• Biomarkers
• Iron metabolism
• Liver injury
• Sepsis
• Serum iron
• Total iron-binding capacity

• Humans
• Male
• Female
• Sepsis/complications
• Sepsis/blood
• Prospective Studies
• Biomarkers/blood
• Middle Aged
• Iron/blood
• Iron/metabolism
• Transferrin/metabolism
• Transferrin/analysis
• Aged
• Risk Factors
• ROC Curve
• Ferritins/blood
• Iron Metabolism Disorders/blood
• Iron Metabolism Disorders/diagnosis
• Iron Metabolism Disorders/complications
• Liver Diseases/etiology
• Liver Diseases/blood
• Liver Diseases/diagnosis
• Liver/pathology
• Adult
• Predictive Value of Tests

• extracts
• mechanism
• pharmacological action
• sepsis
• traditional Chinese medicine

• Traditional Chinese Medicine
• active ingredients
• chemical structure
• monomers.
• natural drugs
• sepsis

• Sepsis/drug therapy
• Humans
• Medicine, Chinese Traditional
• Biological Products/chemistry
• Biological Products/pharmacology
• Biological Products/therapeutic use
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• Animals

• 2022T150393,2021M690099 China Postdoctoral Science Foundation
• ZR2020QH309,82004277 National Natural Science Foundation of China (NSFC)

• Arachidonate 15-lipoxygenase
• Ferroptosis
• GPX4
• Genipin
• Liver injury

• Autophagy
• CD36
• liver injury
• proteasomal degradation
• ubiquilin 1

• Animals
• Mice
• Adaptor Proteins, Signal Transducing/metabolism
• Autophagy/physiology
• Autophagy-Related Proteins/metabolism
• Chemical and Drug Induced Liver Injury, Chronic/metabolism
• Hepatocytes/metabolism
• Lipopolysaccharides/pharmacology
• Lysosomes/metabolism
• Sepsis/complications
• Sepsis/metabolism
• SNARE Proteins/metabolism
• Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/metabolism
• Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/pharmacology
• Ubiquitins/metabolism

• Borneol
• hepatoxicity
• metabolic disorder
• zebrafish

The liver plays crucial roles in sepsis and is one of the major targets for sepsis-related injuries. Ferroptosis, a newly emerged form of lytic cell death, has been implicated in sepsis related organ failure. Yes-associated protein1 (YAP1), a key regulator of the Hippo signaling pathway, may be involved in ferroptosis development. This study aimed to elucidate the role of YAP1 in septic liver injury through regulating ferroptosis, especially ferritinophagy-mediated ferroptosis.

Cecal ligation and puncture (CLP) models were constructed in control (Yap1^flfl) and liver-conditional knockout mice (Yap1^fl/fl Alb-Cre) to induce septic liver injury, while LO2 cells with or without YAP1 overexpression/deletion were stimulated by lipopolysaccharide (LPS) in vitro. Our study showed YAP1 knockdown aggravated CLP-induced liver injury and inflammation, as well as accelerated hepatocyte ferroptosis, revealed by down-regulated expression of GPX4, FTH1 and SLC7A11, along with up-regulated expression of SFXN1 and NCOA4. Consistently, YAP1 deficiency aggravated LO2 cells ferroptosis, but YAP1 overexpression alleviated LPS-induced LO2 ferritinophagy, as evidenced by reduced mitochondrial ROS and Fe²⁺, along with down-regulated expression of SFXN1 and NCOA4. Further co-IP assay verified that YAP1 disrupted the interaction between NCOA4 and FTH1, thus prevent the degradation of ferritin to Fe²⁺, further reduced the ROS production and suppressed ferroptosis.

YAP1 inhibits ferritinophagy-mediated ferroptosis in hepatocytes, and YAP1 deficiency aggravates sepsis-induced liver injury.

The online version contains supplementary material available at 10.1186/s13578-022-00902-7.

• Ferritinophagy
• Ferroptosis
• Liver injury
• Sepsis
• YAP1

• acute liver injury
• autophagy
• c-Jun N-terminal kinase
• endotoxemia
• octanoic acid

• Acute Lung Injury
• Animals
• Autophagy
• Caprylates
• Enteral Nutrition
• JNK Mitogen-Activated Protein Kinases/pharmacology
• JNK Mitogen-Activated Protein Kinases/therapeutic use
• Lipopolysaccharides
• Liver/pathology
• Rats
• Rats, Sprague-Dawley
• Sepsis/complications
• Sepsis/therapy

The inner ear can be insulted by various noxious stimuli, including drugs (cisplatin and aminoglycosides) and over-acoustic stimulation. These stimuli damage the hair cells giving rise to progressive hearing loss. Systemic drugs have attempted protection from ototoxicity. Most of these drugs poorly reach the inner ear with consequent ineffective action on hearing. The reason for these failures resides in the poor inner ear blood supply, the presence of the blood-labyrinthine barrier, and the low permeability of the round window membrane (RWM). This article presents a review of the use of nanoparticles (NPs) in otoprotection. NPs were recently used in many fields of medicine because of their ability to deliver drugs to the target organs or cells. The studies included in the review regarded the biocompatibility of the used NPs by in vitro and in vivo experiments. In most studies, NPs proved safe without a significant decrease in cell viability or signs of ototoxicity. Many nano-techniques were used to improve the drugs' kinetics and efficiency. These techniques included encapsulation, polymerization, surface functionalization, and enhanced drug release. In such a way, it improved drug transmission through the RWM with increased and prolonged intra-cochlear drug concentrations. In all studies, the fabricated drug-NPs effectively preserved the hair cells and the functioning hearing from exposure to different ototoxic stimuli, simulating the actual clinical circumstances. Most of these studies regarded cisplatin ototoxicity due to the wide use of this drug in clinical oncology. Dexamethasone (DEX) and antioxidants represent the most used drugs in most studies. These drugs effectively prevented apoptosis and reactive oxygen species (ROS) production caused by ototoxic stimuli. These various successful experiments confirmed the biocompatibility of different NPs and made it successfully to human clinical trials.

• AMPK
• Geniposide
• Myocardial ischemia reperfusion
• NLRP3 inflammasome
• Pyroptosis

• National Natural Science Foundation of China

• Akt
• Autophagy
• Sepsis-induced liver injury
• TSLP

• Cell death
• Immunity
• Inflammation
• STING1
• Sepsis

• Autophagy
• Humans
• Immunity, Innate
• Multiple Organ Failure
• Sepsis
• Shock, Septic

• Genipin
• HtrA2/Omi
• Ischemia–reperfusion injury
• Mitochondria
• UCP2-SIRT3-PGC1 axis

It is important to note that 2-Amino-3-methylimidazole[4,5-f]quinoline (IQ) is one of the most common heterocyclic amines (HCAs), which is a class of mutagenic/carcinogenic harmful compounds mainly found in high-protein thermal processed foods and contaminated environments. However, the pre-carcinogenic toxicity of IQ to the liver and its mechanism are poorly understood, further research is needed. In light of this, we exposed zebrafish to IQ (0, 8, 80, and 800 ng/mL) for 35 days, followed by comprehensive experimental studies. Histopathological and ultrastructural analysis showed that hepatocytes were damaged. TUNEL results showed that IQ induced apoptosis of liver cells, the expression of apoptosis factor gene was significantly increased, and the expression of Bcl-2 protein was significantly decreased. In addition, upregulated expression of the 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) and endoplasmic reticulum stress (ERS)-related factors transcription levels were elevated obviously, suggesting that IQ induced ERS. Decreased protein expression of autophagy-related 5 (Atg5)-Atg12, Beclin1, and LC3-II, increased protein expression of p62, and autophagy-related factors transcription levels were significantly decreased, suggesting that IQ inhibited autophagy. Overall, our research showed that the potential harm of IQ to the liver before the occurrence of liver cancer was related to ERS and its mediated autophagy and apoptosis pathways.

• Apoptosis
• Autophagy
• ERS
• HCAs
• Hepatotoxicity
• IQ

• Chinese herbal medicines
• Qingwen Baidu decoction
• Shengfu injection
• Shengmai
• Xuanbai Chengqi decoction
• XueBiJing injection
• antiseptic actions
• material basis
• sepsis

• COVID-19/virology
• Drug Combinations
• Drugs, Chinese Herbal/therapeutic use
• Humans
• Medicine, Chinese Traditional
• SARS-CoV-2/isolation & purification
• Sepsis/drug therapy
• COVID-19 Drug Treatment

• 82074176 the National Natural Science Foundation of China

• BATF
• GBP-5
• NLRP3 inflammasome
• acute liver injury
• inflammation

• autophagy
• mitochondria
• mitophagy
• organ dysfunction
• sepsis

• autophagy
• mitochondria
• mitophagy
• organ dysfunction
• sepsis

• autophagy
• mitochondria
• mitophagy
• organ dysfunction
• sepsis

• Anemoside B4
• Autophagy
• Liver injury
• Sepsis
• mTOR

• Genipin
• Liver disease
• Regulated cell death
• Toxicity
• Traditional Chinese medicine

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/toxicity
• Antioxidants/pharmacology
• Antioxidants/toxicity
• Cell Death/drug effects
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Cholagogues and Choleretics/pharmacology
• Cholagogues and Choleretics/toxicity
• Humans
• Iridoids/pharmacology
• Iridoids/toxicity
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Massive Hepatic Necrosis/drug therapy
• Massive Hepatic Necrosis/metabolism
• Massive Hepatic Necrosis/pathology
• Mitochondria, Liver/drug effects
• Mitochondria, Liver/metabolism
• Mitochondria, Liver/pathology
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Uncoupling Protein 2/metabolism

Sepsis‐associated encephalopathy (SAE) has typically been associated with a poor prognosis. Although sestrin 2 (SESN2) plays a crucial role in metabolic regulation and the stress response, its expression and functional roles in SAE are still unclear. In the present study, SAE was established in mice through caecal ligation and puncture (CLP). The adeno‐associated virus 2 (AAV2)‐mediated SESN2 expression (ie overexpression and knockdown) system was injected into the hippocampi of mice with SAE, and subsequently followed by electron microscopic analysis, the Morris water maze task and pathological examination. Our results demonstrated an increase of SESN2 in the hippocampal neurons of mice with SAE, 2‐16 hours following CLP. AAV2‐mediated ectopic expression of SESN2 attenuated brain damage and loss of learning and memory functions in mice with SAE, and these effects were associated with lower pro‐inflammatory cytokines in the hippocampus. Mechanistically, SESN2 promoted unc‐51‐like kinase 1 (ULK1)‐dependent autophagy in hippocampal neurons through the activation of the AMPK/mTOR signalling pathway. Finally, AMPK inhibition by SBI‐0206965 blocked SESN2‐mediated attenuation of SAE in mice. In conclusion, our findings demonstrated that SESN2 might be a novel pharmacological intervention strategy for SAE treatment through promotion of ULK1‐dependent autophagy in hippocampal neurons.

• SESN2
• autophagy
• sepsis-associated encephalopathy
• unc-51-like kinase 1

• Animals
• Circular Dichroism
• Fruit/chemistry
• Gardenia/chemistry
• Lipopolysaccharides/chemistry
• Magnetic Resonance Spectroscopy
• Monoterpenes/analysis
• Monoterpenes/chemistry
• Rats
• Terpenes/analysis
• Terpenes/chemistry
• Triterpenes/analysis
• Triterpenes/chemistry
• Triterpenes/isolation & purification

• Alpha 7 nicotinic acetylcholine receptor
• Autophagy
• Caecal ligation and puncture
• Cholinergic anti-inflammatory pathway

• autophagy
• cell stress
• medicinal herbs
• monoterpenes
• programmed cell death

Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl₄-) induced acute liver injury (ALI) and its underlying molecular machinery. Our results indicated that treatment with genipin significantly reduced CCl₄-induced hepatotoxicity by ameliorating histological liver changes, decreasing the aspartate aminotransferase and alanine transaminase levels, alleviating the secretion of inflammatory cytokines, and promoting autophagic flux. Moreover, genipin effectively induced the conversion of LC3 and inhibition of p62 accumulation. The liver expressions of ATG5, ATG7, and ATG12 were significantly increased by genipin pretreatment in the ALI mice model. This protective effect may be mediated by the inhibition of mTOR and the activation of p38 MAPK signaling pathways. Meanwhile, genipin attenuated CCl₄-induced inflammatory response by inhibiting the NF-κB and STAT3 signaling pathway. In addition, pretreatment with autophagy inhibitor 3-methyladenine (3-MA) or inhibition of p38 MAPK by SB203580 abolished the hepatoprotective effect of genipin. Taken together, our study implicates that genipin has a protective potential against CCl₄-induced hepatotoxicity, which might be strongly associated with the induction of autophagy and the attenuation of inflammatory response.

• Acute lung injury
• Apoptosis
• Endoplasmic reticulum stress
• Genipin
• Inflammation

Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.

• autophagy
• immunity
• ncRNAs
• oxidative stress
• sepsis

• Cisplatin
• Dexamethasone
• Genipin
• Guinea pig
• Hydrogel
• Ototoxicity

• Acute lung injury
• Apoptosis
• Autophagy
• Genipin
• Inflammation
• Mitochondria

• A549 Cells
• Acute Lung Injury/drug therapy
• Acute Lung Injury/immunology
• Acute Lung Injury/pathology
• Animals
• Autophagy/drug effects
• Bronchoalveolar Lavage Fluid/immunology
• Cell Survival/drug effects
• Cytokines/immunology
• Humans
• Iridoids/pharmacology
• Iridoids/therapeutic use
• Lipopolysaccharides
• Lung/drug effects
• Lung/pathology
• Male
• Protective Agents/pharmacology
• Protective Agents/therapeutic use
• Rats, Sprague-Dawley

• Alzheimer’s disease
• apoptosis
• autophagy
• ferroptosis
• iron
• neuron loss

• Cytokines
• Inflammation
• Natural products
• Terpenes

Sepsis is the leading cause of death in intensive care units worldwide. Autophagy has recently been shown to protect against sepsis-induced liver injury. Here, we investigated the roles of homeodomain-interacting protein kinase 2 (HIPK2) in the molecular mechanism of sepsis-induced liver injury. HIPK2 expression was reduced in sepsis-induced liver injury, and HIPK2 overexpression increased the survival rate and improved caecal ligation and puncture (CLP)-induced liver injury by reducing serum and liver aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) levels in mice with sepsis. HIPK2 overexpression significantly decreased CLP-induced release of inflammatory cytokines into the serum and attenuated oxidative stress-associated indicators in mice with CLP-induced liver injury, whereas HIPK2 knockdown produced the opposite results, suggesting that HIPK2 is a negative regulator of sepsis. Furthermore, HIPK2 overexpression inhibited lipopolysaccharide (LPS)-induced apoptosis of primary hepatocytes, increased the autophagic flux, and restored both autophagosome and autolysosome formation in the livers of CLP-induced mice by suppressing calpain signalling. Importantly, HIPK2 overexpression reduced the elevated cytosolic Ca²⁺ concentration in LPS-treated primary hepatocytes by interacting with calpain 1 and calmodulin. Finally, several anti-inflammatory drugs, including resveratrol, aspirin, vitamin E and ursolic acid, significantly increased the levels of the HIPK2 mRNA and protein by modulating promoter activity and the 3′-UTR stability of the HIPK2 gene. In conclusion, HIPK2 overexpression may improve sepsis-induced liver injury by restoring autophagy and thus might be a promising target for the clinical treatment of sepsis.

Genipin (GP) is commonly used to treat cardiovascular diseases; however, the protective action of GP against vascular hyperpermeability (VH) has not been reported. We previously reported that intrinsic apoptotic signaling (IAS) is involved in VH following hemorrhagic shock (HS). GP inhibits apoptosis, but the specific mechanism remains unclear. In the present study, we observed that GP protects against HS-induced VH in vitro and in vivo. We report that this protective effect is related to the inhibition of IAS by up-regulation of autophagy via sirtuin 3 (SIRT3). The endothelial cell hyperpermeability induced by HS was enhanced by GP; this was attenuated by 3-methyladenine (3MA), a specific inhibitor of autophagy, indicating the involvement of autophagy. Consistent with these results, we found that 3MA reversed the effects of GP on up-regulation of autophagy, and also diminished the protective effect of GP against IAS activation following HS. Furthermore, knockout of SIRT3 inhibited GP-induced autophagy, indicating the requirement of SIRT3 in the regulation of autophagy by GP. In rats, GP improved HS-induced VH, which was repressed by 3MA and 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), a SIRT3 inhibitor. In conclusion, these findings suggest that autophagy plays a protective effect in VH following HS; the protective effect of autophagy is reinforced by GP, which protects against IAS and VH by up-regulating SIRT3.

This study investigated the enhanced antiproliferative effect of Lactobacillus casei strain Shirota (LcS) on geniposide actions in human oral squamous carcinoma HSC-3 cells. An MTT assay, flow cytometry, qPCR assay, western blot and HPLC were used for this study. The concentration of 1.0 × 10⁶ CFU/mL of LcS had no effect on the HOK normal oral epithelial cells and HSC-3 cancer cells. The 25 and 50 µg/mL geniposide concentrations also had no impact on HOK normal oral epithelial cells, but they had remarkable inhibitory effects on the growth of HSC-3 cancer cells, which are enhanced in the presence of LcS. By the flow cytometry assay, the LcS-geniposide-H (1.0 × 10⁶ CFU/mL LcS and 50 µg/mL geniposide)-treated HSC-3 cancer cells had the largest number of cells undergoing apoptosis compared to cells treated with other combinationsand obviously more than cells treated with only geniposide-H (50 µg/mL geniposide). Geniposide-H could increase the mRNA and protein expressions of caspase-3, caspase-8, caspase-9, Bax, p53, p21, IκB-α, Fas, FasL, TIMP-1, and TIMP-2 as well as decrease those of Bcl-2, Bcl-xL, HIAP-1, HIAP-2, NF-κB, COX-2, iNOS, MMP-2, and MMP-9 compared to other groups of cells, and LcS further enhanced these changes, with results that are greater than for the cells treated with only a high concentration of geniposide. The results of this study show thatLcS enhanced the antiproliferative effect of geniposide in HSC-3 cancer cells.

• Lactobacillus casei strain Shirota
• antiproliferative effect
• geniposide
• human oral squamous carcinoma HSC-3 cells

Sepsis remains the leading cause of mortality in intensive care units and an intractable condition due to uncontrolled inflammation together with immune suppression. Dysfunction of immune cells is considered as a major cause for poor outcome of septic patients but with little specific treatments. Currently, autophagy that is recognized as an important self-protective mechanism for cellular survival exhibits great potential for maintaining immune homeostasis and alleviating multiple organ failure, which further improves survival of septic animals. The protective effect of autophagy on immune cells covers both innate and adaptive immune responses and refers to various cellular receptors and intracellular signaling. Multiple drugs and measures are reportedly beneficial for septic challenge by inducing autophagy process. Therefore, autophagy might be an effective target for reversing immunosuppression compromised by sepsis.

• apoptosis
• autophagy
• immunosuppression
• sepsis
• treatment

• autophagy
• immune response
• liver
• mitochondrial dysfunction
• mitophagy
• non-canonical autophagy
• secretion
• sepsis

• Lactobacillus rhamnosus GG strain
• expression
• geniposide
• human oral keratinocytes
• human oral squamous carcinoma HSC-3 cells

• Genipin
• Ischemia and reperfusion
• Mitochondrial quality control
• Oxidative stress