Hepatic ischemia‒reperfusion injury (HIRI) occurs during liver surgery, contributing to postoperative complications such as liver failure, prolonged hospital stays, and increased morbidity and mortality rates. Yet, the mechanism underlying HIRI remains unclear. Nicotinamide N-methyltransferase (NNMT) facilitates the conversion of nicotinamide into N1-methylnicotinamide (1-MNA) and plays crucial roles in various pathophysiological processes. In this study, we find a decrease in hepatic NNMT expression and serum 1-MNA levels during HIRI. Both NNMT overexpression and exogenous 1-MNA treatment alleviate HIRI in male mice HIRI models and primary hepatocytes H/R models. Mechanistically, NNMT/1-MNA plays key roles in inflammation, apoptosis, and vascular injury during HIRI through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT leads to increased ANGPT2 expression and exacerbates HIRI, effects that can be mitigated by ANGPT2 knockdown. Our findings suggest that NNMT/1-MNA/ANGPT2 may regulate HIRI via the JNK signaling pathway. In summary, we present the function of NNMT and its underlying mechanism in liver injury, providing potential new therapeutical strategies for addressing HIRI.

Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.

Liver transplantation is the key treatment for liver failure, yet organ scarcity, exacerbated by high discard rates of steatotic livers, leads to high waitlist mortality. Preclinical models of steatosis are necessary to understand the pathophysiology of the disease and to develop pharmacological interventions to decrease disease burden and liver discard rate. In this paper, we develop an expedited 3D steatotic organoid model containing primary human hepatocytes and non-parenchymal cells. We present our iterative approach as we transition from 2D to 3D models and from immortalized to primary cells to optimize conditions for the development of a 3D human steatosis model. Both primary cell aggregation and steatosis induction time were reduced from the standard, 5-7 days, to 2 days. Our 3D model incorporates human primary hepatocytes from discarded liver tissues, which have not been used in organoids previously due to their rapid loss of phenotype in culture. After optimizing our steatosis induction media there was a mix of macro- and micro-steatosis in these primary hepatocytes which is consistent with the human pathology. Our approach achieves a model reflective of the liver pathology, preserving cellular phenotypes and viability while exhibiting markers of oxidative stress, a key factor contributing to complications in the transplantation of steatotic livers.

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.

The superoxide anion radical (O2˙-) represents the primary reactive oxygen species generated in biological systems. Real-time monitoring of its dynamic fluctuations provides valuable insights into disease progression and enables early diagnosis of hepatic ischemia-reperfusion injury (HIRI). In this work, we developed a novel dual-color fluorescent carbon dot (CD) probe through a one-step hydrothermal synthesis for reversible O2˙- detection. The CDs demonstrated excellent sensitivity, dynamically detecting O2˙- concentrations ranging from 0 to 60 μM with a detection limit of 0.56 μM. The probe exhibited remarkable reversibility, maintaining stable performance through at least three complete oxidation-reduction cycles following glutathione (GSH) treatment. In practical applications, the CDs achieved 95.2-104% recovery rates when detecting O2˙- in serum samples. Cellular imaging experiments confirmed the probe's effectiveness in normal hepatocytes (LO2), showing clear reversible responses to O2˙- fluctuations. Application in a HIRI cell model revealed significant elevation of O2˙- levels and provided new evidence for its role in HIRI-related signaling pathways. This study not only presents an effective dual-color fluorescent probe for dynamic O2˙- monitoring but also establishes a versatile synthetic strategy that could be adapted for imaging other biologically relevant molecules in living cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia.

This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers.

Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD.

Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels.

Hepatic steatosis significantly elevates the vulnerability of the graft to ischemia-reperfusion (I/R) injury during liver transplantation (LT). We investigated the protective role of insulin-induced gene 2 (Insig2) in steatotic liver's I/R injury and underlying mechanisms. Employing mouse model with Insig2 knock-out or hepatocyte-specific overexpression and high-fat diets to induce steatosis, we subjected these mice to hepatic I/R injury. The primary hepatocytes isolated from steatotic liver were used in in vitro hypoxia/reoxygenation (H/R) experiment. Our integrated in vivo and in vitro approach uncovered that Insig2 deficiency exacerbated steatotic liver's damage following hepatic I/R injury, whereas its overexpression offers protection. Mechanically, integrative analysis of transcriptome, proteome, and metabolome found that Insig2 deficiency disturbed lipid metabolism and oxidative stress homeostasis, particularly inhibiting GPX4 expression to induce ferroptosis. Furthermore, chemical inhibition of ferroptosis reversed the deleterious effect of Insig2 deficiency; whereas the protective influence of Insig2 overexpression was negated by the target inhibition of GPX4, leading to an exacerbation of hepatic I/R damage. These insights underscored the potential of the Insig2-GPX4 axis as a therapeutic target, presenting a novel avenue for enhancing the resilience of steatotic liver grafts against I/R injury.

This study aims to investigate whether thioredoxin-interacting protein (TXNIP) regulates cell viability, cell apoptosis and mitochondrial damage in OGD/R-induced hepatocytes and to explore its underlying mechanism. AML12 cells were cultured under oxygen-glucose deprivation/reperfusion (OGD/R) conditions. TXNIP mRNA was detected using qRT-PCR, and the TXNIP protein was analyzed using western blotting. TXNIP-targeted short hairpin RNA (sh-TXNIP) lentivirus was used to infect the AML12 cells. CCK8 and TUNEL assays were applied to detect cell viability and apoptosis, respectively. DCFH-DA probe was used to determine reactive oxygen species (ROS) release level, and JC-1 probe was used to evaluate mitochondrial membrane potential (MMP). The localization of TXNIP and HIF-1α was observed using immunofluorescence. Our results showed that TXNIP markedly increased in AML12 cells treated with OGD/R. TXNIP knockdown increased cell viability and reduced cell apoptosis under OGD/R treatment. Moreover, MMP significantly increased and ROS release decreased in cells after TXNIP knockdown under OGD/R treatment. Additionally, TXNIP knockdown markedly increased the expression of HIF-1α. HIF-1α exhibited nuclear translocation following OGD/R induction, and TXNIP knockdown further promoted it. Compared with the OGD/R + sh-TXNIP group, HIF-1α agonist ML228 inhibited cell apoptosis and ROS release, and increased MMP. However, HIF-1α inhibitor PX478 had the opposite effect. In summary, TXNIP deletion ameliorated AML12 cell injury caused by OGD/R via promoting HIF-1α expression and nuclear translocation, manifested by inhibiting cell apoptosis and alleviating mitochondrial dysfunction.

Hepatic sinusoidal obstruction syndrome (HSOS) is a rare liver disorder with potentially life-threatening consequences for colorectal chemotherapy and haematopoietic stem cell transplant recipients. MALT1 (mucous-associated lymphoid tissue lymphoma translocation protein-1) is a protein that plays a key role in the production of inflammatory cytokines, ischemia, atherosclerosis, apoptosis and thromboinflammation; however, its role in HSOS is largely unknown. We aimed to investigate the effect of MALT-1 inhibition in in vitro and in vivo models of HSOS.

Two mouse models (FOLFOX challenge in immunocompetent and immunocompromised mice) were used to investigate the therapeutic benefits of the MALT-1 inhibitor (MI-2) in vivo. HHSEC, HLEC and RAW-264.7 cells served as in vitro models. HSOS-responsible genes, marker levels and downstream signalling were examined using quantitative real-time PCR, western blot, immunocytochemistry and immunohistochemistry analysis.

In the current investigation, MI-2 significantly reduced FOLFOX-induced HSOS in both mouse models by inhibiting the occlusion of sinusoids, RBC extravasation and bridging fibrosis in liver sections. MI-2 treatment also dramatically reduced specific SOS markers (vWF, VEGF, ephrin, bilirubin and PECAM) and other inflammatory markers. Mechanistic investigation in in vitro models using macrophages, sinusoidal and endothelial cells demonstrated that MI-2 treatment significantly diminished the inflammatory marker levels/expression by lowering ROS production. In addition to the pharmacological approach, siRNA-mediated MALT1 suppression remarkably reduced chemokine and cytokine marker expression in sinusoidal cells.

Thus, our findings demonstrate that MALT1 suppression dramatically reduces FOLFOX-induced inflammatory and fibrotic conditions by modulating the NF-κB activation, paving the way for innovative HSOS therapy approaches.

Liver ischemia-reperfusion injury (LIRI) is a major reason for liver injury that occurs during surgical procedures such as hepatectomy and liver transplantation and is a major cause of graft dysfunction after transplantation. Programmed cell death (PCD) has been found to correlate with the degree of LIRI injury and plays an important role in the treatment of LIRI. We aim to comprehensively explore the expression patterns and mechanism of action of PCD-related genes in LIRI and to find novel molecular targets for early prevention and treatment of LIRI.

We first compared the expression profiles, immune profiles, and biological function profiles of LIRI and control samples. Then, the potential mechanisms of PCD-related differentially expressed genes in LIRI were explored by functional enrichment analysis. The hub genes for LIRI were further screened by applying multiple machine learning methods and Cytoscape. GSEA, GSVA, immune correlation analysis, transcription factor prediction, ceRNA network analysis, and single-cell analysis further revealed the mechanisms and regulatory network of the hub gene in LIRI. Finally, potential therapeutic agents for LIRI were explored based on the CMap database and molecular docking technology.

Forty-seven differentially expressed genes associated with PCD were identified in LIRI, and functional enrichment analysis showed that they were involved in the regulation of the TNF signaling pathway as well as the regulation of hydrolase activity. By utilizing machine learning methods, 11 model genes were identified. ROC curves and confusion matrix from the six cohorts illustrate the superior diagnostic value of our model. MYC was identified as a hub PCD-related target in LIRI by Cytoscape. Finally, BMS-536924 and PF-431396 were identified as potential therapeutic agents for LIRI.

This study comprehensively characterizes PCD in LIRI and identifies one core molecule, providing a new strategy for early prevention and treatment of LIRI.

Alcoholic hepatic steatosis (AHS) is a common early-stage symptom of liver disease caused by alcohol consumption. Accordingly, several aspects of AHS have been studied as potential preventive and therapeutic targets. In this study, a novel strategy was employed to inhibit fatty liver accumulation and counteract AHS through the consumption of microorganism-fermented Protaetia brevitarsis larvae (FPBs). By using an AHS rat model, we assessed the efficacy of FPB by examining the lipid profile of liver/serum and liver function tests to evaluate lipid metabolism modulation. After FPB administration, the lipid profile-including high-density lipoprotein, total cholesterol, and total triglycerides-and histopathological characteristics exhibited improvement in the animal model. Interestingly, AHS amelioration via FPBs administration was potentially associated with poly-γ-glutamic acid (PγG), which is produced by Bacillus species during fermentation. These findings support the formulation of novel natural remedies for AHS through non-clinical animal studies, suggesting that PγG-enriched FPBs are a potentially valuable ingredient for functional foods, providing an ameliorative effect on AHS.

Acetaminophen (APAP) is widely used as an analgesic and antipyretic. However overdose APAP can lead to acute liver injury (ALI), representing a significant challenge for public health due to limited treatment options. Current research highlights the need for safer and more effective therapies for APAP-induced liver injury, especially those that target oxidative and endoplasmic reticulum (ER) stress pathways. This study investigates the protective effects of Thonningianin A (TA), a flavonoid compound derived from Penthorum chinense Pursh, in mitigating APAP-induced hepatotoxicity.

The experimental design involved administering TA at doses of 20 mg/kg and 40 mg/kg to C57BL/6 mice prior to inducing hepatotoxicity with APAP.

TA treatment significantly lowered plasma ALT and AST levels, inhibited the production of inflammatory cytokines, and reduced oxidative stress markers in liver tissues. Furthermore, TA modulated apoptosis-related proteins by increasing BCL-2 expression while decreasing CHOP and BAX levels. It alleviated endoplasmic reticulum (ER) stress by downregulating GRP78, p-PERK, and ATF4. Notably, liver-specific GPX4 knockdown, achieved through AAV-8-mediated shRNA delivery, abolished the hepatoprotective effects of TA, underscoring GPX4's essential role in mediating TA-induced hepatoprotection. These findings suggest TA as a promising therapeutic agent in managing APAP-induced liver injury, with its unique action on both oxidative and ER stress pathways contributing to its hepatoprotective efficacy.

Pterocarpus soyauxii (P. soyauxii) is a Fabaceae family traditionally used to treat menopausal disorders. This study aims to investigate the effect of P. soyauxii on menopause-related non-alcoholic fatty liver disease (NAFLD) and to determine its mechanisms of action and signaling pathways. The pharmacokinetic and dynamic properties and the toxicological profile of P. soyauxii compounds were assessed using the SwissADME and Protox III databases. A pharmacology network was constructed to identify active compound targets and corresponding genes. Compound target and protein-protein interaction networks were created using Cytoscape software. Molecular docking studies were conducted to assess the binding affinity of P. soyauxii compounds with specific proteins. In vitro experiments evaluated the antioxidant properties of P. soyauxii. In vivo studies using ovariectomized (Ovx) rat models underlined pathways and effects of P. soyauxii on biochemical and histological features linked with NAFLD. Findings suggest that P. soyauxii compounds are readily absorbed through the intestine and exhibit a relatively low level of toxicity. Protein-protein interaction, compound-target networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed several pathways and target proteins of P. soyauxii compounds. Indeed, they target specific proteins such as estrogen receptor alpha/beta ERα/β, nicotinamide adenine dinucleotide phosphate oxidase (NADPH-O), epidermal growth factor receptor (EGFR), MAPK1, peroxisome proliferator-activated receptors alpha/gamma (PPARα/G), and HMG-CoA reductase. Molecular docking revealed that P. soyauxii compounds demonstrate high binding affinity to various proteins. In vitro, P. soyauxii inhibits the oxidative power of OH, H2O2, and NO. In vivo, P. soyauxii significantly (p < 0.01, p < 0.001, and p < 0.01, respectively) reduces ALAT (25.14%), hepatic cholesterol (15.27%), and malondialdehyde (MDA) (26.78%) levels at 200 mg/kg and prevents steatosis in the liver. These findings suggest that P. soyauxii may have a protective role against menopause-related NAFLD.

Liver ischemia-reperfusion injury (LIRI) is a critical condition after liver transplantation. Understanding the role of immunogenic cell death (ICD) may provide insights into its diagnosis and potential therapeutic targets.

Differentially expressed genes (DEGs) between LIRI and normal samples were identified, and pathway enrichment analyses were performed, followed by immune infiltration assessment through the CIBERSORT method. The consensus clustering analysis was conducted to separate LIRI clusters and single-sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the distinct immune states between clusters. Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to identify hub genes associated with ICD. To establish diagnostic models, four machine learning techniques, including Random Forest (RF), XGBoost (XGB), Support Vector Machine (SVM), and Generalized Linear Models (GLM), were applied to filter gene sets. The receiver operating characteristic (ROC) curves were utilized to assess the performance of the models.

Pathway enrichment results revealed significant involvement of cytokines and chemokines among DEGs of LIRI. Immune infiltration analysis indicated higher levels of specific immune functions in Cluster 2 compared to Cluster 1. WGCNA identified significant modules linked to LIRI with strong correlations between module membership and gene significance. The RF and SVM machine learning algorithms were finally chosen to construct the models. Both demonstrated high predictive accuracy for diagnosing LIRI not only in training cohort GSE151648 but also in validation cohorts GSE23649 and GSE15480.

The study highlights the pivotal roles of ICD-related genes in LIRI, providing diagnosis models with potential clinical applications for early detection and intervention strategies against LIRI.

Acute Osteofascial Compartment Syndrome (AOCS) stands as a critical surgical emergency, often secondary to various diseases. Its clinical manifestation arises from increased pressure within the fascial compartment, resulting in diminished tissue perfusion and consequential ischemic damage. Presently, clinical diagnostics lack effective biological markers, and patients face a grim prognosis, experiencing muscle contractures, necrosis, amputations, renal failure, and even mortality. The primary treatment, fasciotomy, poses infection risks and potential nerve damage. Hence, there is an urgent need for research elucidating AOCS's pathogenic mechanism and exploring novel treatments.

To address this, we established a rat model of AOCS, extracting toe flexor muscles from both experimental and control groups. Employing second-generation high-throughput sequencing, we obtained comprehensive mRNA, lncRNA, circRNA, and miRNA data. Comparative analysis of expression differences between AOCS and control groups, followed by in-depth examination, allowed us to unravel the intricacies of AOCS occurrence from a multi-omics perspective.

Our research findings indicate that AOCS is an immune-mediated inflammatory disease, primarily involving immune cells, especially neutrophils. In addition, genes associated with ferroptosis, a form of regulated cell death, are found to be upregulated in the rat model, with non-coding RNAs playing a role in regulatory interactions.

These results suggest that neutrophils may undergo ferroptosis, thereby enhancing inflammation and immune responses in the fascial compartment, which promotes disease progression. Furthermore, these findings reveal the interactions between immune molecules and pathways in AOCS, which are significant for a deeper understanding of the pathogenesis of the disease and the development of targeted therapeutic strategies.

Liver ischemia reperfusion (IR) injury significantly impacts clinical outcomes by increasing the risk of hepatic dysfunction after liver surgery. Fatty livers are more susceptible to IR stress. Recent studies have demonstrated that S100A9 plays a crucial role in both IR injury and the progression of liver steatosis. Nevertheless, the precise mechanisms underlying these effects remain unclear. In our study, transcriptome analysis of fatty livers subjected to IR insult in mice identified S100A9 as an important mediator. Employing loss-of-function approaches, we investigated the immune regulatory function of S100A9 and its downstream signaling in fatty liver IR injury. As expected, S100A9 emerged as one of the most significantly upregulated genes during the reperfusion stage in fatty livers. Genetic knockdown of S100A9 markedly ameliorated liver pathological damage, evidenced by reduced macrophage/neutrophil infiltration as well as the decreased expression of proinflammatory factors. Transcriptome/functional studies revealed that S100A9 triggered liver inflammatory response via regulating toll-like receptor 2 (TLR2)/activating transcription factor 4 (ATF4) signaling. Additionally, TLR2 expression was notably increased in macrophages from ischemic fatty livers. In vitro , recombinant S100A9-stimulated macrophages exhibited the elevated production of proinflammatory factors and TLR2/ATF4 pathway activation. Intriguingly, S100A9 facilitated ATF4 nuclear translocation and enhanced NEK7/NLRP3 inflammasome activation in macrophages. In conclusion, our study identified S100A9 as a key regulator responsible for macrophage NLRP3 inflammasome activation and subsequent inflammatory injury in fatty liver IR process. Targeting TLR2/ATF4 signaling may offer a novel therapeutic strategy for mitigating S100A9-mediated liver injury.

Acteoside (ACT) is one of the primary bioactive ingredients in Cistanche tubulosa (Schenk). Its remarkable efficacy in treating immune-related and inflammatory disorders has garnered significant interest among scientific circles. However, the anti-inflammatory and antioxidant effects of ACT and its underlying molecular mechanisms require further investigation. In this study, pharmacophore-based reverse docking and molecular dynamics simulations identified potential anti-inflammatory targets in silico. Studies conducted in vitro with lipopolysaccharide (LPS)-induced RAW264.7 cells validated the anti-inflammatory properties of ACT. Methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays indicated ACT's non-toxic and growth-promoting effects on cells. ACT significantly reduced nitric oxide (NO) and reactive oxygen species (ROS) production and restored levels of antioxidant enzymes. It also decreased pro-inflammatory cytokines. Western blotting assays indicated that ACT inhibited p38, TNF-α, PI3 K/AKT, and NF-κB signaling pathways. These findings underscore ACT's ability to mitigate acute inflammation in RAW264.7 cells by modulating key signaling pathways and provide the scientific basis for enhancing the medicinal value of ACT and future drug development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.

The use of fatty livers in liver transplantation has emerged as a crucial strategy to expand the pool of donor livers; however, fatty livers are more sensitive to ischemia‒reperfusion injury (IRI). Excessive congenital inflammatory responses are crucial in IRI. Hypothermic oxygenated perfusion (HOPE) is a novel organ preservation technique that may improve marginal donor liver quality by reducing the inflammatory response. Tissue factor pathway inhibitor-2 (TFPI2) and CAP-Gly domain-containing linker protein 1 (CLIP1) exhibit modulatory effects on the inflammatory response. However, the underlying mechanisms of HOPE in fatty liver and the effects of TFPI2 and CLIP1 in fatty liver IRI remain unclear. Here, we aimed to explore the impact of HOPE on the inflammatory response in a rat model of fatty liver IRI and the mechanisms of action of TFPI2 and CLIP1. HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates damage to hepatocytes and endothelial cells. Mechanistically, HOPE exerts its effects by inhibiting TFPI2, and CLIP1 can rescue the damaging effects of TFPI2. Moreover, HOPE promoted the ubiquitination and subsequent degradation of Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) by regulating the binding of R24 of the KD1 domain of TFPI2 with CLIP1, thereby negatively regulating the TLR4/NF-κB-mediated inflammatory response and reducing IRI. Furthermore, TFPI2 expression increased and CLIP1 expression decreased following cold ischemia in human fatty livers. Overall, our results suggest that targeting the inflammatory response by modulating the TFPI2/CLIP1/TIRAP signaling pathway via HOPE represents a potential therapeutic approach to ameliorate IRI during fatty liver transplantation.

Background: The interplay between breast cancer treatment and osteoporosis has important consequences for anticancer therapy and patient bone health. Many breast cancer therapies involve hormonal treatments that lower estrogen levels, which can lead to an increased risk of osteoporosis due to reduced bone mineral density. Aromatase inhibitors, chemotherapy, and surgeries such as oophorectomy can further aggravate bone loss, highlighting the necessity of prioritizing bone health during cancer treatment. Objective: This review is aimed at investigating the complex relationship between breast cancer therapies and bone health by examining the molecular and cellular mechanisms through which anticancer treatments lead to bone loss. It also seeks to assess the effects of various treatment options, such as selective estrogen receptor modulators (SERMs) and bisphosphonates, on reducing bone loss and maintaining bone health during cancer therapy. Method: The review explores the mechanisms underlying bone loss in breast cancer patients undergoing treatment, focusing on factors such as estrogen depletion, inflammatory cytokines, and changes in bone remodelling processes. Additionally, it evaluates the efficacy of different therapeutic interventions, including pharmacological treatments like bisphosphonates and third-generation SERMs, in mitigating bone-related side effects. Results: The findings indicate a critical need to balance the effectiveness of breast cancer treatments with the preservation of bone health. Pharmacological treatments like bisphosphonates and denosumab have been identified as essential for managing bone health in breast cancer patients. Furthermore, third-generation SERMs show potential in reducing bone loss associated with cancer therapy.

The study aims to analyze transcriptomic profiles in adipose tissues postconsumption of elaidic acid (EA; trans-18:1n-9) and trans-palmitoleic acid (TPA; trans-16:1n-7), elucidating their different effects on inflammation and glucose metabolism.

Twenty C57BL/6 mice are divided into four groups. Each group receives one of the following formulations in drinking water: lecithin nanovesicles, nanovesicles containing either lecithin with EA or TPA (86:14 w/w), or water (control) for 28 days with a regular fat diet (18% calories from fat). Total RNA is extracted, and paired-end sequencing is performed. TPA intake alters the expression of 351 genes compared to EA intake, including 11 downregulated and 340 upregulated genes (fold change [FC] >1.5, p < 0.05). TPA compares to EA upregulated: Slc5a8, Lcn2, Csf3, Scube1, Mapk13, Bdkrb2, Ctla2a, Slc2a1, Oas3, Cx3cl1, Oas2, Nlrp6, Pycard, Cyba, Ddr1, and Prkab1 and downregulated Fas gene. These genes are related to the NOD-like receptor, lipid and atherosclerosis, IL-17 signaling, TNF, nonalcoholic fatty liver disease, cytokine-cytokine receptor interaction, adipocytokine, glucagon, insulin resistance, and inflammatory mediator regulation of TRP channels signaling.

TPA intake has a distinct impact on the regulation of inflammation and diabetes-related pathways in adipose tissue compared to EA.

Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.

In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.

Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3β (GSK-3β) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3β provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3β inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3β roles in IRI. First, we provide an overview of GSK-3β's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3β in accelerating IRI, and highlight the latest progress of GSK-3β in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3β inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3β as a potential target for future IRI therapy.

Post-traumatic stress disorder (PTSD) is a complex psychological disorder provoked by distressing experiences, and it remains without highly effective intervention strategies. The exploration of PTSD's underlying mechanisms is crucial for advancing diagnostic and therapeutic approaches. Current studies primarily explore PTSD through the lens of the central nervous system, investigating concrete molecular alterations in the cerebral area and neural circuit irregularities. However, the body's response to external stressors, particularly the changes in cardiovascular function, is often pronounced, evidenced by notable cardiac dysfunction. Consequently, examining PTSD with a focus on cardiac function is vital for the early prevention and targeted management of the disorder. This review undertakes a comprehensive literature analysis to detail the alterations in brain and heart structures and functions associated with PTSD. It also synthesizes potential mechanisms of heart-brain axis interactions relevant to the development of PTSD. Ultimately, by considering cardiac function, this review proposes novel perspectives for PTSD's prophylaxis and therapy.

With its annually increasing prevalence, non-alcoholic fatty liver disease (NAFLD) has become a serious threat to people's life and health. After a preliminary research, we found that Lactucopicrin has pharmacological effects, such as lowering blood lipids and protecting the liver. Further research showed its significant activation for fatty acid β-oxidase hydroxyacyl-coenzyme A (CoA) dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), so we hypothesized that Lactucopicrin could ameliorate lipid accumulation in hepatocytes by promoting fatty acid β-oxidation. In this study, free fatty acid (FFA)-induced human hepatoblastoma cancer cells (HepG2) were used to establish an in vitro NAFLD model to investigate the molecular basis of Lactucopicrin in regulating lipid metabolism. Staining with Oil red O and measurements of triglyceride (TG) content, fatty acid β-oxidase (FaβO) activity, reactive oxygen species (ROS) content, mitochondrial membrane potential, and adenosine triphosphate (ATP) content were used to assess the extent to which Lactucopicrin ameliorates lipid accumulation and promotes fatty acid β-oxidation. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot methods were used to explore the regulatory effects of Lactucopicrin on factors related to fatty acid β-oxidation. Results showed that Lactucopicrin downregulated phosphorylated mammalian target of rapamycin (P-mTOR) by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway and upregulated the messenger RNA (mRNA) and protein expression levels of coactivators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)), transcription factors (peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ)), and oxidative factors (carnitine palmitoyltransferase 1A (CPT1A) and HADHA). This phenomenon resulted in a significant increase in FaβO activity, ATP content, and JC-1 and a significant decrease in ROS level, TG content, and intracellular lipid droplets. With the addition of Dorsomorphin, all the effects of Lactucopicrin intervention were suppressed. In summary, Lactucopicrin promotes fatty acid β-oxidation by activating the AMPK pathway, thereby ameliorating FFA-induced intracellular lipid accumulation in HepG2 cells.

Nonalcoholic fatty liver disease (NAFLD), which is a major cause of chronic liver disease, is characterized by fat accumulation in the liver. Existing models struggle to assess medication effects on liver function in the context of NAFLD's unique inflammatory environment. We address this by developing a 3D in vitro NAFLD model using HepG2 and THP-1 cells (mimicking liver and Kupffer cells) cocultured using transwell and hydrogel system. This mimics liver architecture and allows for manipulation of the immune environment. We demonstrate that the model recapitulates key NAFLD features: steatosis (induced by fatty acids), oxidative stress, inflammation, and impaired liver function embodying the interrelationship between NAFLD and the surrounding immune environment. This versatile model offers a valuable tool for preclinical NAFLD research by incorporating a disease-relevant immune environment.

The purpose of this study was to investigate effect of liver Transplants (LT) with retrograde reperfusion on early postoperative recovery of liver function and its risk factors.

We conducted a retrospective analysis of clinical data from 136 liver transplantation (LT) patients at the 900th Hospital of the Chinese People's Liberation Army Joint Support Army, covering the period from January 2015 to January 2021. All participants provided informed consent, adhering to medical ethics guidelines. Patients were stratified into two groups based on the liver perfusion technique used: retrograde reperfusion (RTR, n = 108) and initial portal reperfusion (IPR, n = 28). Our study focused on a subset of 23 patients from each group to compare postoperative liver function recovery. The final analysis included 86 RTR and 28 IPR cases after excluding 8 RTR patients who underwent initial hepatic artery reperfusion and 14 who received simultaneous hepatic artery and portal vein reperfusion. Further subdivision within the RTR group identified 19 patients with early hepatic allograft dysfunction (EAD) and 67 without, allowing for an assessment of the influence of preoperative and intraoperative parameters, as well as perfusion methods, on EAD incidence post-LT.

Alanine aminotransferase (ALT) was 329 (211 ~ 548) and 176 (98 ~ 282) U/L on the 3rd and 7th day after RTR, respectively, which was significantly lower than 451 (288 ~ 918) and 251 (147 ~ 430) U/L in the IPR group (Z =-1.979, -2.299, P = 0.048, 0.021). Aspartate aminotransferase (AST) on postoperative days 3, 5, and 7 was 252 (193, 522), 105 (79, 163), and 93 (41, 135) U/L in the RTR group, respectively; it was also significantly lower than 328 (251, 724), 179 (129, 306), and 150 (91, 200)U/L in the IPR group (Z=-2.212, -3.221, -2.979; P = 0.027, 0.001, 0.003). Logistic regression analysis showed that MELD score was an independent risk factor for EAD after LT.

RTR LT is more favorable for patients' early postoperative liver function recovery. For patients undergoing LT for RTR, preoperative MELD score was an independent risk factor for their postoperative development of EAD.

Ischemia-reperfusion (I/R) injury, resulting from blood flow interruption and its subsequent restoration, is a prevalent complication in liver surgery. The liver, as a crucial organ for carbohydrate and lipid metabolism, exhibits decreased tolerance to hepatic I/R in patients with diabetes mellitus (DM), resulting in a significant increase in hepatic dysfunction following surgery. This may be attributed to elevated oxidative stress and inflammation. Our prior research established sinomenine's (SIN) protective role against hepatic I/R injury. Nevertheless, the impact of SIN on hepatic I/R injury in DM rats remains unexplored.

This study aimed to investigate the therapeutic potential of SIN in hepatic I/R injury in DM rats and elucidate its mechanism. Diabetic and hepatic I/R injury models were established in rats through high-fat/sugar diet, streptozotocin injection, and hepatic blood flow occlusion. Liver function, oxidative stress, inflammatory reaction, histopathology, and Nrf-2/HO-1 signaling pathway were evaluated by using UV spectrophotometry, biochemical assays, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Western blot analysis.

High-dose SIN (300 mg/kg) significantly attenuated hepatic I/R injury in DM rats, reducing serum activities of ALT and AST, decreasing the AST/ALT ratio, enhancing tissue contents of SOD and GSH-Px, suppressing the levels of TNF-α and IL-6, improving the liver histopathology, and activating Nrf-2/HO-1 signaling by promoting Nrf-2 trans-location from cytoplasm to nucleus. Low-dose SIN (100 mg/kg) was ineffective.

This study demonstrates that high-dose sinomenine's mitigates hepatic I/R-induced inflammation and oxidative stress in diabetes mellitus (DM) rats via Nrf-2/HO-1 activation, suggesting its potential as a preventive strategy for hepatic I/R injury in DM patients.

Long-term hepatic damage is associated with human morbidity and mortality owing to numerous pathogenic factors. A variety of studies have focused on improving liver health using natural products and herbal medicines. We aimed to investigate the effect of enzyme-treated Zizania latifolia ethanol extract (ETZL), which increases the content of tricin via enzymatic hydrolysis, for 8 weeks on liver-related outcomes, lipid metabolism, antioxidant activity, and fatigue compared to a placebo. Healthy Korean adult males aged 19-60 years were randomized into ETZL treatment and placebo groups, and alcohol consumption was 24.96 and 28.64 units/week, respectively. Alanine transaminase, a blood marker associated with liver cell injury, significantly decreased after 8 weeks compared to the baseline in the ETZL treatment group (p = 0.004). After 8 weeks, the treatment group showed significant changes in the levels of high-density lipoprotein and hepatic steatosis index compared to the baseline (p = 0.028 and p = 0.004, respectively). ETZL treatment tended to reduce antioxidant-activity-related factors, total antioxidant status, and malondialdehyde, but there was no significant difference. In the multidimensional fatigue scale, ETZL treatment showed a significant reduction in general fatigue and total-fatigue-related values after 8 weeks compared to the baseline (p = 0.012 and p = 0.032, respectively). Taken together, the 8-week treatment of enzyme-treated Zizania latifolia ethanol extract demonstrated positive effects on liver-related outcomes, lipid metabolism, and mental fatigue without adverse effects on safety-related parameters.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Accumulating evidence in animal models suggests that loss of interleukin-10 (IL-10) anti-inflammatory actions might contribute to lobular inflammation, considered one of the first steps toward NASH development. However, the role of IL-10 in lobular inflammation remains poorly explored in humans. We examined mRNA and protein levels of IL-10 in liver biopsies and serum samples from morbidly obese patients, investigating the relationship between IL-10 and lobular inflammation degree. Materials and Methods: We prospectively enrolled morbidly obese patients of both sexes, assessing the lobular inflammation grade by the Brunt scoring system to categorize participants into mild (n = 7), moderate (n = 19), or severe (n = 13) lobular inflammation groups. We quantified the hepatic mRNA expression of IL-10 by quantitative polymerase chain reaction and protein IL-10 levels in liver and serum samples by Luminex Assay. We estimated statistical differences by one-way analysis of variance (ANOVA) and Tukey's multiple comparison test. Results: The hepatic expression of IL-10 significantly diminished in patients with severe lobular inflammation compared with the moderate lobular inflammation group (p = 0.01). The hepatic IL-10 protein levels decreased in patients with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.008 and p = 0.0008, respectively). In circulation, IL-10 also significantly decreased in subjects with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.005 and p < 0.0001, respectively). Conclusions: In liver biopsies and serum samples of morbidly obese patients, the protein levels of IL-10 progressively decrease as lobular inflammation increases, supporting the hypothesis that lobular inflammation develops because of the loss of the IL-10-mediated anti-inflammatory counterbalance.

Non-alcoholic fatty liver disease (NAFLD) presents as a common liver disease characterized by an indistinct pathogenesis. Disulfidptosis is a recently identified mode of cell death. This study aimed to investigate the potential role of disulfidptosis-related genes (DRGs) in the pathogenesis of NAFLD.

Gene expression profiles were obtained from the bulk RNA dataset GSE126848 and the single-cell RNA dataset GSE136103, both associated with NAFLD. Our study assessed the expression of DRGs in NAFLD and normal tissues. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were employed to identify the key NAFLD-specific differentially expressed DRGs (DE-DRGs). To explore the biological functions and immune regulatory roles of these key DE-DRGs, we conducted immune infiltration analysis, functional enrichment analysis, consensus clustering analysis, and single-cell differential state analysis. Finally, we validated the expression and biological functions of DRGs in NAFLD patients using histology and RNA-sequencing transcriptomic assays with human liver tissue samples.

Through the intersection of WGCNA, differentially expressed genes, and DRGs, two key DE-DRGs (DSTN and MYL6) were identified. Immune infiltration analysis indicated a higher proportion of macrophages, T cells, and resting dendritic cells in NAFLD compared to control liver samples. Based on the key DE-DRGs, Two disulfidptosis clusters were defined in GSE126848. Cluster 1, with higher expression of the key DE-DRGs, exhibited increased immune infiltration abundance and was closely associated with oxidative stress and immune regulation compared to cluster 2. High-resolution analysis of mononuclear phagocytes highlighted the potential role of MYL6 in intrahepatic M1 phenotype Kupffer cells in NAFLD patients. Our transcriptome data revealed that the expression levels of the majority of DRGs were significantly increased in NAFLD patients. NAFLD patients exhibit elevated MYL6 correlating with inflammation, oxidative stress, and disease severity, offering promising diagnostic specificity.

This comprehensive study provides evidence for the association between NAFLD and disulfidptosis, identifying potential target genes and pathways in NAFLD. The identification of MYL6 as a possible treatment target for NAFLD provided a novel understanding of the disease's development.

Wound infections are a significant concern in healthcare, leading to long healing times. Traditional approaches for managing wound infections rely heavily on systemic antibiotics, which are associated with the emergence of antibiotic-resistant bacteria. Therefore, the development of alternative antibacterial materials for wound care has gained considerable attention. In today's world, new generations of wound dressing are commonly used to heal wounds. These new dressings keep the wound and the area around it moist to improve wound healing. However, this moist environment can also foster an environment that is favorable for the growth of bacteria. Excessive antibiotic use poses a significant threat to human health and causes bacterial resistance, so new-generation wound dressings must be designed and developed to reduce the risk of infection. Wound dressings using antimicrobial compounds minimize wound bacterial colonization, making them the best way to avoid open wound infection. We aim to provide readers with a comprehensive understanding of the latest advancements in antibacterial materials for wound management.

Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI).

The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes.

Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues.

Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

Placenta is a kind of traditional Chinese medicine, known as "Ziheche", which has the function of tonifying qi and blood, nourishing liver and kidney. Placenta extract (PE) has been used for delaying organismal aging and treating various liver diseases. Cow placenta is a rich natural resource with large mass. Its composition is similar to that of human placenta, but it has not been effectively utilized. However, little is known about the effect of CPE on the liver of aging mice.

The aim of this study is to explore the protective effect and mechanism of CPE on the liver of d-galactose (D-gal) induced aging mice.

Statistical methods were used to calculate mouse body weight and liver index. Hematoxylin-eosin (H&E) and transmission electron microscopy (TEM) were used to detect the morphological structure of the liver. Automatic biochemical analyzer was used to measure serum biochemical indicators. Three special staining methods were used to observe hepatocytes apoptosis, senescence and proliferation respectively. Relative kits were used to detect oxidative, inflammatory, and aging markers in the liver. Finally, real-time quantitative polymerase chain reaction and western-blot were used to detect aging related signaling pathways.

CPE significantly improved the morphological damage and dysfunction of liver, restored the activities of liver enzymes in serum, and alleviated liver oxidative stress and inflammatory response in D-gal induced aging mice. Furthermore, CPE inhibited hepatocyte apoptosis and senescence, and promoted hepatocyte proliferation by regulating BAX/CASP3 and p53/p21/p16 signaling pathways, ultimately reduced the effects of aging on the liver.

CPE effectively ameliorated the impact of aging on the liver by inhibiting free radical production or scavenging excessive free radicals, and its mechanism is associated to the regulation of apoptosis and proliferation-related factors.

Reactive oxygen species (ROS) constitute a spectrum of oxygenic metabolites crucial in modulating pathological organism functions. Disruptions in ROS equilibrium span various diseases, and current insights suggest a dual role for ROS in tumorigenesis and the immune response within cancer. This review rigorously examines ROS production and its role in normal cells, elucidating the subsequent regulatory network in inflammation and cancer. Comprehensive synthesis details the documented impacts of ROS on diverse immune cells. Exploring the intricate relationship between ROS and cancer immunity, we highlight its influence on existing immunotherapies, including immune checkpoint blockade, chimeric antigen receptors, and cancer vaccines. Additionally, we underscore the promising prospects of utilizing ROS and targeting ROS modulators as novel immunotherapeutic interventions for cancer. This review discusses the complex interplay between ROS, inflammation, and tumorigenesis, emphasizing the multifaceted functions of ROS in both physiological and pathological conditions. It also underscores the potential implications of ROS in cancer immunotherapy and suggests future research directions, including the development of targeted therapies and precision oncology approaches. In summary, this review emphasizes the significance of understanding ROS-mediated mechanisms for advancing cancer therapy and developing personalized treatments.

Flap placement remains the primary method for wound repair, but postoperative ischemic flap necrosis is of major concern. This study explored whether rivaroxaban, a factor Xa inhibitor, enhanced flap survival.

Thirty-six rats were randomly divided into control, low-dose rivaroxaban (3 mg/kg/day), and high-dose rivaroxaban (7 mg/kg/day) groups. On postoperative day 7, the flap survival rate was analyzed and the average survival area calculated. After the rats were euthanized, immunological and molecular biological techniques were employed to assess vascular regeneration, pyroptosis, and inflammation.

Rivaroxaban upregulated VEGF expression, in turn enhancing angiogenesis, and it downregulated IL-1β, IL-6, and TNF-α expression, thereby mitigating inflammation. The drug also suppressed TLR4, NF-κB p65, NLRP3, caspase-1, and IL-18 syntheses, thus inhibiting pyroptosis.

Rivaroxaban enhanced random flap survival by down-regulating the TLR4/NF-κB/NLRP3 signaling pathway to suppress pyroptosis, promoting vascular regeneration and inhibiting inflammation.