Sepsis, defined as a dysregulated host response to infection, is one of the leading causes of mortality worldwide. It unleashes in the organism a cascade of molecules, cytokines, and proteins which leads to an inflammatory storm. If this response to infection is uncontrolled, any organ is susceptible to damage. Acute kidney injury (AKI) is one of the most frequent organ dysfunctions in septic patients, and while it can be reversible, its presence leads to a higher burden of morbidity and mortality. While serum creatinine is essential in evaluating kidney function, the pathophysiology of AKI is not completely elucidated, and a plethora of novel biomarkers have been studied in the hope of an early diagnosis and fast treatment. While the liver is not as affected by sepsis, it plays an important role as a guardian by providing acute-phase proteins, activating neutrophils, and controlling iron balance. Acute liver failure (ALF) could impair the organism's capacity to contain and eliminate pathogens. Some molecules have been associated with either AKI or ALF, although biomarkers specific for organ dysfunction are difficult to validate. The aim of this review is to understand the role of several molecules in the pathophysiology of sepsis and their clinical ability for diagnosing or predicting sepsis-induced hepato-renal dysfunction.

Antibacterial, antioxidant, and antilipidemic properties of Ocimum tenuiflorum are well known from previous studies. This study was designed to study the phytochemical constituents, antioxidant efficacy, in vivo nephroprotective activity, and immunomodulatory potential of Ocimum tenuiflorum hydroethanolic extract in gentamicin-induced acute kidney injury (AKI) rat model.

Ocimum tenuiflorum extract was given for 8 days to gentamicin-induced toxicity (100 mg/kg) in rats. Nephroprotective and immunomodulatory efficacy of O. tenuiflorum extract was evaluated based on urine and serum biochemistry, blood and tissue oxidative stress indices, cytokine levels, kidney injury biomarkers, and histopathology.

Gentamicin toxicity resulted in a reduction in catalase, glutathione reductase, superoxide dismutase, and interleukin-10 levels in blood and tissue homogenates, while an increase in serum creatinine, blood urea nitrogen, lipid peroxide, tumor necrosis factor-alpha, cystatin C, kidney injury molecule-1, and gamma-glutamyl transpeptidase levels. Treatment with O. tenuiflorum ameliorated oxidative stress, cytokine imbalance, and kidney injury; however, the results were almost similar to standard drug. Furthermore, histopathological analysis of kidney, liver, and heart tissues confirmed the organoprotective efficacy of O. tenuiflorum extract.

The present findings demonstrate the curative efficacy of O. tenuiflorum in gentamicin-induced AKI, probably mediated through phenolic and flavonoid phytoconstituents, antioxidant properties, and down-regulation of inflammatory cytokines. Therefore, future studies may be established to evaluate its efficacy and safety for clinical trials.

Acute kidney injury (AKI) occurs when there is an imbalance in the immune microenvironment, leading to ongoing and excessive inflammation. Numerous immunomodulatory therapies have been suggested for the treatment of AKI, the current immunomodulatory treatment delivery systems are suboptimal and lack efficiency. Given the lack of effective treatment, AKI can result in multi-organ dysfunction and even death, imposing a significant healthcare burden on both the family and society. This underscores the necessity for innovative treatment delivery systems, such as nanomaterials, to better control pathological inflammation, and ultimately enhance AKI treatment outcomes. Despite the modification of numerous immunomodulatory nanomaterials to target the AKI immune microenvironment with promising therapeutic results, the literature concerning their intersection is scarce. In this article, the pathophysiological processes of AKI are outlined, focusing on the immune microenvironment, discuss significant advances in the comprehension of AKI recovery, and describe the multifunctionality and suitability of nanomaterial-based immunomodulatory treatments in managing AKI. The main obstacles and potential opportunities in the swiftly advancing research field are also clarified.

Acute kidney injury (AKI) is one of the nonnegligible causes of mortality worldwide. It is important to understand the underlying molecular mechanism of AKI to effective therapeutic targets. miR-155 has been found to play a pivotal role in the development of AKI, while a comprehensive review on this topic is currently still lacking. Based on this review, we found that miR-155and is strongly correlated with the pathophysiological development of AKI by modulating cell apoptosis, inflammation, and proliferation. Mechanistically, miR-155 exerts a promoting function in multiple types of AKI by regulating multiple proteins or signaling pathways, such as SOCS-1, ERRFI1, SOCS-1, TRF1, CDK12, and TCF4/Wnt/β-catenin pathway. The inhibition of miR-155 has a renoprotective effect in drug- or substance-induced AKI. Therefore, drugs or biological compounds targeted by miR-155 and its pathways may recover the process of AKI by altering apoptosis, inflammation, and pyroptosis. A miRNA nanocarrier system that has already been developed could offer a novel approach to treat AKI, providing a direction for future research. Further large-scale studies are necessary to elucidate the clinical significance of miR-155 as a potential therapeutic target for multiple types of AKI.

Electrospun nanofibers have a number of qualities that make them a suitable choice for skin wound healing. Lysophosphatidic acid (LPA) stimulates the keratinocytes and fibroblasts to proliferate, differentiate, and migrate and enhances skin wound healing. Here, we developed the electrospun scaffolds contained in polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA). The scaffolds loaded with LPA nanoparticles retained a porous nanofiber structure and showed better physicochemical properties and biocompatibility. The scaffold continuously releases LPA to quickly initiate cell signaling and maintain long-term anti-inflammatory activity. In this study, we found that PP scaffold with LPA reduces the disordered collagen deposition and the thickness of the newborn epidermis, improves skin healing, and reduces scar formation. Explaining the mechanism of LPA mineralized tissue regeneration in skin wound healing, LPA inhibited the pyroptosis of keratinocyte, a cell death process that induces inflammation and scar formation by inhibiting the expression of TNF-α and β-catenin proteins. Thus, the electrospun PP scaffold with LPA can be potentially developed as a therapeutic avenue to target skin wound healing.

Acute liver failure (ALF) is a loss of liver function due to a severe hepatic insult. Studies utilizing the azoxymethane (AOM) mouse model of ALF, which also generates hepatic encephalopathy, have primarily focused on development of neurological deficits. However, the molecular processes that generate liver damage have not been fully characterized. Therefore, a more comprehensive characterization of the hepatic consequences of AOM toxicity is needed to better understand this disease model.

To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.

C57BL/6 mice were injected with AOM to produce ALF and hepatic encephalopathy. Tissue was collected at defined stages of neurological decline up to coma. Liver injury, CYP2E1 expression, oxidative stress, inflammation, apoptosis, necroptosis, and hepatocellular senescence were assessed.

Increased hepatic necrosis and exacerbated liver injury were observed after AOM injection as mice progressed towards coma. CYP2E1 expression decreased in AOM-treated mice as liver injury progressed. Malondialdehyde, myeloperoxidase and other measures of oxidative stress were significantly increased during AOM-induced ALF. Hepatic CCL2 and tumor necrosis factor α expression increased as AOM-induced liver injury progressed. Mixed lineage kinase domain-like protein phosphorylation was increased early during the progression of AOM-induced liver injury. Measures of apoptosis and cellular senescence all increased as the time course of AOM progressed.

These data support that necrosis, oxidative stress, inflammation, apoptosis, and senescence were elevated in AOM-treated mice, with inflammation being the earliest significant change.

Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival. Mesenchymal stem cells (MSCs) have the potential to enhance renal function by suppressing the expression of cell cycle inhibitors and reducing the expression of senescence markers and microRNAs via paracrine and endocrine mechanisms. MSC-derived exosomes can alleviate AKI symptoms by regulating DNA damage, apoptosis, and other related signaling pathways through the delivery of proteins, microRNAs, long-chain noncoding RNAs, and circular RNAs. This technique is both safe and effective. MSC-derived exosomes may have great application prospects in the treatment of AKI. Understanding the underlying mechanisms will foster the development of new and promising therapeutic strategies against AKI. This review focused on recent advancements in the role of MSCs in AKI repair as well as the mechanisms underlying the role of MSCs and their secreted exosomes. It is anticipated that novel and profound insights into the functionality of MSCs and their derived exosomes will emerge.

Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. Previous studies have found that Farnesyltransferase (FTase) inhibitors improve disease progression in mouse models of endotoxemia, sepsis, and autoimmune hepatitis. PANoptosis is a novel type of programmed cell death (PCD), including pyroptosis, apoptosis, and necrosis, that plays an important role in ALF. This study was designed and investigated whether the FTase inhibitor PD083176 (d2,d3,d5) could attenuate ALF progression by modulating PANoptosis.

Combining the technical tools of computational biology, structural biology and pharmacology, we designed and obtained three high-affinity human FTase inhibitors of PD083176(d2,d3,d5). Then, these FTase inhibitors were investigated by animal experiments by administering PD083176(d2,d3,d5) (10 mg/kg) before modeling with LPS (100 μg/kg)/D-GalN (300 mg/kg) or TAA (800 mg/kg).

We found that ALF induced by LPS/D-GaIN or TAA were associated with increased farnesylated protein in the liver. PD083176(d2,d3,d5) not only inhibited hepatic farnesylated proteins but also significantly attenuated liver injury and mortality in ALF mice. Importantly, PD083176(d2,d3,d5) treatment effectively inhibited hepatocyte apoptosis (Bax, Bcl-xL and TUNEL cell counts), pyroptosis (Caspase-1 and GSDMD), and necrotic apoptosis (RIPK1 and RIPK3).

Collectively, these findings demonstrate that PD081376(d2,d3,d5) could alleviate LPS/D-GaIN or TAA-induced ALF by regulating apoptosis, pyroptosis, and necrotizing apoptosis, which might provide a new therapeutic strategy and scalability challenge for ALF.

Yi-Shen-Hua-Shi granules (YSHSG) have been shown to improve kidney function in various renal disorders, which are characterized by the sudden decline and impairment of kidney function.

To investigate the precise mechanisms and targets of YSHSG in combating sepsis-induced AKI.

Through network pharmacology, the active ingredients, main target proteins, and related signaling pathways of YSHSG in the treatment of sepsis-induced AKI were predicted. The AKI model was induced by sepsis using the cecal ligation and puncture (CLP) technique. Prior to the operation, YSHSG was administered intragastrically once daily for 1 week. Blood and kidney tissues were collected 48 h post-CLP to verify the network pharmacology analysis.

The core target proteins of YSHSG in the treatment of sepsis-induced AKI include AKT1, JUN, IL6, PTGS2, NFKBIA, MAPK3, Caspase-3 and MMP9, which were further confirmed by molecular docking. Pathway analyses such as Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) show that YSHSG plays a role in protecting the kidneys from sepsis-induced AKI through the PI3K/AKT, TNF, and IL17 signaling pathways. These findings were validated using qPCR and western blotting. In vivo experiments demonstrated that YSHSG inhibits the activation of TNF and IL17 signaling pathways while protecting against deactivation of the PI3K/AKT signaling pathway in sepsis-induced AKI. YSHSG also exhibits an effect on attenuating inflammation response and pyroptosis processes associated with the PI3K/AKT, TNF, and IL17 signaling pathways.

YSHSG mitigated sepsis-induced AKI by influencing the PI3K/AKT, TNF, and IL17 signaling pathways associated with inflammation and pyroptosis.

Baicalin is a flavonoid of Scutellaria baicalensis Georgi. It possesses antipyretic, analgesic, and anti-inflammatory effects. It has great potential to treat gout. A network pharmacology approach, molecular docking and experimental validation were applied to investigate the pharmacological mechanisms of baicalin in treating gout.

The potential targets of baicalin were retrieved from the TCMSP, PharmMapper, STITCH, and Swiss Target Prediction databases. The gout-related targets were retrieved from the DrugBank, TTD, and Genecards databases. Then, the potential targets and signaling pathways were acquired via protein-protein interaction (PPI), as well as the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, the key targets were selected to dock with baicalin based on molecular docking. Finally, in vitro experiments were conducted to further validate the predictions.

A total of 318 potential targets of baicalin and 752 gout-related targets were screened. TNF, VEGFA, MMP9, PTGS2, and TLR4 might be the hub therapeutic target genes. The TLR4/NF-κB signaling pathway might be the foremost pathway in baicalin against gout. Moreover, molecular docking showed that baicalin combined well with TNF, VEGFA, MMP9, COX-2, and TLR4, respectively. The results of cell experiments suggested that baicalin could reduce the levels of inflammatory cytokines by inhibiting the TLR4/NF-κB signaling pathway in MSU-stimulated THP-1 cells and regulate the expression of these hub targets.

These results revealed that baicalin possesses "multitarget, multipathway, multilevel" regulatory effects. From a therapeutic standpoint, baicalin may be a promising anti-inflammatory agent for alleviating gout.

T-2 toxin, a potent environmental pollutant, has been proved to stimulate neuroinflammation, while the connection between T-2 toxin and pyroptosis remain elusive. Dimethyl fumarate (DMF), recently identified as a neuroprotectant and pyroptosis inhibitor, has potential therapeutic applications that are underexplored. Based on present study in vitro and vivo, we demonstrated that T-2 toxin induced the activation of NLRP3-Caspase-1 inflammasome in hippocampal neurons. In addition to proinflammatory mediator overexpression, gasdermin D (GSDMD)-dependently pyroptosis in the mouse hippocampal neuron cell line (HT22) treated by T-2 toxin was determined in our study. Moreover, the palliative effect of knockdown sequence of high mobility group B1 protein (HMGB1) provided more details for T-2 toxin-initiated pyroptosis. Importantly, we confirmed that DMF, as a novel inhibitor of GSDMD, could alleviate pyroptosis induced by T-2 toxin in an GSDMD targeting manner. In summary, our studies exposed the evidence that T-2 toxin could induce NLRP3 inflammasome activation and hippocampal neuronal pyroptosis. More notably, DMF was turn out to be a critical executioner for attenuating GSDMD-mediated pyroptosis. Our data found a new function of DMF and suggested a novel therapy strategy against mycotoxin-triggered neuronal inflammation, which leads to varieties of neurological diseases.

Cell death is a normal physiological process within cells that involves multiple pathways, such as normal DNA damage, cell cycle arrest, and programmed cell death (PCD). Cell death has been a hot spot of research in tumor-related fields, especially programmed cell death, which is a key form of cell death and is classified into different types according to the mechanism of occurrence, such as apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and disulfidptosis. Given the important role of PCD in maintaining tissue homeostasis and inhibiting tumorigenesis and development, more and more basic and clinical studies are devoted to revealing its potential application in anti-tumor strategies. The purpose of this review is to systematically review the regulatory mechanisms of PCD and to summarize the latest research progress of anti-tumor treatment strategies based on PCD.

Cigarette smoking is a well-established risk factor for renal dysfunction. Smoking associated with renal damage bears distinct physiological correlations in conditions such as diabetic nephropathy and obesity-induced glomerulopathy. However, the cellular and molecular basis of such an association remains poorly understood. High mobility group box 1(HMGB1) is a highly conserved non-histone chromatin associated protein that largely contributes to the pathogenesis of chronic inflammatory and autoimmune diseases such as sepsis, atherosclerosis, and chronic kidney diseases. Hence, the present study tested whether HMGB1 contributes to nicotine-induced podocyte injury.

Biochemical analysis showed that nicotine treatment significantly increased the HMGB1 expression and release compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin (Gly), a HMGB1 binder, abolished the nicotine-induced HMGB1 expression and release in podocytes. Furthermore, immunofluorescent analysis showed that nicotine treatment significantly decreased the expression of podocyte functional proteins- podocin and nephrin as compared to control cells. However, prior treatment with Gly attenuated the nicotine-induced nephrin and podocin reduction. In addition, nicotine treatment significantly increased desmin expression and cell permeability compared to vehicle treated podocytes. However, prior treatment with Gly attenuated the nicotine-induced desmin expression and cell permeability. Mechanistic elucidation revealed that nicotine treatment augmented the expression of toll like receptor 4 (TLR4) and pre-treatment with Gly abolished nicotine induced TLR4 upregulation. Pharmacological inhibition of TLR4 with Resatorvid, a TLR4 specific inhibitor, also attenuated nicotine induced podocyte damage.

HMGB1 is one of the important mediators of nicotine-induced podocyte injury through TLR4 activation.

Sepsis-associated acute kidney injury (SA-AKI) is a common and serious complication with high morbidity and mortality. The pathophysiology of SA-AKI is complex. The underlying mechanisms of SA-AKI remain unclear, and effective therapeutic strategies are limited. Butyrate is a type of short-chain fatty acid (SCFA) derived from the gut microbiota that plays a key role in kidney disease. However, the effect of butyrate on SA-AKI and its underlying mechanisms remain unclear. In this study, LPS was used to establish an SA-AKI model in C57BL/6 mice. Our results indicated that butyrate levels were substantially reduced in SA-AKI model mice. Notably, butyrate intervention attenuated kidney injury and inflammation in SA-AKI model mice. Moreover, the levels of NLRP3, STING, and GSDMD (a marker of pyroptosis) were significantly decreased by butyrate intervention. An in vitro model induced by LPS was established using HK-2 cells. Butyrate mitigated pyroptosis and reduced NLRP3, STING, and GSDMD protein expression. Furthermore, STING overexpression abrogated the downregulation of several proteins (NLRP3 and caspase 1) invovled in NLRP3 inflammsome-mediated pyroptosis and weakened the protective effect of butyrate. Hence, butyrate may attenuate SA-AKI by inhibiting pyroptosis via the STING-GSDMD axis, which provides a potential therapeutic strategy for preventing SA-AKI progression.

High-mobility group box-1 (HMGB1) is an architectural chromosomal protein with various roles depending on its cellular localization. Extracellular HMGB1 functions as a prototypical damage-associated molecular pattern that triggers inflammation and adaptive immune responses, mediated by specific cell surface receptors, including receptors for advanced glycation end products and toll-like receptors. Post-translational modifications of HMGB1 significantly impact various cellular processes that contribute to the pathogenesis of liver diseases. Recent studies have highlighted the close relationship between HMGB1 and the pathogenesis of acute liver injuries, including acetaminophen-induced liver injury, hepatic ischemia-reperfusion injury, and acute liver failure. In chronic liver diseases, HMGB1 plays a role in nonalcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, and hepatocellular carcinoma. Targeting HMGB1 as a therapeutic approach, either by inhibiting its release or blocking its extracellular function, is a promising strategy for treating liver diseases. This review aimed to summarize the available evidence on HMGB1's role in liver disease, focusing on its multifaceted signaling pathways, impact on disease progression, and the translation of these findings into clinical interventions.

Sono-photodynamic therapy (SPDT), the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT), is a promising tumor treatment method. However, the hypoxic tumor microenvironment greatly compromises the efficacy of SPDT. Pyroptosis, a new type of programmed cell death, is mainly induced by some chemotherapeutic drugs in the current research, and rarely by SPDT. RNA sequencing (RNA-seq) is a high-throughput sequencing technique that comprehensively profiles the transcriptome, revealing the full spectrum of RNA molecules in a cell. Here, we constructed IR780@O2 nanobubbles (NBs) with photoacoustic dual response and hypoxia improvement properties to fight triple negative breast cancer (TNBC), and demonstrated that SPDT could kill TNBC cells through pyroptosis pathway. RNA-seq further revealed potential mechanisms and related differentially expressed genes.

Thin-film hydration and mechanical vibration method were utilized to synthesize IR780@O2 NBs. Subsequently, we characterized IR780@O2 NBs and examined the cytotoxicity as well as ROS production ability. A series of experiments were conducted to verify that SPDT killed TNBC cells through pyroptosis.

IR780@O2 NBs were successfully prepared and had certain stability. Compared with SDT alone, SPDT increased therapeutic effect by 1.67 times by generating more ROS, and the introduction of NBs and O2 NBs (2.23 times and 2.93 times compared with SDT alone) could further promote this process. Other experiments proved that TNBC cells died by pyroptosis pathway. Moreover, the in-depth mechanism revealed that colony stimulating factor (CSF) and C-X-C motif chemokine ligand (CXCL) could be potential targets for the occurrence of pyroptosis in TNBC cells.

The IR780@O2 NBs prepared in this study increased the degree of TNBC cell pyroptosis through SPDT effect and alleviation of hypoxia, and cellular senescence might be a biological process closely related to pyroptosis in TNBC.

Renal ischemia-reperfusion injury (IRI) is an important cause of acute kidney injury (AKI). However, the pathophysiological changes and mechanisms during IRI-AKI progression remain unclear. This study aims toinvestigate the potential mechanisms in the progression of IRI-AKI by integrating metabolomics and transcriptomics data, providing a reference for the subsequent identification of biomarkers and therapeutic targets. IRI-AKI rat models with 30 min of ischemia and 24-72 h of reperfusion surgery simulating the progression of AKI were established. Compared to the control group underwent sham surgery (NC group), most of the differentially expressed metabolites (DEMs) in IRI-AKI 24 h and IRI-AKI 72 h decreased, mainly including amino acids, organic acids, and carnitines. Additionally, we found that DEMs were mainly enriched in amino acid-related pathways, among which valine, leucine, and isoleucine biosynthesis were dramatically altered in all comparisons. Transcriptomics revealed that differentially expressed genes (DEGs) were primarily involved in amino acid, lipid, and fatty acid metabolism. By integrating metabolomics and transcriptomics, we found valine, leucine, and isoleucine biosynthesis play key roles in IRI-AKI development. Our findings concluded that valine, leucine, and isoleucine pathways are hubs that potentially connect transcriptomes to metabolomes, providing new insights regarding the pathogenesis of IRI-AKI and its potential biomarkers and therapeutic strategies.

Childhood asthma, a common chronic childhood disease, leads to high mortality and morbidity in the world. Airway smooth muscle cells (ASMCs) is a group of multifunctional cells that has been found to be correlated with the pathogenesis of asthma. Astragaloside IV (AS-IV) is a compound extracted from Astragalus membranaceus, which has the anti-asthmatic effect. However, the role of molecular mechanisms regulated by AS-IV in the biological processes of ASMCs in asthma remains unclear. Our current study aims to investigate the downstream molecular mechanism of AS-IV in modulating the aberrant proliferation and pyroptosis of ASMCs in asthma. At first, we determined that the viability of ASMCs could be efficiently suppressed by AS-IV treatment (200 μM). Moreover, AS-IV promoted the pyroptosis and suppressed PDGF-BB-induced aberrant proliferation. Through mechanism investigation, we confirmed that AS-IV could suppress high mobility group box 1 (HMGB1) expression and prevent it from entering the cytoplasm. Subsequently, AS-IV blocked the interaction between HMGB1 and advanced glycosylation end product-specific receptor (RAGE) to inactivate NF-κB pathway. Finally, in vivo experiments demonstrated that AS-IV treatment can alleviate the lung inflammation in asthma mice. Collectively, AS-IV alleviates asthma and suppresses the pyroptosis of AMSCs through blocking HMGB1/RAGE axis to inactivate NF-κB pathway.

Remote limb ischemic pre-conditioning (RIPreC) can invoke potent renal protection. The involvement of oxidative stress and inflammatory pathways in renal ischemia/reperfusion injury (I/RI) was also confirmed. This study was designed to investigate the RIPreC effects on IRI-induced kidney dysfunction in rats through NFĸB/TNF-α/TGF-ꞵ/apelin signaling pathway.

Renal I/RI was induced by occluding the kidney arteries for 45 min, then reperfusion for 24 h. Four similar cycles of left femoral artery ischemia (2 min)/reperfusion (3 min) before the onset of kidney ischemia were performed to create RIPreC. Animals were randomly divided into three groups: sham, I/R, and RIPreC + I/R. Following the reperfusion phase, urine and blood samples were taken, and the kidney was removed for functional, molecular, and histological examination.

When compared to sham rats, renal IRI resulted in decreased creatinine clearance and increased sodium fractional excretion, lower antioxidant enzyme activities, higher malondialdehyde content and higher nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), transforming growth factor-betta (TGF-β), and Apelin expression levels, and histologically damaged kidney tissue. All of the alterations, as mentioned earlier, were alleviated using the RIPreC treatment.

Thus, RIPreC can protect against renal dysfunction after renal I/RI via modulation of the TNF-α/NF-κB/TGF-ꞵ/Apelin signaling pathway and strengthening the antioxidant defense system.

Hemorrhagic shock (HS) is a life-threatening condition with high mortality rates despite current treatments. This study investigated whether targeted temperature management (TTM) could improve outcomes by modulating inflammation and protecting organs following HS. Using a rat model of HS, TTM was applied at 33°C and 36°C after fluid resuscitation. Surprisingly, TTM at 33°C increased mortality, while TTM at 36°C significantly improved survival rates. It also reduced histological damage in lung and kidney tissues, lowered serum lactate levels, and protected against apoptosis and excessive reactive oxygen species production. TTM at 36°C inhibited the release of high mobility group box 1 protein (HMGB1), a key mediator of inflammation, and decreased proinflammatory cytokine levels in the kidneys and lungs. Moreover, it influenced macrophage behavior, suppressing the harmful M1 phenotype while promoting the beneficial M2 polarization. Cytokine array analysis confirmed reduced levels of proinflammatory cytokines with TTM at 36°C. These results collectively highlight the potential of TTM at 36°C as a therapeutic approach to improve outcomes in HS. By addressing multiple aspects of injury and inflammation, including modulation of macrophage responses and cytokine profiles, TTM at 36°C offers promising implications for critical care management after HS, potentially reducing mortality and improving patient recovery.

Methyltransferase-like 3 (METTL3) plays a role in the development of knee osteoarthritis (KOA). However, the mechanism underlying the role of METTL3 in KOA is unclear. This work investigated the effects of MELLT3 on ferroptosis and pain relief in in vitro and in vivo KOA models. Chondrocytes were treated with 10 ng/mL interleukin-1β (IL-1β) or 5 μM Erastin (ferroptosis inducer). IL-1β or Erastin treatment inhibited cell viability and glutathione levels; increased Fe2+, lipid reactive oxygen species and malondialdehyde production; and decreased glutathione peroxidase 4, ferritin light chain and solute carrier family 7 member 11 levels. The overexpression of METTL3 facilitated the N6-methyladenosine methylation of high mobility group box 1 (HMGB1). HMGB1 overexpression reversed the effect of sh-METTL3 on IL-1β-treated chondrocytes. A KOA rat model was established by the injection of monosodium iodoacetate into the joints and successful model establishment was confirmed by haematoxylin and eosin staining and Safranin O/Fast Green staining. METTL3 depletion alleviated cartilage damage, the inflammatory response, ferroptosis and knee pain in KOA model rats, and these effects were reversed by the addition of HMGB1. In conclusion, METTL3 depletion inhibited ferroptosis and the inflammatory response, and ameliorated cartilage damage and knee pain during KOA progression by regulating HMGB1.

Sepsis-associated acute kidney injury (AKI) has high morbidity and mortality, but without cause-specific treatment. Erythropoietin derived Helix B surface peptide (HBSP) alleviates AKI, whereas its underlying mechanisms remain to be further explored. Here, the effects of HBSP on pyroptosis, apoptosis, macrophage polarization and repair were investigated in lipopolysaccharide (LPS)-induced AKI mouse model and cultured kidney epithelial cells. Systemic inflammation, compromised renal function and histology were demonstrated in LPS-treated mice, with upregulated pyroptotic and apoptotic key proteins in the kidneys including GSDMD-N, cleaved IL-1β, IL-18 and caspase-3. These proteins were localized in tubular areas and colocalized with aquaporin-1 (AQP1), with increased F4/80+ M1 macrophages. However, HBSP mitigated pyroptosis, apoptosis and inflammation, and promoted macrophage M2 polarization. In addition, HMGB1 and erythropoietin receptor (EPOR) were increased by LPS and decreased by HBSP, both of which were positively correlated with pyroptotic and apoptotic proteins. Moreover, HBSP reduced TNF-α and IL-6 mRNA levels, as well as pyroptosis and apoptosis in LPS-stimulated TCMK-1 cells. In conclusion, HBSP inhibited tubular pyroptosis and apoptosis, EPOR expression, promoted macrophage M2 polarization, and protected against LPS-induced AKI. These findings provide new mechanistic insights into the renoprotection of HBSP, and facilitate its potential for clinical applications and therapeutic strategies in sepsis-associated AKI.

Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.

The disease burden of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Emerging evidence has revealed that silica nanoparticles (SiNPs) could disorder the liver lipid metabolism and cause hepatotoxicity, but the underlying mechanism remains unknown. The purpose of this study is to elucidate the molecular mechanism of hepatic lipid metabolism disorder caused by SiNPs, and to reveal the role of ferroptosis in SiNPs-induced hepatotoxicity. To explore the phenotypic changes in liver, the wild-type C57BL/6J mice were exposed to different doses of SiNPs (5, 10, 20 mg/kg·bw) with or without melatonin (20 mg/kg·bw). SiNPs accelerated hepatic oxidative stress and promoted pathological injury and lipid accumulation, resulting in NAFLD development. Melatonin significantly inhibited the oxidative damage caused by SiNPs. Then, the hepatocytes were treated with SiNPs, the ferroptosis inducer and inhibitor, respectively. In vitro, SiNPs (25 μg/mL) generated mitochondrial and intracellular Fe2+ accumulation and lipid peroxidation repair ability impairment, decreased the activity of GPX4 through ACSL4/p38 MAPK signaling pathway, resulting in ferroptosis of hepatocytes. Notably, Erastin (the ferroptosis activator, 5 μM) increased the sensitivity of hepatocytes to ferroptosis. Ferrostatin-1 (Fer-1, the ferroptosis inhibitor, 5 μM) restored GPX4 activity and protected against deterioration of lipid hydroperoxides (LOOHs) to salvage SiNPs-induced cytotoxicity. Finally, the liver tissue conditional ACSL4 knockout (cKO) mice and ACSL4-KO hepatocytes were adopted to further identify the role of the ACSL4-mediated ferroptosis on SiNPs-induced NAFLD development. The results displayed ACSL4 knockout could down-regulate the lipid peroxidation and ferroptosis, ultimately rescuing the progression of NAFLD. In summary, our data indicated that ACSL4/p38 MAPK/GPX4-mediated ferroptosis was a novel and critical mechanism of SiNPs-induced NAFLD.

Objective: We investigated the effect of high mobility group box 1 (HMGB1) on intracranial aneurysms (IAs) by analyzing single-nucleotide polymorphisms (SNPs) based on genome-wide association study (GWAS) data. HMGB1 mRNA and protein expression levels in plasma were also analyzed. Methods: This study was a comprehensive analysis of a GWAS dataset, including 250 patients with IAs and 294 controls. The HMGB1 gene region was targeted within SNP rs3742305 ± 10 kbp. Multivariate logistic regression analysis determined its association with IAs after adjusting for relevant clinical factors. HMGB1 mRNA expression was analyzed in the plasma of 24 patients selected from the GWAS dataset. The HMGB1 protein was analyzed by Western blotting. Results: A total of seven polymorphisms, including rs1360485, rs185382445, rs2039338, rs1045411, rs3742305, rs2249825, and rs189034241, were observed. Two SNPs, including rs1045411 (UTR-3) and rs3742305 (intron), showed strong linkage disequilibrium (r2 = 0.99). However, none of the seven SNPs associated with IAs had an adjusted p-value of < 0.0016 on multiple comparison analysis. HMGB1 mRNA levels (2-ΔCt) did not differ significantly between patients with IAs and the control subjects [1.07 (1.00-1.15) in patients with IAs vs. 1.05 (0.94-1.12) in controls; p = 0.67)]. Also, no significant difference in the degree of plasma HMGB1 protein expression was seen between the two groups (p = 0.82). Conclusions: The number of SNPs associated with HMGB1 and the degree of HMGB1 mRNA and protein expression were not significantly different between patients diagnosed with IAs and the controls.

In this editorial, we comment on the article by Zhou et al. The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1 (SIRT1) activation in acute liver failure (ALF). ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage, often posing a high risk of mortality. The predominant form of hepatic cell death in ALF involves apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Glutathione peroxidase 4 (GPX4) inhibition sensitizes the cell to ferroptosis and triggers cell death, while Gasdermin D (GSDMD) is a mediator of pyroptosis. The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway, bridging the gap between the two processes. The inhibition of p53 elevates the levels of GPX4, reducing the levels of inflammatory and liver injury markers, ferroptotic events, and GSDMD-N protein levels. Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction. SIRT1 is a NAD-dependent deacetylase, and its activation attenuates liver injury and inflammation, accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF. SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation, attenuating LPS/D-GalN-induced ALF.

Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some breakthroughs in recent decades, PH remains incurable. Therefore, innovative clinical treatment methods and drugs for PH are still urgently needed. DYZY01 is a new drug whose main ingredient is high-purity cannabidiol, a non-psychoactive constituent of cannabinoids that was demonstrated to have anti-inflammatory and anti-pyroptosis properties. Several recent studies have found cannabidiol could improve experimental PH, whereas the mechanistic effect of it warrants further investigation. Thus, this study aimed to investigate whether DYZY01 can treat PH by inhibiting inflammation and pyroptosis and to reveal its underlying mechanism. We established hypoxia and monocrotaline (MCT)-induced PH rat models in vivo and treated them with either DYZY01 (10,50 mg/kg/d) or Riociguat (10 mg/kg/d) by oral administration. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and extent of vascular remodeling were measured. Meanwhile, the effect of DYZY01 on human pulmonary arterial endothelial cells (HPAECs) was assessed in vitro. The results indicated that DYZY01 significantly reduced mPAP and RVHI in PH rats and reversed the extent of pulmonary vascular remodeling. This improvement may have been achieved by reducing endothelial cell pyroptosis via inhibiting the NF-κB/NLRP3/Caspase-1 pathway. Furthermore, DYZY01 could improve endothelial vascular function, possibly by regulating the secretion of vasodilator factors and inhibiting the proliferation and migration of pulmonary endothelial cells.

Sepsis is a disease that is typically treated in intensive care units with high mortality and morbidity. Pyroptosis is a newly identified type of programmed cell death and is characterized by inflammatory cytokine secretion. However, the role of pyroptosis in sepsis remains unclear.

GSE28750 and GSE134347 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed pyroptosis genes (DEPGs) were identified between sepsis and healthy controls. Machine learning was used to further narrow the gene range. Receiver operating curves (ROC) were generated to estimate the diagnostic efficacy. Immune infiltration levels were estimated via single-sample gene set enrichment analysis (ssGSEA). A network database was used to predict the upstream transcription factors and miRNAs of DEPGs. Finally, the expression of the genes was validated by qRT-PCR between sepsis patients and healthy controls.

We found that the pyroptosis pathway was enriched and activated in sepsis. 8 DEPGs were identified. A heatmap showed that the genes, NLRC4, NAIP, IL-18, AIM2 and ELANE, were abundant in the sepsis samples, and the genes, NLRP1, CHMP7 and TP53, were abundant in the healthy control samples. The ssGSEA results showed that the abundances of activated dendritic cells, MDSC, macrophage, plasmacytoid dendritic cells, regulatory T-cells, and Th17-cells were significantly higher, while the activated B-cell, activated CD8 T-cell, CD56 dim tural killer cell, immature B-cell, monocyte, and T follicular helper cell abundances were lower in sepsis samples compared to healthy controls. The qRT-PCR results showed that the expression levels of NAIP, IL-18, TP53, CHMP7, NLRC4, ELANE and NLRP1 were consistant with the bioinformatic analyses, while the expression level of AIM2 has no significant difference.

Our study identified seven potential pyroptosis-related genes, NAIP, IL-18, TP53, CHMP7, NLRC4, ELANE and NLRP1. This study revealed that pyroptosis may promote sepsis development by activating the immune response.

The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD.

Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes.

Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4-knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content.

FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD.

This study explores the mechanism by which obstructive jaundice (OJ) induces liver damage through pyroptosis. We induced OJ in rats via bile duct ligation and assessed liver damage using serum biochemical markers and histological analysis of liver tissue. Pyroptosis was investigated through immunofluorescence, ELISA, Western blot, and quantitative RT-PCR techniques. Additionally, we examined intestinal function and fecal microbiota alterations in the rats using 16S rDNA sequencing. In vitro experiments involved co-culturing Kupffer cells and hepatocytes, which were then exposed to bile and lipopolysaccharide (LPS). Our findings indicated that OJ modified the gut microbiota, increasing LPS levels, which, in conjunction with bile, initiated a cycle of inflammation, fibrosis, and cell death in the liver. Mechanistically, OJ elevated necrotic markers such as ATP, which in turn activated pyroptotic pathways. Increased levels of pyroptosis-related molecules, including NLRP3, caspase-1, gasdermin D, and IL-18, were confirmed. In our co-cultured cell model, bile exposure resulted in cell death and ATP release, leading to the activation of the NLRP3 inflammasome and its downstream effectors, caspase-1 and IL-18. The combination of bile and LPS significantly intensified pyroptotic responses. This study is the first to demonstrate that LPS and bile synergistically exacerbate liver injury by promoting necrosis and pyroptosis, unveiling a novel mechanism of OJ-associated hepatic damage and suggesting avenues for potential preventive or therapeutic interventions.

We proposed a link between the first systemic inflammatory response index (SIRI) and acute kidney injury (AKI), as well as the prognosis of pediatric patients in intensive care units (PICU).

This study comprised 5114 children from the pediatric-specific intensive care (PIC) database. SIRI was estimated as a neutrophil monocyte lymphocyte ratio. All patients were arbitrarily allocated to the training set (n = 3593) and the validation cohort (n = 1521) and divided into two groups depending on their SIRI levels. The diagnostic value of SIRI for pediatric ICU patients was subsequently determined using LASSO regression models.

After controlling for additional confounding variables in the training set, the higher SIRI value (≥ 0.59) had a greater risk of AKI (adjusted odds ratio, OR, 3.95, 95% confidence interval, 95%CI, 2.91-5.36, P<0.001) and in-hospital mortality (hazard ratio, HR, 5.01, 95%CI 2.09-12.03, P<0.001). Similar findings were discovered in the validation set. Furthermore, the suggested nomogram derived from SIRI and other clinical metrics showed outstanding calibration capability as well as therapeutic usefulness in both groups.

SIRI is a reliable and useful factor for AKI and fatality in pediatric ICU patients, and the proposed nomogram based on SIRI yields an appropriate prediction value for critically sick pediatric patients.

Osteoporosis (OP) has a significant detrimental impact on the health of the elder. Long-term clinical effectiveness of current drugs used for OP treatment is limited. Therefore, it is very important to explore novel treatment targets for OP. The expression of SNHG1, HMGB1, OCN and OPN in gene level was measured using RT-qPCR, and the protein expression was determined by Western blotting assay. The concentration of IL-1β and IL-18 in supernatant of the bone marrow mesenchymal stem cells (BMSCs) was measured by ELISA. The interaction between SNHG1 and HMGB1 was confirmed by RNA pull down. Besides, alizarin red staining was performed to evaluate the differentiation of BMSCs into osteoblast. SNHG1 and HMGB1 were found to be upregulated in the serum of OP patients. During the osteogenic differentiation of BMSCs, the expression of osteoblastogenesis markers (OCN and OPN) and the activity of ALP were upregulated, while the expression levels of SNHG1 and HMGB1 were decreased in a time-dependent manner. In addition, the interaction between SNHG1 and HMGB1, expression of pyroptosis-associated factors (caspase-1 p20 and GSDMD-N), and secretion of IL-1β and IL-18 were also decreased during osteogenic differentiation. Interestingly, increasing SNHG1 promoted HMGB1 expression, activated pyroptosis, but inhibited osteogenic differentiation. Silencing HMGB1 or inhibiting caspase-1 partially rescued the inhibitory effect of SNHG1 on osteogenic differentiation. Our findings indicate that SNHG1 suppresses the osteogenic differentiation of BMSCs by activating pyroptosis through interaction with HMGB1 and promotion of HMGB1 expression. Our work provides further evidence supporting SNHG1 acts as a potential target for OP treatment, and reveals for the first time that SNHG1 regulates osteogenic differentiation by affecting pyroptosis.

Clinical observations suggest that acute kidney injury (AKI) occurs in approximately 20-50% of hospitalized cirrhotic patients, suggesting a link between the liver and kidney. Bone morphogenetic protein 9 (BMP9) is a protein produced primarily by the liver and can act on other tissues at circulating systemic levels. Previous studies have demonstrated that controlling abnormally elevated BMP9 in acute liver injury attenuates liver injury; however, reports on whether BMP9 plays a role in liver injury-induced AKI are lacking. By testing we found that liver injury in mice after bile duct ligation (BDL) was accompanied by a significant upregulation of the kidney injury marker kidney injury molecule (KIM-1). Interestingly, all these impairments were alleviated in the kidneys of hepatic BMP9 knockout (BMP9-KO) mice. Peritubular capillary injury is a key process leading to the progression of AKI, and previous studies have demonstrated that vascular endothelial growth factor A (VEGFA) plays a key role in maintaining the renal microvascular system. In animal experiments, we found that high levels of circulating BMP9 had an inhibitory effect on VEGFA expression, while renal tubular epithelial cell injury was effectively attenuated by VEGFA supplementation in the hypoxia-enriched-oxygen (H/R) constructs of the AKI cell model in both humans and mice. Overall, we found that elevated BMP9 in hepatic fibrosis can affect renal homeostasis by regulating VEGFA expression. Therefore, we believe that targeting BMP9 therapy may be a potential means to address the problem of clinical liver fibrosis combined with AKI.

Exogenous polysulfhydryls (R-SH) supplementation and nitric oxide (NO) gas molecules delivery provide essential antioxidant buffering pool components and anti-inflammatory species in cellular defense against injury, respectively. Herein, the intermolecular disulfide bonds in bovine serum albumin (BSA) molecules were reductively cleaved under native and mild conditions to expose multiple sulfhydryl groups (BSA-SH), then sulfhydryl-nitrosylated (R-SNO), and nanoprecipitated to form injectable self-sulfhydrated, nitro-fixed albumin nanoparticles (BSA-SNO NPs), allowing albumin to act as a NO donor reservoir and multiple sulfhydryl group transporter while also preventing unfavorable oxidation and self-cross-linking of polysulfhydryl groups. In two mouse models of ischemia/reperfusion-induced and endotoxin-induced acute liver injury (ALI), a single low dosage of BSA-SNO NPs (S-nitrosothiols: 4 μmol·kg-1) effectively attenuated oxidative stress and systemic inflammation cascades in the upstream pathophysiology of disease progression, thus rescuing dying hepatocytes, regulating host defense, repairing microcirculation, and restoring liver function. By mechanistically upregulating the antioxidative signaling pathway (Nrf-2/HO-1/NOQ1) and inhibiting the inflammatory cytokine storm (NF-κB/p-IκBα/TNF-α/IL-β), BSA-SNO NPs blocked the initiation of the mitochondrial apoptotic signaling pathway (Cyto C/Bcl-2 family/caspase-3) and downregulated the cell pyroptosis pathway (NLRP3/ASC/IL-1β), resulting in an increased survival rate from 26.7 to 73.3%. This self-sulfhydrated, nitro-fixed functionalized BSA nanoformulation proposes a potential drug-free treatment strategy for ALI.

This study explores the role of SIRT2 in regulating autophagy and its interaction with AMPK in the context of acute liver failure (ALF). This study investigated the effects of SIRT2 and AMPK on autophagy in ALF mice and TAA-induced AML12 cells. The results revealed that the liver tissue in ALF model group had a lot of inflammatory cell infiltration and hepatocytes necrosis, which were reduced by SIRT2 inhibitor AGK2. In comparison to normal group, the level of SIRT2, P62, MDA, TOS in TAA group were significantly increased, which were decreased in AGK2 treatment. Compared with normal group, the expression of P-PRKAA1, Becilin1 and LC3B-II was decreased in TAA group. However, AGK2 enhanced the expression of P-PRKAA1, Becilin1 and LC3B-II in model group. Overexpression of SIRT2 in AML12 cell resulted in decreased P-PRKAA1, Becilin1 and LC3B-II level, enhanced the level of SIRT2, P62, MDA, TOS. Overexpression of PRKAA1 in AML12 cell resulted in decreased SIRT2, TOS and MDA level and triggered more autophagy. In conclusion, the data suggested the link between AMPK and SIRT2, and reveals the important role of AMPK and SIRT2 in autophagy on acute liver failure.

Percutaneous coronary intervention (PCI) is a crucial diagnostic and therapeutic approach for coronary heart disease. Contrast agents' exposure during PCI is associated with a risk of contrast-induced acute kidney injury (CI-AKI). CI-AKI is characterized by a sudden decline in renal function occurring as a result of exposure to intravascular contrast agents, which is associated with an increased risk of poor prognosis. The pathophysiological mechanisms underlying CI-AKI involve renal medullary hypoxia, direct cytotoxic effects, endoplasmic reticulum stress, inflammation, oxidative stress, and apoptosis. To date, there is no effective therapy for CI-AKI. High-mobility group box 1 (HMGB1), as a damage-associated molecular pattern molecule, is released extracellularly by damaged cells or activated immune cells and binds to related receptors, including toll-like receptors and receptor for advanced glycation end product. In renal injury, HMGB1 is expressed in renal tubular epithelial cells, macrophages, endothelial cells, and glomerular cells, involved in the pathogenesis of various kidney diseases by activating its receptors. Therefore, this review provides a theoretical basis for HMGB1 as a therapeutic intervention target for CI-AKI.

Retinal diseases encompass various conditions associated with sight-threatening immune responses and are leading causes of blindness worldwide. These diseases include age-related macular degeneration, diabetic retinopathy, glaucoma and uveitis. Emerging evidence underscores the vital role of the innate immune response in retinal diseases, beyond the previously emphasized T-cell-driven processes of the adaptive immune system. In particular, pyroptosis, a newly discovered programmed cell death process involving inflammasome formation, has been implicated in the loss of membrane integrity and the release of inflammatory cytokines. Several disease-relevant animal models have provided evidence that the formation of inflammasomes and the induction of pyroptosis in innate immune cells contribute to inflammation in various retinal diseases. In this review article, we summarize current knowledge about the innate immune system and pyroptosis in retinal diseases. We also provide insights into translational targeting approaches, including novel drugs countering pyroptosis, to improve the diagnosis and treatment of retinal diseases.