisms including lncRNA-proteins/microRNAs to mediate drug resistance. Furthermore, we highlight that lncRNAs serve as upstream regulators of TKs mediating drug resistance. Finally, we display the clinical significance of TKs (AXL, EGFR, IGF1R, and MET), clinical trials, and lncRNAs (LINC00460, PVT1, HIF1A-AS1). In the future, TKs and lncRNAs may become diagnostic and prognostic biomarkers or drug targets to overcome the drug resistance of PC.

ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis.

Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H2S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H2S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H2S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

Simultaneous Delivery of antimiR-21 and Doxorubicin by Graphene Oxide for Reducing Toxicity in Cancer Therapy.

Graphene oxide (GO) has been studied by many researchers for its potential drug-delivery value. In order to reduce the side effects of anticancer drugs by decreasing the dosage and maintain the therapeutic effects, a dual drug-delivery system that used GO as a carrier and simultaneously loaded with antitumor drugs and antimir-21 was rationally designed for the cooperative treatment of tumors. Results obtained from our studies have found that MDA-MB-231 cells were inhibited in low Dox dose. The outcomes of confocal microscopy indicated that Dox and antimiR-21 could be released rapidly in cancer cells, which is good for killing cancer cells. In addition, qRT-PCR further demonstrated that miR-21 was silenced by antimiR-21. Consequently, GO has a great potential to codeliver chemotherapeutic drugs and gene drugs in cancer combination therapy for reducing toxicity.