Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769HK2 vs. ARG 313HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.

Alcoholic pancreatitis is a progressive condition characterized by susceptibility to recurrence, progression to chronic pancreatitis, complications, and high morbidity.

The main causes include long-term alcoholism, excessive drinking, the toxic effects of alcohol metabolites, interactions with biliary diseases, and genetic factors. Alcohol is the second leading cause of acute pancreatitis (AP) in the USA, accounting for one-third of all AP cases. A follow-up study on readmission revealed that the readmission rate of alcoholic acute pancreatitis (AAP) patients within 11 months was 43.1%, of which men dominated the admissions and readmissions of AAP. Among this population, 82.3% have alcohol use disorder, over half have tobacco use disorders, 6.7% have tobacco use disorder, 4.5% have opioid use disorder, and 18.5% of patients exhibit signs of potential alcoholic chronic pancreatitis. Numerous animal and clinical studies suggest that alcohol alone does not cause pancreatitis; rather, additional factors such as smoking, endotoxin lipopolysaccharide (LPS), genetic mutations, or other genetic predispositions - are necessary for the disease's progression.

Given the high rates of admission and readmission for alcoholic pancreatitis, it is essential to further investigate its pathogenesis and pathological processes to develop more effective treatment strategies. Therefore, this paper summarizes the current understanding of the pathogenesis and treatment status of alcoholic pancreatitis, drawing on recently published literature and data to provide insights and references for future research and treatment efforts.

Hepatic fibrosis, a chronic pathological condition resulting from various forms of persistent liver injury, in the later stage, it can evolve into cirrhosis and even liver cancer. Curcumae Rhizoma (CR), traditionally recognized for its properties in line qi break blood, eliminate accumulation and relieve pain. According to traditional Chinese medicine (TCM) principles, vinegar-processing enhances CR's ability to enter the liver meridian and act on the blood level, potentially augmenting its therapeutic effects on hepatic diseases. Therefore, vinegar-processed Curcumae Rhizoma (VCR) is frequently employed in treating liver fibrosis and related hepatic conditions. However, the underlying mechanisms of vinegar processing in enhancing its therapeutic efficacy remain unclear.

The anti-liver fibrosis effects of CR and VCR were verified at individual and cellular levels. Subsequently, HPLC-Q-TOFMS and pharmacokinetic analysis were utilized to elucidate the potential bioactive substances underlying the enhanced anti-fibrotic efficacy of VCR. Building upon these findings, network pharmacology and metabolomics were integrated to screen for key effect components and regulatory pathways. Finally, the mechanisms of action were further analyzed and validated at the tissue and cellular levels through Western blotting (WB) and molecular docking studies.

Both CR and VCR exhibited therapeutic effects against hepatic fibrosis, with VCR demonstrating enhanced efficacy after vinegar processing. 6 sesquiterpenes including furanodiene and curdione, showed significant alterations in plasma exposure and hepatic distribution post-processing. VCR significantly improved pathological liver conditions, lipid accumulation, and fibrosis severity. Additionally, VCR markedly reduced the expression of α-SMA in the liver and attenuated the elevations in liver function markers such as ALT and AST. Combined network pharmacology, metabolomics, and hepatic tissue WB analysis revealed that the reduced phosphorylation of the PI3K/Akt/mTOR pathway is a critical mechanism in VCR's anti-fibrotic effects. Experiments on LX-2 cells demonstrated that four sesquiterpenes, including furanodiene and curdione, effectively inhibited the proliferation of activated hepatic stellate cells (HSCs). Furanodiene, in particular, promoted apoptosis in activated HSCs by reducing phosphorylation levels of the PI3K/Akt/mTOR pathway proteins, increasing BAX expression, and activating downstream caspase-3 to achieve the effect of anti-liver fibrosis.

Vinegar-processing significantly increases the plasma exposure and hepatic distribution of components such as furanodiene in VCR, enhancing anti-fibrotic efficacy by downregulating the phosphorylation levels of the PI3K/Akt/mTOR pathway and promoting HSC apoptosis. This study provides a comprehensive explanation of the vinegar-processing mechanism and its role in enhancing the anti-fibrotic effects of VCR, offering insights for its clinical application in liver fibrosis treatment and reference for the mechanistic study of other vinegar-processed herbal medicines.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption.

Metabolic dysfunction-associated steatosis liver disease (MASLD) is one of the most common metabolic liver diseases around the world, whose prevalence continues to increase. Currently, there are few medications to treat MASLD. Ergothioneine is a natural compound derived from mushrooms whose sulfhydryl groups confer unique antioxidant, anti-inflammatory and detoxifying effects. Currently, research on the therapeutic effects of ergothioneine in MASLD is unknown. Therefore, this study explored the effect and mechanism of EGT in MASLD.

The ameliorative effects and mechanisms of ergothioneine on MASLD were evaluated using HFD mice and PA-treated AML12 cells. Mouse body weight, body fat, IPGTT, IPITT, immunohistochemistry, serum biochemical indices, and staining of liver sections were assayed to verify the protective role of ergothioneine in MASLD. RNA-seq was applied to explore the mechanism of action of ergothioneine. The role of ergothioneine in AML12 was confirmed by western blotting, qPCR, ELISA, Oil Red O staining, flow cytometry, and ROS assays. Subsequently, the 3-methyladenine (3-MA, an autophagy inhibitor) was subsequently used to confirm that ergothioneine alleviated MASLD by promoting autophagy.

Ergothioneine reduced body weight, body fat and blood lipids, and improved insulin resistance and lipid and glycogen deposition in MASLD mice. Furthermore, ergothioneine was found to increase autophagy levels and attenuate oxidative damage, inflammation, and apoptosis. In contrast, intervention with 3-MA abrogated these effects, suggesting that ergothioneine ameliorated effects by promoting autophagy.

Ergothioneine may be a drug with great therapeutic potential for MASLD. Furthermore, this protective effect was mediated through the activation of autophagy.

The health advantages of Ramadan fasting, a time-restricted eating from dawn to dusk, have garnered attention. Nevertheless, prior observational studies have found inconsistent findings because of challenges regulating variables such as sleep patterns, dietary habits, and physical activity. This study sought to investigate the impact of the Ramadan fasting model (RFM) on longevity and metabolic biomarkers in obese and non-obese rats. For 12 weeks, 48 male Wistar albino rats were separated into two groups and fed either a standard or a high-fat diet (HFD). During the final four weeks, rats in each group were separated into four subgroups to investigate the effect of RFM with/without training (on Treadmill) or glucose administration on the biomarkers of interest. The HFD groups subjected to RFM had significantly lower Insulin-like growth factor 1 (IGF-1) and mechanistic target of rapamycin (mTOR) serum, whereas AMPK, anti-inflammatory, and antioxidative stress serum levels were significantly higher. All groups reported decreased serum levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) compared to the HFD control group. Furthermore, the Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) results indicated a significant elevation in the TP53 gene expression in groups subjected to RFM. The data indicate that RFM can improve longevity and metabolic biomarkers and reduce pro-inflammation and oxidative stress. Also, RFM improves anti-inflammatory and antioxidant markers in HFD-induced obese rats.

Previous studies have established that hyperhomocysteinemia (HHcy) significantly contributes to the development of non-alcoholic steatohepatitis (NASH). Conversely, hydrogen sulfide (H2S) has shown potential in mitigating NASH. Despite these findings, it remains uncertain whether H2S can serve as a therapeutic agent against HHcy-induced liver damage.

Mice were fed a high-methionine diet to induce HHcy and HepG2 cells were exposed to homocysteine (Hcy). In both models, we assessed liver injury, H2S concentration, and autophagy levels. For rescue, sodium hydrosulfide (NaHS), an H2S donor, was used to test its potential in reversing hepatic pathological features induced by HHcy.

1) Hcy accumulation led to liver damage and increased autophagy. This was linked to insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 (SGK1) at Cys244 and Cys282, a crucial autophagy regulator. The deficiency in S-sulfhydration was resulted from downregulation of cystathionine-γ-lyase (CSE) and subsequent H2S decrease, leading to SGK1 inactivation. 2) Administration of NaHS reduced the liver damage caused by high Hcy levels and restored H2S levels, promoting the S-sulfhydration and activation of SGK1. 3) Pharmacological inhibition of SGK1 induced autosis, a specific type of cell death caused by overactivation of autophagy. Conversely, a constitutively active mutant of SGK1 (SGK1S422D) significantly decreased autophagy and improved cell viability.

NaHS supplementation mitigates HHcy-induced liver injury by downregulating hepatic autophagy through the S-sulfhydration and activation of SGK1. This post-translational modification by H2S holds promise as a therapeutic approach for HHcy-induced liver injury.

Endoplasmic reticulum stress (ERS) plays an important role in the development of Alcoholic liver injury (ALI), but the exact mechanism needs further exploration. This study aims to investigate the role of ERS-XBP1s in ALI, and providing new target for the treatment of liver injury.

The ALI model was constructed using the NIAAA method and was validated by several methods. ERS was detected using western-blot, RT-qPCR and immunohistochemistry. Apoptosis was measured by TUNEL staining, Hoechst staining, western-blot and Annexin V-FITC. Lysosomal function and autophagy were measured by Lyso-Tracker Green probe, western-blot and immunofluorescence, respectively.

The ALI model was successfully constructed as demonstrated by increased liver steatosis, inflammation and oxidative stress, and higher levels of serum ALT, AST and TG. Alcohol significantly increased the expression of ERS-related molecules, such as PERK, IRE1α, GRP78 and XBP1s, and promoted the nuclear translocation of XBP1s. Moreover, alcohol significantly increased apoptosis and inhibition of XBP1s could reverse this effect in vivo and in vitro. Interestingly, we found that alcohol significantly elevated hepatocyte LC3-II/I levels and concomitantly accumulation of P62, and this phenomenon was reversed by inhibiting XBP1s both in vivo and in vitro. Mechanistically, we found that alcohol activation of ER stress sensor XBP1s which promoted liver injury via inhibiting lysosomal function and autophagy activity in hepatocytes, whereas inhibition of XBP1s reduces hepatocyte apoptosis by restoring lysosomal activity and activating of autophagy.

Alcohol promotes hepatocytes injury via ER stress sensor XBP1s mediated inhibition of autophagy. Therefore, inhibition of XBP1 may protect the liver from alcohol-induced damage.

This study investigates the effects of bariatric surgery on non-alcoholic fatty liver disease (NAFLD) by examining the interplay between gut microbiota, epigenetics, and metabolic health. A cohort of 22 patients undergoing sleeve gastrectomy (SG) was analyzed for changes in gut microbial composition and DNA methylation profiles before and six months after surgery. Correlations between gut microbial abundance and clinical markers at baseline revealed that certain genera were associated with worse metabolic health and liver markers. Following SG, significant improvements were observed in the clinical, anthropometric, and biochemical parameters of the NAFLD patients. Although alpha-diversity indices (i.e., Chao1, Simpson, Shannon) did not show significant changes, beta-diversity analysis revealed a slight shift in microbial composition (PERMANOVA, p = 0.036). Differential abundance analysis identified significant changes in specific bacterial taxa, including an increase in beneficial Lactobacillus species such as Lactobacillus crispatus and Lactobacillus iners and a decrease in harmful taxa like Erysipelotrichia. Additionally, DNA methylation analysis revealed 609 significant differentially methylated CpG sites between the baseline values and six months post-surgery, with notable enrichment in genes related to the autophagy pathway, such as IRS4 and ATG4B. The results highlight the individualized responses to bariatric surgery and underscore the potential for personalized treatment strategies. In conclusion, integrating gut microbiota and epigenetic factors into NAFLD management could enhance treatment outcomes, suggesting that future research should explore microbiome-targeted therapies and long-term follow-ups on liver health post-surgery.

Fibronectin (FN) is an extracellular matrix glycoprotein essential for the development and function of major vertebrate organ systems. Mutations in FN result in an autosomal dominant skeletal dysplasia termed corner fracture-type spondylometaphyseal dysplasia (SMDCF). The precise pathomechanisms through which mutant FN induces impaired skeletal development remain elusive. Here, we have generated patient-derived induced pluripotent stem cells as a cell culture model for SMDCF to investigate the consequences of FN mutations on mesenchymal stem cells (MSCs) and their differentiation into cartilage-producing chondrocytes. In line with our previous data, FN mutations disrupted protein secretion from MSCs, causing a notable increase in intracellular FN and a significant decrease in extracellular FN levels. Analyses of plasma samples from SMDCF patients also showed reduced FN in circulation. FN and endoplasmic reticulum (ER) protein folding chaperones (BIP, HSP47) accumulated in MSCs within ribosome-covered cytosolic vesicles that emerged from the ER. Massive amounts of these vesicles were not cleared from the cytosol, and a smaller subset showed the presence of lysosomal markers. The accumulation of intracellular FN and ER proteins elevated cellular stress markers and altered mitochondrial structure. Bulk RNA sequencing revealed a specific transcriptomic dysregulation of the patient-derived cells relative to controls. Analysis of MSC differentiation into chondrocytes showed impaired mesenchymal condensation, reduced chondrogenic markers, and compromised cell proliferation in mutant cells. Moreover, FN mutant cells exhibited significantly lower transforming growth factor beta-1 (TGFβ1) expression, crucial for mesenchymal condensation. Exogenous FN or TGFβ1 supplementation effectively improved the MSC condensation and promoted chondrogenesis in FN mutant cells. These findings demonstrate the cellular consequences of FN mutations in SMDCF and explain the molecular pathways involved in the associated altered chondrogenesis.

Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis.

Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications.

The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including ACADVL, HYOU1, DAP, AUP1, PRXAB2, LSS, and PLIN2, were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers.

The lipophagy-related genes ACADVL, HYOU1, DAP, AUP1, PRXAB2, LSS, and PLIN2 can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.

The Plasmodium parasites that cause malaria undergo asymptomatic development in the parenchymal cells of the liver, the hepatocytes, prior to infecting erythrocytes and causing clinical disease. Traditionally, hepatocytes have been perceived as passive bystanders that allow hepatotropic pathogens such as Plasmodium to develop relatively unchallenged. However, now there is emerging evidence suggesting that hepatocytes can mount robust cell-autonomous immune responses that target Plasmodium, limiting its progression to the blood and reducing the incidence and severity of clinical malaria. Here we discuss our current understanding of hepatocyte cell-intrinsic immune responses that target Plasmodium and how these pathways impact malaria.

Diabetic liver injury (DLI) is one of the complications of diabetes mellitus, which seriously jeopardizes human health. Punicalagin (PU), a polyphenolic compound mainly found in pomegranate peel, has been shown to ameliorate metabolic diseases such as DLI, and the mechanism needs to be further explored. In this study, a HFD/STZ-induced diabetic mouse model is established to investigate the effect and mechanism of PU on DLI. The results show that PU intervention significantly improves liver histology and serum biochemical abnormalities in diabetic mice, significantly inhibits the expression of pyroptosis-related proteins such as NLRP3, Caspase1, IL-1β, and GSDMD in the liver of diabetic mice, and up-regulated the expression of autophagy-related proteins. Meanwhile, PU treatment significantly increases FoxO1 protein expression and inhibits TXNIP protein expression in the liver of diabetic mice. The above results are further verified in the HepG2 cell injury model induced by high glucose. AS1842856 is a FoxO1 specific inhibitor. The intervention of AS1842856 combined with PU reverses the regulatory effects of PU on pyroptosis and autophagy in HepG2 cells. In conclusion, this study demonstrates that PU may inhibit pyroptosis and upregulate autophagy by regulating FoxO1/TXNIP signaling, thereby alleviating DLI.

This study was conducted to elucidate the critical molecular pathways underlying the protective effects of remifentanil against hepatic ischemia-reperfusion injury in rats. Our approach integrated network pharmacology analysis with high-throughput sequencing to achieve a comprehensive understanding of the mechanisms involved.

The study utilized GSE24430 gene expression data from GEO to investigate remifentanil's impact on Hepatic Ischemia-Reperfusion Injury in rats. Weighted Correlation Network Analysis (WGCNA) was employed to pinpoint crucial genes and identify modules of co-expressed genes. Differential analysis with the "Limma" package revealed genes differentially expressed in IRI vs. control groups. PubChem and PharmMapper provided target genes affected by remifentanil. Protein-protein interaction networks were constructed via GeneCards and STRING. Functional analysis pinpointed core genes involved in remifentanil's IRI alleviation. IRI rat models were established, and hepatic injury indicators, liver structure via H&E staining, autophagosome counts via electron microscopy, and gene/protein expression via RT-qPCR and Western blot were assessed. High-throughput sequencing analyzed molecular pathways affected by varying remifentanil doses in IRI rats.

In the study, we discovered four primary co-expression modules associated with hepatic IRI, and the grey module exhibited the highest correlation with hepatic IRI.A total of sixty-eight genes that were differentially expressed were found to have a connection with hepatic IRI.Network pharmacology analysis found that remifentanil may alleviate hepatic IRI through Fmol.found that the Fmol/Parkin signaling pathway may alleviate hepatic IRI via Additionally, the database autophagy. The established hepatic IRI rat models further confirmed the above findings.

Our study established that remifentanil triggers the Fmol/Parkin signaling cascade, amplifying the expression levels of Fmol and Parkin. This process culminates in the activation of autophagy within hepatic cells, ultimately alleviating hepatic ischemia-reperfusion injury (IRI).

Myelodysplastic syndromes (MDS) encompass a collection of clonal hematopoietic malignancies distinguished by the depletion of peripheral blood cells. The treatment of MDS is hindered by the advanced age of patients, with a restricted repertoire of drugs currently accessible for therapeutic intervention. In this study, we found that ES-Cu strongly inhibited the viability of MDS cell lines and activated cuproptosis in a copper-dependent manner. Importantly, ferroptosis inducer IKE synergistically enhanced ES-Cu-mediated cytotoxicity both in vitro and in vivo. Of note, the combination of IKE and ES-Cu intensively impaired mitochondrial homeostasis with increased mitochondrial ROS, MMP hyperpolarized, down-regulated iron-sulfur proteins and declined oxygen consumption rate. Additionally, ES-Cu/IKE treatment could enhance the lipoylation-dependent oligomerization of the DLAT. To elucidate the specific order of events in the synergistic cell death, inhibitors of ferroptosis and cuproptosis were utilized to further characterize the basis of cell death. Cell viability assays showed that the glutathione and its precursor N-acetylcysteine could significantly rescue the cell death under either mono or combination treatment, demonstrating that GSH acts at the crossing point in the regulation network of cuproptosis and ferroptosis. Significantly, the reconstitution of xCT expression and knockdown of FDX1 cells have been found to contribute to the tolerance of mono treatment but have little recovery impact on the combined treatment. Collectively, these findings suggest that a synergistic interaction leading to the induction of multiple programmed cell death pathways could be a promising approach to enhance the effectiveness of therapy for MDS.

Exposure to the organophosphate esters (OPEs), used as flame retardants and plasticizers, is associated with a variety of adverse health effects including an increase in the incidence of fatty liver diseases. The goal of this study was to investigate the effects of six OPEs, all detected in Canadian house dust, on the phenotype and function of HepG2 liver cells. We used high-content imaging to investigate the effects of these OPEs on cell survival, mitochondria, oxidative stress, lipid droplets, and lysosomes. Effects on the autophagy/lipophagy pathway were evaluated using confocal microscopy. The triaryl OPEs (isopropylated triphenylphosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) were more cytotoxic than non-triaryl OPEs (tris(2-butoxyethyl) phosphate [TBOEP], tris(1-chloro-2-propyl) phosphate [TCIPP], and tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]). Exposure to most OPEs increased total mitochondria, reduced reactive oxygen species, and increased total lipid droplet areas and lysosomal intensity. Potency ranking was done using the lowest benchmark concentration/administered equivalent dose method and toxicological prioritization index analyses to integrate all phenotypic endpoints. IPPP, TBOEP, and TPHP ranked as the most potent OPEs, whereas TMPP, TCIPP, and TDCIPP were relatively less bioactive. Confocal microscopic analysis demonstrated that IPPP reduced the colocalization of lipid droplets (PLIN2), lysosomes (LAMP1), and autophagosomes (p62), disrupting autophagy. In contrast, TBOEP rescued cells from bafilomycin A1-induced inhibition of autophagy and/or increased autophagic flux. Together, these data demonstrate that OPEs have adverse effects on HepG2 cells. Further, OPE-induced dysregulation of autophagy may contribute to the association between OPE exposure and adverse effects on liver lipid homeostasis.

An extensive body of research has explored the role of autophagy in hepatocellular carcinoma (HCC), revealing its critical involvement in the disease's pathogenesis, progression, and therapeutic targeting. However, there is a discernible deficit in quantitative, analytical studies concerning autophagy in the context of HCC. Accordingly, this investigation endeavored to meticulously assess the evolution of autophagy research, employing bibliometric citation analysis to offer a comprehensive evaluation of the findings in this field.

The authors conducted a literature search on 2 August 2023, to extract relevant publications spanning from 2013 to 2022, indexed in the Science Citation Index-Expanded (SCIE) of the Web of Science Core Collection (WOSCC). Subsequently, the authors performed a bibliometric assessment of the compiled documents using visualization tools such as CiteSpace and VOSviewer.

The search yielded 734 publications penned by 4699 authors, encompassing contributions from 41 countries and 909 institutions, disseminated across 272 journals, and comprising 26 295 co-cited references from 2667 journals. Notably, China led in publication volume with 264 articles (amounting to 35.9%) and exhibited the most robust collaboration with the United States. The mechanisms underlying autophagy's influence on the emergence and advancement of HCC, as well as the implicated proteins and genes, have garnered significant attention. In recent years, investigations of targeting autophagy and the resistance to sorafenib have surfaced as pivotal themes and emerging frontiers in this domain.

This study rigorously collated and distilled the prevailing research narratives and novel insights on autophagy in HCC. The resultant synthesis provides a substantive foundation for medical professionals and researchers, as well as pivotal implications for future investigative endeavors in this arena.

Autophagy plays a critical role in maintaining cellular homeostasis and responding to various stress conditions by the degradation of intracellular components. In this narrative review, we provide a comprehensive overview of autophagy's cellular and molecular basis, biological significance, pharmacological modulation, and its relevance in lifestyle medicine. We delve into the intricate molecular mechanisms that govern autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy. Moreover, we highlight the biological significance of autophagy in aging, immunity, metabolism, apoptosis, tissue differentiation and systemic diseases, such as neurodegenerative or cardiovascular diseases and cancer. We also discuss the latest advancements in pharmacological modulation of autophagy and their potential implications in clinical settings. Finally, we explore the intimate connection between lifestyle factors and autophagy, emphasizing how nutrition, exercise, sleep patterns and environmental factors can significantly impact the autophagic process. The integration of lifestyle medicine into autophagy research opens new avenues for promoting health and longevity through personalized interventions.

Currently, it is acknowledged that vitamin E, insulin sensitizers and anti-diabetic drugs are used to manage non-alcoholic fatty liver disease (NAFLD), however, these therapeutic interventions harbour adverse side effects. Pioglitazone, an anti-diabetic drug, is currently the most effective therapy to manage NAFLD. The use of natural medicines is widely embraced due to the lack of evidence of their negative side effects. Rooibos has been previously shown to decrease inflammation and oxidative stress in experimental models of diabetes, however, this is yet to be explored in a setting of NAFLD. This study was aimed at investigating the effects of an aspalathin-rich green rooibos extract (Afriplex GRTTM) against markers of hepatic oxidative stress, inflammation and apoptosis in an in vitro model of NAFLD.

Oleic acid [1 mM] was used to induce hepatic steatosis in C3A liver cells. Thereafter, the therapeutic effect of Afriplex GRTTM, with or without pioglitazone, was determined by assessing its impact on cell viability, changes in mitochondrial membrane potential, intracellular lipid accumulation and the expression of genes and proteins (ChREBP, SREBF1, FASN, IRS1, SOD2, Caspase-3, GSTZ1, IRS1 and TNF-α) that are associated with the development of NAFLD.

Key findings showed that Afriplex GRTTM added to the medium alone or combined with pioglitazone, could effectively block hepatic lipid accumulation without inducing cytotoxicity in C3A liver cells exposed oleic acid. This positive outcome was consistent with effective regulation of genes involved in insulin signaling, as well as carbohydrate and lipid metabolism (IRS1, SREBF1 and ChREBP). Interestingly, in addition to reducing protein levels of an inflammatory marker (TNF-α), the Afriplex GRTTM could ameliorate oleic acid-induced hepatic steatotic damage by decreasing the protein expression of oxidative stress and apoptosis related markers such as GSTZ1 and caspase-3.

Afriplex GRTTM reduced hepatic steatosis in oleic acid induced C3A liver cells by modulating SREBF1, ChREBP and IRS-1 gene expression. The extract may also play a role in alleviating inflammation by reducing TNF-α expression, suggesting that additional experiments are required for its development as a suitable therapeutic option against NAFLD. Importantly, further research is needed to explore its antioxidant role in this model.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month old) and aged (23-month old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. To better assess the impact of chronic alcohol exposure, we fed young and aged mice alcohol for four weeks before completing Morris Water and Barnes Maze spatial memory testing. The aged mice showed worse spatial memory on both tests. While alcohol feeding slightly impaired spatial memory in the young mice, it had little effect or even slightly improved spatial memory in the aged mice. These findings suggest that aging is a far more important driver of spatial memory impairment and reduced autophagy flux than alcohol consumption.

This study aims to identify the periodontitis factor that activates excessive autophagy in pancreatic β cells, resulting in organic lesions of pancreatic islet tissues and diminished insulin secretion, thereby accelerating the progression of diabetes mellitus (DM).

Sprague-Dawley (SD) rats were induced with periodontitis (PD), type 2 diabetes mellitus (T2DM), or the combination of T2DM and PD (DP) through a high-sugar/high-fat diet and ligation of the tooth neck with silk thread. Alveolar bone resorption was assessed using Micro-CT, blood glucose levels were measured with a blood glucose meter, pancreatic tissue pathology was examined through HE staining, and the expression of autophagy-related proteins Beclin1 and LC3II/LC3I was analyzed using Western blotting.

Micro-CT results revealed more pronounced alveolar bone resorption and root bifurcation exposure in the PD and DP groups compared to the control group, with the DP group exhibiting the most severe condition. HE staining demonstrated the formation of periodontal pockets, severe alveolar bone destruction, and abnormal pancreatic islet tissue morphology in the PD and DP groups. The serum levels of IL-6, TNF-α, and IL-1β increased sequentially in the control, DM, PD, and DP groups (P < 0.05). Relative expressions of GCK and GLUT-2 mRNA decreased in the PD group compared to the control group (P > 0.05), while the mRNA expressions in the DP and DM groups increased (P < 0.05), with the DP group exhibiting higher levels than the DM group (P < 0.05). Western blot results indicated increased expression levels of autophagy proteins Beclin1 and LC3II/LC3I in the DM and DP groups compared to the control group (P < 0.05), with the DP group exhibiting higher levels than the DM group (P < 0.05).

The findings demonstrate that periodontal inflammatory factors may promote the enhancement of pancreatic cell autophagy in diabetic rats.

Hypoxia and its induced autophagy are involved in the initiation and progression of liver fibrosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a potential regulator of autophagy. Our previously reported study found that PCSK9 expression increased in liver fibrosis and that anti-PCSK9 treatment alleviated liver injury. This study aimed to investigate the mechanism of anti-PCSK9 treatment on liver fibrosis by inhibiting hypoxia-induced autophagy. Carbon tetrachloride-induced mouse liver fibrosis and mouse hepatocyte line AML12, cultured under the hypoxic condition, were established to undergo PCSK9 inhibition. The degree of liver fibrosis was shown with histological staining. The reactive oxygen species (ROS) generation was detected by flow cytometry. The expression of PCSK9, hypoxia-inducible factor-1α (HIF-1α), and autophagy-related proteins was examined using Western blot. The autophagic flux was assessed under immunofluorescence and transmission electron microscope. The mouse liver samples were investigated via RNA-sequencing to explore the underlying signaling pathway. The results showed that PCSK9 expression was upregulated with the development of liver fibrosis, which was accompanied by enhanced autophagy. In vitro data verified that PCSK9 increased via hypoxia and inflammation, accompanied by the hypoxia-induced autophagy increased. Then, the validation was acquired of the bidirectional interaction of hypoxia-ROS and PCSK9. The hypoxia reversal attenuated PCSK9 expression and autophagy. Additionally, anti-PCSK9 treatment alleviated liver inflammation and fibrosis, reducing hypoxia and autophagy in vivo. In mechanism, the AMPK/mTOR/ULK1 signaling pathway was identified as a target for anti-PCSK9 therapy. In conclusion, anti-PCSK9 treatment could alleviate liver inflammation and fibrosis by regulating AMPK/mTOR/ULK1 signaling pathway to reduce hypoxia-induced autophagy in hepatocytes.

Studies have found that intermittent fasting (IF) can prevent diabetes, cancer, heart disease, and neuropathy, while in humans it has helped to alleviate metabolic syndrome, asthma, rheumatoid arthritis, Alzheimer's disease, and many other disorders. IF involves a series of coordinated metabolic and hormonal changes to maintain the organism's metabolic balance and cellular homeostasis. More importantly, IF can activate hepatic autophagy, which is important for maintaining cellular homeostasis and energy balance, quality control, cell and tissue remodeling, and defense against extracellular damage and pathogens. IF affects hepatic autophagy through multiple interacting pathways and molecular mechanisms, including adenosine monophosphate (AMP)-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), silent mating-type information regulatory 2 homolog-1 (SIRT1), peroxisomal proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR), as well as signaling pathways and molecular mechanisms such as glucagon and fibroblast growth factor 21 (FGF21). These pathways can stimulate the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), play a cytoprotective role, downregulate the expression of aging-related molecules, and prevent the development of steatosis-associated liver tumors. By influencing the metabolism of energy and oxygen radicals as well as cellular stress response systems, IF protects hepatocytes from genetic and environmental factors. By activating hepatic autophagy, IF has a potential role in treating a variety of liver diseases, including non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis, hepatic fibrosis, and hepatocellular carcinoma. A better understanding of the effects of IF on liver autophagy may lead to new approaches for the prevention and treatment of liver disease.

Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5' splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.

Preeclampsia (PE) is usually associated with the accumulation of reactive oxygen species (ROS) resulting from heightened oxidative stress (OS). Ferroptosis is a unique type of lipid peroxidation-induced iron-dependent cell death distinct from traditional apoptosis, necroptosis, and pyroptosis and most likely contributes considerable to PE pathogenesis. At approximately 10-12 weeks of gestation, trophoblasts create an environment rich in oxygen and iron. In patients with PE, ferroptosis-related genes such as HIF1 and MAPK8 are downregulated, whereas PLIN2 is upregulated. Furthermore, miR-30b-5p overexpression inhibits solute carrier family 11 member 2, resulting in a decrease in glutathione levels and an increase in the labile iron pool. At the maternal-fetal interface, physiological hypoxia/reperfusion and excessive iron result in lipid peroxidation and ROS production. Owing to the high expression of Fpn and polyunsaturated fatty acid-containing phospholipid-related enzymes, including acyl-CoA synthetase long-chain family member 4, lysophosphatidylcholine acyl-transferase 3, and spermidine/spermine N1-acetyltransferase 1, trophoblasts become more susceptible to OS and ROS damage. In stage 1, the injured trophoblasts exhibit poor invasion and incomplete uterine spiral artery remodeling caused by ferroptosis, leading to placental ischemia and hypoxia. Subsequently, ferroptosis marked by OS occurs in stage 2, eventually causing PE. We aimed to explore the new therapeutic target of PE through OS in ferroptosis.

Per- and polyfluoroalkyl substances (PFAS) are man-made long-lasting chemical compounds that are found in everyday household items. Today they occur in the environment as a major group of pollutants. These compounds are broadly used in commercial product preparation such as, for food packaging, nonstick coatings, and firefighting foam. In humans, PFAS can cause immune disorders, impaired fetal development, abnormal skeletal tissue development, osteoarthritis, thyroid dysfunctions, cholesterol changes, affect insulin regulation and lipid metabolism, and are also involved in the development of fatty liver disease. In the current study, we investigated the effect of low, but physiologically relevant, concentrations of perfluorooctanoic acid (PFOA), heptafluorobutyric acid (HFBA), and perfluorotetradecanoic acid (PFTA) on gene expression markers of an inflammatory response (tnfa, il-1b, il-6, rplp0, edem1, and dnajc3a), unfolded protein response (UPR) (bip, atf4a, atf6, xbp1, and ddit3), senescence (p21, pai1, smp30, mdm2, and baxa), lipogenesis (scd1, acc, srebp1, pparγ, and fasn) and autophagy (p62, atg3, atg7, rab7, lc3b, and becn1) in AB wild-type (+/+), spns1-wt sibling (+/+), (+/-) and spns1 homozygous mutant (-/-) zebrafish embryos. Exposure to PFOA and HFBA (50 and 100 nM) specifically modulated inflammatory, UPR, senescence, lipogenic, and autophagy signaling in spns1-wt (+/+), (+/-), and spns1-mutant (-/-) zebrafish embryos. Furthermore, PFOA, but not HFBA, upregulated lipogenic-related gene expression and enhanced hepatic steatosis in spns1-wt (+/+), (+/-) zebrafish embryos. Combined exposure to PFOA, HFBA, and PFTA differentially expressed inflammatory, senescence, lipogenic, and autophagy-associated gene expression in spns1-mutant (-/-) zebrafish embryos compared with spns1-wt (+/+), (+/-) and AB-wt (+/+) zebrafish embryos. In addition, chronic exposure (∼2 months) to PFOA (120-600 nM) upregulated the expression of hepatic lipogenic and steatosis biomarkers in AB-wt (+/+) zebrafish. Collectively, our data suggest that acute/chronic physiologically relevant concentrations of PFOA upregulate inflammatory, UPR, senescence, and lipogenic signaling in spns1-wt (+/+), (+/-) and spns1-mutant (-/-) zebrafish embryos as well as in two-month-old AB-wt zebrafish, by targeting autophagy and hence induces toxicity that could promote nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that is associated with the accumulation of triglycerides (TG) in hepatocytes. Resveratrol (RSV), as a natural product, and metformin have been reported to have potential lipid-lowering effects for the treatment of NAFLD via autophagy, but the combined effects of both have not yet been studied. The current study aimed to investigate the role of autophagy in the lipid-lowering effects of RSV, alone and in combination with metformin, on the hepatic steatosis model of HepG2 cells and elucidate the mechanism of action. Triglyceride measurement and real-time PCR showed that RSV-metformin reduced lipid accumulation and the expression of lipogenic genes in palmitic acid (PA)-induced HepG2 cells. Additionally, the LDH release assay indicated that this combination protected HepG2 cells against PA-induced cell death through autophagy. The western blotting analysis revealed that RSV-metformin induced autophagy by reducing the expression of p62 and increasing LC3-I and LC3-II proteins. This combination also enhanced cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels in HepG2 cells. Furthermore, SIRT1 inhibitor treatment inhibited autophagy induced by RSV-metformin, which indicated the autophagy induction is SIRT1-dependent. This study demonstrated for the first time that RSV-metformin reduced hepatic steatosis by triggering autophagy via the cAMP/AMPK/SIRT1 signaling pathway.

The treatment of depression with pharmaceuticals is associated with many adverse side effects, including male fertility problems. The precise mechanisms by which these agents affect testicular cells remain largely unknown, but they are believed to induce cellular stress, which is sensed by the endoplasmic reticulum (ER) and the Golgi apparatus. These organelles are responsible for maintaining cellular homeostasis and regulating signal pathways that lead to autophagy or apoptosis. Therefore, in this study, we aimed to investigate the autophagy, ER, and Golgi stress-related pathways in mouse testis following treatment with antidepressant-like substances (ALS) and ALS combined with lipopolysaccharide (LPS). We found that most ALS and activated proteins are associated with the induction of apoptosis. However, when imipramine (IMI) was combined with NS-398 (a cyclooxygenase-2 inhibitor) after LPS administration, we observed a marked increase in the BECLIN1, Bcl-2, ATG16L, and LC3 expression, which are marker proteins of autophagosome formation. The expression of the BECN1 and ATG16L genes was also high compared to the control, indicating the induction of autophagy processes that may potentially protect mouse testicular cells from death and regulate metabolism in the testis. Our findings may provide a better understanding of the stress-related effects of specific ALS on the testis. Video Abstract.

Liver fibrosis is characterized by the excessive deposition and accumulation of extracellular matrix components, mainly collagens, and occurs in response to a broad spectrum of triggers with different etiologies. Under stress conditions, autophagy serves as a highly conserved homeostatic system for cell survival and is importantly involved in various biological processes. Transforming growth factor-β1 (TGF-β1) has emerged as a central cytokine in hepatic stellate cell (HSC) activation and is the main mediator of liver fibrosis. A growing body of evidence from preclinical and clinical studies suggests that TGF-β1 regulates autophagy, a process that affects various essential (patho)physiological aspects related to liver fibrosis. This review comprehensively highlights recent advances in our understanding of cellular and molecular mechanisms of autophagy, its regulation by TGF-β, and the implication of autophagy in the pathogenesis of progressive liver disorders. Moreover, we evaluated crosstalk between autophagy and TGF-β1 signalling and discussed whether simultaneous inhibition of these pathways could represent a novel approach to improve the efficacy of anti-fibrotic therapy in the treatment of liver fibrosis.

Patients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation.

We report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 μmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy.

No serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 μmol per liter. The patients who received the higher dose had bilirubin levels below 300 μmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 μmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 μmol per liter).

No serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

The objective of our study was to assess the effect of rumen-protected niacin supplementation on the transcriptome of liver tissue in growing Angus × Simmental steers and heifers through RNA-seq analysis. Consequently, we wanted to assess the known role of niacin in the physiological processes of vasodilation, detoxification, and immune function in beef hepatic tissue. Normal weaned calves (~8 months old) were provided either a control diet or a diet supplemented with rumen-protected niacin (6 g/hd/d) for a 30-day period, followed by a liver biopsy. We observed a significant list of changes at the transcriptome level due to rumen-protected niacin supplementation. Several metabolic pathways revealed potential positive effects to the animal's liver metabolism due to administration of rumen-protected niacin; for example, a decrease in lipolysis, apoptosis, inflammatory responses, atherosclerosis, oxidative stress, fibrosis, and vasodilation-related pathways. Therefore, results from our study showed that the liver transcriptional machinery switched several metabolic pathways to a condition that could potentially benefit the health status of animals supplemented with rumen-protected niacin. In conclusion, based on the results of our study, we can suggest the utilization of rumen-protected niacin supplementation as a nutritional strategy could improve the health status of growing beef cattle in different beef production stages, such as backgrounding operations or new arrivals to a feedlot.

Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing.

Liver cell death represents a basic biological process regulating the progression of liver diseases via distinct mechanisms. Accumulating evidence has uncovered participation of interleukin (IL)-1 family cytokines in liver cell death. Upon activation of cell death induced by hepatotoxic stimuli, IL1 family cytokines released by hepatic dead cells stimulate recruitment of immune cells, which in turn influence inflammation and subsequent liver injury, thus highlighting their potential as therapeutic targets in liver diseases. Enhancing our comprehension of mechanisms underlying IL1 family cytokine signaling in cell death responses could pave the way for novel therapeutic interventions aimed at addressing liver cell death-related liver pathologies.

This review summarizes the recent findings reported in preclinical and clinical studies on mechanisms of liver cell death, alongside participation of IL1 family members consisting of IL1α, ILβ, IL18, and IL33 in liver cell death and their significant implications in liver diseases.

Discovery of new and innovative therapeutic approaches for liver diseases will need close cooperation between fundamental and clinical scientists to better understand the multi-step processes behind IL1 family cytokines' contributions to liver cell death.

Hepatic ischemia-reperfusion injury is a phenomenon in which exacerbating damage of liver cells due to restoration of blood flow following ischemia during liver surgery, especially those involving liver transplantation. Mitochondria, the energy-producing organelles, are crucial for cell survival and apoptosis and have evolved a range of quality control mechanisms to maintain homeostasis in the mitochondrial network in response to various stress conditions. Hepatic ischemia-reperfusion leads to disruption of mitochondrial quality control mechanisms, as evidenced by reduced mitochondrial autophagy, excessive division, reduced fusion, and inhibition of biogenesis. This leads to dysfunction of the mitochondrial network. The accumulation of damaged mitochondria ultimately results in apoptosis of hepatocytes due to the release of apoptotic proteins like cytochrome C. This worsens hepatic ischemia-reperfusion injury. Currently, hepatic ischemia-reperfusion injury protection is being studied using different approaches such as drug pretreatment, stem cells and exosomes, genetic interventions, and mechanical reperfusion, all aimed at targeting mitochondrial quality control mechanisms. This paper aims to provide direction for future research on combating HIRI by reviewing the latest studies that focus on targeting mitochondrial quality control mechanisms.

Alzheimer's disease (AD) is the most common form of progressive dementia and there is no truly efficacious treatment. Accumulating evidence indicates that impaired autophagic function for removal of damaged mitochondria and protein aggregates such as amyloid and tau protein aggregates may contribute to the pathogenesis of AD. Epidemiologic studies have implicated alcohol abuse in promoting AD, yet the underlying mechanisms are poorly understood. In this review, we discuss mechanisms of selective autophagy for mitochondria and protein aggregates and how these mechanisms are impaired by aging and alcohol consumption. We also discuss potential genetic and pharmacological approaches for targeting autophagy/mitophagy, as well as lysosomal and mitochondrial biogenesis, for the potential prevention and treatment of AD.

Maternal obesity is the key predictor for childhood obesity and neurodevelopmental delay in the offspring. Medicinal plants are considered to be the safe and best option, and at the same time, probiotic consumption during pregnancy provides beneficial effects for both the mother and the child. Current research has shown that Elateriospermum tapos (E. tapos) yoghurt is safe to consume and consists of many bioactive compounds that can exert an anti-obesity effect. Thus, this study has been designed to study the role of E. tapos yoghurt in mitigating maternal obesity. In this study, a total of 48 female Sprague Dawley (SD) rats were assigned to six groups, with eight rats per group, and obesity was induced over 16 weeks with a high-fat diet (HFD) pellet. On the 17th week, the rats were allowed to mate and pregnancy was confirmed through vaginal smear. The obese induced group was further divided into negative and positive control groups, followed by E. tapos yoghurt treatment groups with three different concentrations (5, 50, and 500 mg/kg). The changes in body weight, calorie intake, lipid profile, liver profile, renal profile, and histopathological analysis were measured on postnatal day (PND) 21. The results show that the group with the highest concentration of E. tapos yoghurt (HYT500) supplementation shows gradual reduction in body weight and calorie intake on PND 21 and modulates the lipid level, liver, and renal enzymes to a normal level similar to the normal group. In histological analysis, HYT500 reverses the damage caused by HFD in liver and colon, and reverses the adipocytes' hypertrophy in retroperitoneal white adipose tissue and visceral fat. In conclusion, supplementation of E. tapos yoghurt during the gestational period up to weaning is effective in the gradual weight loss of maternal obese dams from the 500-mg/kg-supplemented group in this study.