Hepatic Cells Research Articles

Pathological Microenvironment-Remodeling Nanoparticles to Alleviate Liver Fibrosis: Reversing Hepatocytes-Hepatic Stellate Cells Malignant Crosstalk.

During the onset and malignant development of liver fibrosis, the pernicious interplay between damaged hepatocytes and activated hepatic stellate cells (HSCs) induce a self-perpetuating vicious cycle, deteriorating fibrosis progression and posing a grave threat to public health. The secretions released by damaged hepatocytes and activated HSCs interact through autocrine or paracrine mechanisms, involving multiple signaling pathways. This interaction creates a harsh microenvironment and weakens the therapeutic efficacy of single-cell-centric drugs. Herein, a malignant crosstalk-blocking strategy is prompted to remodel vicious cellular interplay and reverse pathological microenvironment to put an end to liver fibrosis. Collagenases modified, bardoxolone and siTGF-β co-delivered nanoparticles (C-NPs/BT) are designed to penetrate the deposited collagen barriers and further regulate the cellular interactions through upregulating anti-oxidative stress capacity and eliminating the pro-fibrogenic effects of TGF-β. The C-NPs/BT shows successful remodeling of vicious cellular crosstalk and significant disease regression in animal models. This study presents an innovative strategy to modulate cellular interactions for enhanced anti-fibrotic therapy and suggests a promising approach for treating other chronic liver diseases.

Modulation of Notch signaling pathway in activated hepatic stellate cells does not ameliorate the outcome of liver fibrosis in carbon tetrachloride and DDC-feeding models

BackgroundRecent research suggests a possible role of Notch signaling pathway in development of liver fibrosis, but exact cellular and molecular mechanisms are still not well defined. Methods: We modulated Notch signaling in activated hepatic stellate cells/myofibroblasts using the model of inducible activation or inhibition of Notch signaling selective for αSMA positive cells in murine models of toxic fibrosis induced by CCl4 and cholestatic fibrosis induced by DDC supplemented feeding.ResultsOur results confirm that Notch signaling pathway is activated in both CCL4 and DDC model of liver fibrosis and that αSMA positive myofibroblasts are of activated hepatic stellate cells origin. However, neither the inhibition of canonical Notch signaling (in tamoxifen treated αSMACreER/RBP-Jfl/fl mice) nor its overactivation (in tamoxifen treated αSMACreER/NICD1 mice) changed the degree of liver fibrosis in comparison to the control groups in either of the investigated models. Furthermore, after the withdrawal of the fibrogenic treatment the degree of resolution of fibrosis was similar between the animals with Notch overactivation and controls. In addition to genetic manipulation, we investigated the effect of antibodies against NOTCH1 and NOTCH2 on the development of liver fibrosis. Treatment with antibodies had effects on thymus and spleen respectively, but failed to ameliorate liver fibrosis. In conclusion, our data demonstrate that modulation of Notch activity in activated HSC is not sufficient to change the outcome of liver fibrosis. The results obtained with inhibitory antibodies further demonstrate limitations of targeting Notch 1 and 2 receptors as antifibrotic therapy. Notch pathway remains a potential target for the treatment of liver fibrosis, but future studies should be directed to Notch 3 signaling and/or targeting different populations of cells.

E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.

Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid-specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu-mTORC1-dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5- Leu-mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.

Massive simultaneous hepatic and renal perivascular epithelioid cell tumor benefitted from surgery and everolimus treatment: A case report

Massive simultaneous hepatic and renal perivascular epithelioid cell tumor benefitted from surgery and everolimus treatment: A case report

Oxidative Stress Associated With Increased Reactive Nitrogen Species Generation in the Liver and Kidney Caused by a Major Metabolite Accumulating in Tyrosinemia Type 1.

Tyrosinemia type 1 (TT1) is caused by fumarylacetoacetate hydrolase activity deficiency, resulting in tissue accumulation of upstream metabolites, including succinylacetone (SA), the pathognomonic compound of this disease. Since the pathogenesis of liver and kidney damage observed in the TT1-affected patients is practically unknown, this study assessed the effects of SA on important biomarkers of redox homeostasis in the liver and kidney of adolescent rats, as well as in hepatic (HepG2) and renal (HEK-293) cultured cells. SA significantly increased nitrate and nitrite levels and decreased the concentrations of reduced glutathione (GSH) in the liver and kidney, indicating induction of reactive nitrogen species (RNS) generation and disruption of antioxidant defenses. Additionally, SA decreased the GSH levels and the activities of glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in hepatic and renal cells. Noteworthy, melatonin prevented the SA-induced increase of nitrate and nitrite levels in the liver. Therefore, SA-induced increase of RNS generation and impairment of enzymatic and nonenzymatic antioxidant defenses may contribute to hepatopathy and renal disease in TT1.

Hepatic Stellate Cell-mediated Increase in CCL5 Chemokine Expression after X-ray Irradiation Determined In Vitro and In Vivo.

Radiation exposure causes hepatitis which induces hepatic steatosis and fibrosis. Although hepatic stellate cells (HSCs) have been considered potential pathological modulators for the development of hepatitis due to viral and microbial infections, their involvement in radiation-induced hepatitis is yet to be determined. This study aimed to clarify the relationship between radiation exposure and expressions of inflammatory cytokines and chemokines in HSCs in vitro and invivo. HSCs were obtained from 1-week-old mice, known to be highly sensitive to radiation-induced hepatocellular carcinoma, using a newly established method combining liver perfusion, cell dissociation, and density gradient centrifugation, followed by magnetic negative selection of hematopoietic and endothelial cells with anti-CD45.2 and CD146 antibodies. The isolated HSCs were confirmed by the expression of desmin and glial fibrillary acidic protein (GFAP). We demonstrated that primary cultured HSCs, exposed to X-ray irradiation (0, 1.9, and 3.8 Gy) and cultured for 3 and 7 days, produced elevated levels of C-C motif chemokine ligand 5 (CCL5, also known as RANTES) inflammatory chemokine in a dose-dependent manner. An invivo immunofluorescence method confirmed that increased CCL5 signals were observed in GFAP-positive HSCs in mouse livers 7 days after whole-body X-ray irradiation (1.9 and 3.8 Gy). Adequate expression of C-C motif chemokine receptor 5 (Ccr5), a receptor for CCL5, was also detected using real-time PCR in the liver of both irradiated and non-irradiated mice. Taken together, our data suggest that HSCs may drive hepatitis via CCL5/CCR5 axis in the liver under radiation-induced stress. Furthermore, this newly established experimental protocol can help evaluate the expression of other inflammatory cytokines in primary cultures of HSCs isolated from infant mice.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health.

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

The NIPBL-gene mutation of a Cornelia de Lange Syndrome patient causes deficits in the hepatocyte differentiation of induced Pluripotent Stem Cells via altered chromatin-accessibility

The Cornelia de Lange syndrome (CdLS) is a rare genetic disease, which is characterized by a cohesinopathy. Mutations of the NIPBL gene are observed in 65% of CdLS patients. A novel iPSC (induced Pluripotent Stem Cell) line was reprogrammed from the leukocytes of a CdLS patient carrying a missense mutation of the NIPBL gene. A mutation-corrected isogenic iPSC-line and two iPSC-lines generated from the healthy parents were used as controls. The iPSC lines were differentiated along the hepatocyte-lineage. Comparative immunofluorescence, RNA-seq and ATAC-seq analyses were performed on undifferentiated and differentiated iPSCs. In addition, chromatin organization was studied by ChIP-Seq analysis on the patient derived iPSCs as well as the respective controls. Relative to the mutation-corrected and the healthy-parents iPSCs, the patient-derived counterparts are defective in terms of differentiation along the hepatocyte-lineage. One-third of the genes selectively up-regulated in CdLS-derived iPSCs and hepatic cells are non-protein-coding genes. By converse, most of the selectively down-regulated genes code for transcription factors and proteins regulating neural differentiation. Some of the transcriptionally silenced loci, such as the DPP6 gene on chromosome 7q36.2 and the ZNF gene cluster on chromosome 19p12, are located in closed-chromatin regions. Relative to the corresponding controls, the global transcriptomic differences observed in CdLS undifferentiated iPSCs are associated with altered chromatin accessibility, which was confirmed by ChIP-Seq analysis. Thus, the deficits in the differentiation along the hepatocyte lineage observed in our CdLS patient is likely to be due to a transcriptional dysregulation resulting from a cohesin-dependent alteration of chromatin accessibility.

Nucleos(t)ide analogues potentially activate T lymphocytes through inducing interferon expression in hepatic cells and patients with chronic hepatitis B

Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8+ T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury.

Hepatic stellate cell-targeted chemo-gene therapy for liver fibrosis using fluorinated peptide-lipid hybrid nanoparticles

Exploring precise and effective treatments for liver fibrosis is urgent. The effective therapy for liver fibrosis depends on the specific delivery of antifibrotic drugs to activated hepatic stellate cells (aHSCs). However, this is a challenging task due to pathological barriers, primarily caused by collagen deposition. This study developed vitamin A-functionalized fluorinated peptide/lipid hybrid nanoparticles to co-deliver sorafenib and siRNA against HSP47 (SF-siHSP47@VFPL NPs). This nanoparticle formulation offers significant advantages due to its fluorine‑fluorine and electrostatic interactions, allowing for high SF and siHSP47 loading efficiency and sustained drug release. Importantly, in vitro cell uptake and in vivo biodistribution revealed that VA functionalization significantly improved aHSC-targeted delivery efficiency by engaging retinol-binding protein receptors on HSCs. Furthermore, it dramatically reduced extracellular matrix deposition, as evidenced by diminished levels of liver fibrosis-associated genes (HSP47, TIMP-1, and collagen I), promoting collagen breakdown and preventing collagen production, thus overcoming drug delivery barriers. Thus, SF-siHSP47@VFPL NPs demonstrated optimal antifibrotic effects by triggering apoptosis and ferroptosis in aHSCs. In liver fibrosis mouse models, SF-siHSP47@VFPL NPs remodeled the pathological environment and restored liver functionality through a marked reduction in serum liver transferases, hydroxyproline content, collagen deposition, and α-SMA and CD31 expression in liver tissue, resulting in alleviated liver fibrosis. Consequently, SF-siHSP47@VFPL NPs showed significant potential for HSC-targeted, chemo-gene therapy in the treatment of liver fibrosis.

The de-sulfinylation enzyme sulfiredoxin-1 attenuates hepatic stellate cell activation and liver fibrosis by modulating the PTPN12-NLRP3 axis.

Liver fibrosis is characterized by the progressive scarring of liver tissue. Oxidative stress is a critical causal factor of hepatic stellate cell (HSC) activation and the subsequent liver fibrogenesis, but the mechanism is not fully understood. Cysteine sulfinic acid (Cys-SO2H), a modification of reactive cysteine residues, is a unique form of oxidative response that alters the structure and function of proteins. Sulfiredoxin 1 (SRXN1) is responsible for ATP-dependent reduction of the Cys-SO2H to sulfenic acid (Cys-SOH). We found that the expression of SRXN1 was increased in activated HSCs and in human and mouse fibrotic livers. HSC-specific ablation of Srxn1 or pharmacological inhibition of Srxn1 exacerbated HSC activation and sensitized mice to liver fibrosis. Mechanistically, SRXN1 inhibited HSC activation by de-sulfinylating the phosphatase protein tyrosine phosphatase non-receptor type 12 (PTPN12), which enhanced its phosphatase activity and protein stability, leading to decreased tyrosine phosphorylation and reduced activation of the pro-fibrotic inflammasome protein NLRP3. The anti-fibrotic effect of SRXN1 was abolished when NLRP3 was inhibited. In contrast, overexpression of PTPN12 attenuated NLRP3 activation, and this effect was further amplified by the C164A S-sulfinylation resistant mutant of PTPN12. Our findings have uncovered an important role of SRXN1 and protein S-sulfinylation in HSC activation and liver fibrosis. The SRXN1-PTPN12-NLRP3 axis represents potential therapeutic targets for liver fibrosis.

Adipose-derived mesenchymal stem cells inhibit hepatic stellate cells activation to alleviate liver fibrosis via Hippo pathway

BackgroundLiver fibrosis is a common pathological process of chronic liver disease, characterized by excessive deposition of extracellular matrix (ECM). Mesenchymal stem cells (MSCs) have been found to have potential therapy effect on liver fibrosis, but the mechanism involved was still unclear. The objective of this study is to investigate the therapeutic efficacy of adipose-derived mesenchymal stem cells (ADMSCs) on the treatment of liver fibrosis, with particular emphasis on elucidating the underlying mechanism of action through which ADMSCs inhibit the activation of hepatic stellate cells (HSCs).MethodsADMSCs were isolated from adipose tissue and injected intravenously into hepatic fibrosis model of rats. The histopathological changes, liver function, collagen deposition, the expression of fibroin and Hippo pathway were evaluated. In vitro, ADMSCs were co-cultured with HSCs activated by transforming growth factor beta 1 (TGF-β1), and the inhibitor of Hippo pathway was used to evaluate the therapeutic mechanism of ADMSCs transplantation.ResultsThe results showed that after the transplantation of ADMSCs, the liver function of rats was improved, the degree of liver fibrosis and collagen deposition were reduced, and the Hippo signaling pathway was activated. In vitro, ADMSCs can effectively inhibit the proliferation and activation of HSCs induced by TGF-β1 treatment. However, the inhibitory effect of ADMSCs was weakened after blocking the Hippo signaling pathway.ConclusionsADMSCs inhibit HSCs activation by regulating YAP/TAZ, thereby promoting functional recovery after liver fibrosis. These findings lay a foundation for further investigation into the precise mechanism by which ADMSCs alleviate liver fibrosis.

Hepatitis B Virus-Associated Liver Carcinoma: The Role of Iron Metabolism and Its Modulation.

Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation

ObjectiveExtracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation,...

Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

Investigating the Mechanisms of Anti-tumoral Effect of Combination Therapy of Calcitriol and Sodium Pentaborate Pentahydrate on HepG2 Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is one of the most common primary liver cancers worldwide and is often associated with poor prognosis due to drug resistance. Combination therapies demonstrate superior efficacy at lower drug dosages on cancer cells compared to single treatments, resulting in less drug resistance in the cells. This study investigates the synergistic anti-tumoral effects of calcitriol, the biologically active form of vitamin D, and sodium pentaborate pentahydrate (NaB) on HepG2 cells. We examined the cell viability of NaB, calcitriol, or the combination of NaB and calcitriol on HepG2 cells and healthy human hepatic stellate cells (HHSC) using MTS. Our findings showed that combination therapy with 3.3mM NaB and 1µM calcitriol has a synergistic effect and a more cytotoxic effect on HepG2 cells. This combination significantly increased apoptosis and ROS levels compared to treatment alone with NaB or calcitriol. Gene expression and proteomics analysis revealed inhibition of DNA replication and the cell cycle process, further confirming the potent anti-proliferative effects of the combination therapy. When HepG2 cells were treated with a combination of 3.3mM NaB and 1µM calcitriol, mRNA levels of apoptosis-related genes AKT1 and MDM2 were downregulated, while p53 was upregulated. Additionally, cell cycle-related genes CDKN1A, GADD45A, and p27 were upregulated, whereas MCM2, MCM5, and MCM7 were downregulated. Furthermore, genes associated with the vitamin D receptor (VDR), including VDR and CYP24A1, were upregulated, while CYP27B1 was downregulated. Our proteomic analysis revealed decreased MCM2 and MCM5 protein expressions which was confirmed by western blotting. In conclusion, this study highlights the potential of NaB and calcitriol as a promising therapeutic strategy for HCC.

Application of Nanotechnology in Liver Fibrosis: An Overview

Chronic liver disease constitutes a global health issue owning to their widespread prevalence and the scarcity of effective curative treatments. They are arising from various causes, both infectious and non-infectious diseases. A rapidly evolving field of interest is the use of nanoparticle (NP) systems for the safe administration of different medications and nucleic acid for the treatment of chronic liver disorder. The review examines the pathophysiology, diagnosis and new developments in nanoparticulate systems for the treatment of liver fibrosis related chronic liver disorder. Hepatic stellate cell (HSC) activation is thought to be the primary cause of liver fibrosis. Because of their unique abilities to transfer medications and other therapeutics moieties, liposomes, nanoparticulate systems have all been extensively researched. Currently, nanoparticle technology is used for liver fibrosis. Liver fibrosis can be caused by alcoholism, hepatitis viruses, genetic disorders, steatohepatitis, autoimmune, and other non-infectious conditions including fatty liver. Advanced liver fibrosis, or cirrhosis, is defined by the formation of nodules of regenerated hepatocytes after a fibrous scar caused by the accumulation of extracellular matrix (ECM) proteins disrupts the architecture of the liver. Keywords: Liver fibrosis,Nanomedicine,Therapy,Theranostics,Application

Retracted] Molecular mechanism of atractylon in the invasion and migration of hepatic cancer cells based on high‑throughput sequencing.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Fig. 5E on p. 9 were strikingly similar to data that had already been published in different form in another article written by different authors at a different research institute [Zuo K, Zhao Y, Zheng Y, Chen D, Liu X, Du S and Liu Q: Long non‑coding RNA XIST promotes malignant behavior of epithelial ovarian cancer. Onco Targets Ther 12: 7261‑7267, 2019]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 25: 112, 2022; DOI: 10.3892/mmr.2022.12628].

Thiazolidinedione-Conjugated Lupeol Derivatives as Potent Anticancer Agents Through a Mitochondria-Mediated Apoptotic Pathway.

To improve the potential of lupeol against cancer cells, a privileged structure, thiazolidinedione, was introduced into its C-3 hydroxy group with ester, piperazine-carbamate, or ethylenediamine as a linker, and three series of thiazolidinedione-conjugated compounds (6a-i, 9a-i, and 12a-i) were prepared. The target compounds were evaluated for their cytotoxic activities against human lung cancer A549, human breast cancer MCF-7, human hepatocarcinoma HepG2, and human hepatic LO2 cell lines, and the results revealed that most of the compounds displayed improved potency over lupeol. Compound 12i exhibited significant activity against the HepG2 cell line, with an IC50 value of 4.40 μM, which is 9.9-fold more potent than lupeol (IC50 = 43.62 μM). Mechanistic studies suggested that 12i could induce HepG2 cell apoptosis, as evidenced by AO/EB staining and annexin V-FITC/propidium iodide dual staining assays. Western blot analysis suggested that compound 12i can upregulate Bax expression, downregulate Bcl-2 expression, and activate the mitochondria-mediated apoptotic pathway. Collectively, compound 12i is worthy of further investigation to support the discovery of effective agents against cancer.