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Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury., (Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Spinal cord ischemia‒reperfusion injury (SCIRI) can lead to paraplegia, which leads to permanent motor function loss. It is a disastrous complication of surgery and causes tremendous socioeconomic burden. However, effective treatments for SCIRI are still lacking. PANoptosis consists of three kinds of programmed cell death, pyroptosis, apoptosis, and necroptosis, and may contribute to ischemia‒reperfusion-induced neuron death. Previous studies have demonstrated that hydrogen sulfide (H2S) exerts a neuroprotective effect in many neurodegenerative diseases. However, whether H2S is anti-PANoptosis and neuroprotective in the progression of acute SCIRI remains unclear. Thus, in this study we aimed to explore the role of H2S in SCIRI and its underlying mechanisms. Methods: Measurements of lower limb function, neuronal activity, microglia/macrophage function histopathological examinations, and biochemical levels were performed to examine the efficacy of H2S and to further demonstrate the mechanism and treatment of SCIRI. Results: The results showed that GYY4137 (a slow-releasing H2S donor) treatment attenuated the loss of Nissl bodies after SCIRI and improved the BBB score. Additionally, the number of TUNEL-positive and cleaved caspase-3-positive cells was decreased, and the upregulation of expression of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 expression were reversed after GYY4137 administration. Meanwhile, both the expression and activation of p-MLKL, p-RIP1, and p-RIP3, along with the number of PI-positive and RIP3-positive neurons, were decreased in GYY4137-treated rats. Furthermore, GYY4137 administration reduced the expression of NLRP3, cleaved caspase-1 and cleaved GSDMD, decreased the colocalization NeuN/NLRP3 and Iba1/interleukin-1β-expressing cells, and inhibited proinflammatory factors and microglia/macrophage polarization. Conclusions: H2S ameliorated spinal cord neuron loss, prevented motor dysfunction after SCIRI, and exerted a neuroprotective effect via the inhibition of PANoptosis and overactivated microglia-mediated neuroinflammation in SCIRI. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorders (PNDs) are some of the most common postoperative complications among the elderly and susceptible individuals, which significantly worsens the clinical outcome of patients. However, the prevention and treatment strategies of PNDs are difficult to determine and implement since the pathogenesis of PNDs is not well understood. The development of living organisms is associated with active and organized cell death, which is essential for maintaining the homeostasis of life. Ferroptosis is a programmed cell death (different from apoptosis and necrosis) mainly caused by an imbalance in the generation and degradation of intracellular lipid peroxides due to iron overload. Pyroptosis is an inflammatory cell death characterized by the creation of membrane holes mediated by the gasdermin (GSDM) family, followed by cell lysis and the release of pro-inflammatory cytokines. Ferroptosis and pyroptosis are involved in the pathogenesis of various central nervous system (CNS) diseases. Furthermore, ferroptosis and pyroptosis are closely associated with the occurrence and development of PNDs. This review summarizes the main regulatory mechanisms of ferroptosis and pyroptosis and the latest related to PNDs. Based on the available evidence, potential intervention strategies that can alleviate PNDs by inhibiting ferroptosis and pyroptosis have also been provided. [ABSTRACT FROM AUTHOR]

• Tumor-specific deep penetration is realized by p-LDM. • Ferroptosis sensitization can be achieved by CA IX inhibition. • Self-amplified ferroptosis is realized by two structural components of p-LDM. • "p-LDM + anti-CD47" achieves enhanced therapeutic efficiency. As an approved chemotherapeutic drug for breast cancer (BC) therapy, the continuous application of doxorubicin (DOX) is unfortunately limited by its poor selectivity and the apoptosis resistance of tumor cells. To cope with the obstacles, this work developed a tumor-specific nanoplatform (named p-LDM) for DOX delivery and combinational ferroptosis-apoptosis activation. p-LDM was fabricated by coating ferric metal–organic framework (MOF) with liposomes and the outer liposomal membrane was further interspersed with targeting peptide-conjugated enzyme-activatiable cell-penetrating peptides (CPPs) to guarantee the tumor-specific penetration. As two components of the MOF core, Fe3+ (metal ion junction) triggered the ferroptosis of 4T1 cells via its self-cyclic valence alteration and terephthalic acid (H 2 BDC, organic ligand) reinforced the Fe3+-triggered ferroptosis by inhibiting carbonic anhydrase IX (CA IX); this self-amplifying strategy delicately boosted robust tumor ferroptosis. By combining DOX and ferroptosis activation, p-LDM performed forceful direct killing effect, immungentic cell death (ICD) stimulation, T cell activation and dendritic cell (DC) maturation promotion, suggesting its potential for synergetic apoptosis/ferroptosis activation and tumor immune microenvironment (TIM) remodeling. Further, p-LDM was combined with CD47-SIRPα blockade therapy, generating reinforced ferroptosis, which was largely attributed to the maximal up-regulation of IFN-γ levels and consequent system Xc- inhibition. Besides, the released "find me" signal from ferroptosis, "eat me" signal from ICD and the inhibited CD47-released "don't eat me" signal jointly remodeled the suppressive TIM, receiving superior synergistic inhibitions on tumor growth, metastasis and recurrence. [ABSTRACT FROM AUTHOR]