Hepatic stellate cells (HSCs) are also known as lipocytes, fat-storing cells, perisinusoidal cells, or Ito cells. These liver-specific mesenchymal cells represent about 5% to 8% of all liver cells, playing a key role in maintaining the microenvironment of the hepatic sinusoid. Upon chronic liver injury or in primary culture, these cells become activated and transdifferentiate into a contractile phenotype, i.e., the myofibroblast, capable of producing and secreting large quantities of extracellular matrix compounds. Based on their central role in the initiation and progression of chronic liver diseases, cultured HSCs are valuable in vitro tools to study molecular and cellular aspects of liver diseases. However, the isolation of these cells requires special equipment, trained personnel, and in some cases needs approval from respective authorities. To overcome these limitations, several immortalized HSC lines were established. One of these cell lines is CFSC, which was originally established from cirrhotic rat livers induced by carbon tetrachloride. First introduced in 1991, this cell line and derivatives thereof (i.e., CFSC-2G, CFSC-3H, CFSC-5H, and CFSC-8B) are now used in many laboratories as an established in vitro HSC model. We here describe molecular features that are suitable for cell authentication. Importantly, chromosome banding and multicolor spectral karyotyping (SKY) analysis demonstrate that the CFSC-2G genome has accumulated extensive chromosome rearrangements and most chromosomes exist in multiple copies producing a pseudo-triploid karyotype. Furthermore, our study documents a defined short tandem repeat (STR) profile including 31 species-specific markers, and a list of genes expressed in CFSC-2G established by bulk mRNA next-generation sequencing (NGS).
Abstract Objective TGF-β/SMAD signaling controls mast cell (MC) development and exerts anti-inflammatory functions, while antigen (Ag)-triggered FcεRI/MAPK activation commands pro-inflammatory processes. SMAD2 is a signaling hub integrating both, TGF-β/ALK5-mediated SMAD2 C-terminal-and ERK-mediated SMAD2 linker-phosphorylation. Here, we analyzed the role of SMAD2 in TGF-β-and Ag-stimulated signaling, and their cross-talk which regulate MC responses. Methods The CRISPR-Cas method was used to disable SMAD2 expression in the PMC-306 cell line. The transcriptome of the corresponding cells was analyzed by NGS in homeostatic and stimulated conditions. Activation of signaling intermediates, target gene responses and effector function were analyzed by qPCR, Western blot and ELISAs. The causal association of SMAD2 with the found effects was proven by re-introduction of a tagged SMAD2 in knock out cells. Results The absence of SMAD2 led to increased proliferation and survival, and decreased transcription of target genes like Smad7 and Jun in steady state and upon TGF-β treatment. Intriguingly, SMAD2 was found to regulate TGF-β-mediated SMAD1/5 activation, resulting in augmented expression of Id3 in SMAD2-deficient MCs. Unexpectedly, we found that SMAD2 is indispensable for Ag-triggered production of pro-inflammatory cytokines, such as IL-6 and TNF. Re-introducing SMAD2 restores these events with varying sensitivity depending on the receptor system triggered. Conclusions Our findings highlight a previously unrecognized role of SMAD2 as a decisive hub in TGF-β-ALK5-SMAD1/5 and Ag-FcεRI-MAPK signaling, suggesting that pharmacological modulation of SMAD2 activity could be leveraged as regulator of both suppressive and inflammatory MC functions.
EDITORIAL article Front. Pharmacol., 24 September 2021 | https://doi.org/10.3389/fphar.2021.773228
Read moreLipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) and myelofibrosis (MF) patients vs. healthy controls. In addition, LCN2 serum levels were significantly increased in polycythemia vera (PV) and MF and positively correlated with JAK2V617F and mutated CALR allele burden and neutrophil counts. Mechanistically, we identified endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a main driver of LCN2 expression in BCR-ABL- and JAK2V617F-positive 32D cells. The UPR inducer thapsigargin increased LCN2 expression >100-fold, and this was not affected by kinase inhibition of BCR-ABL or JAK2V617F. Interestingly, inhibition of the UPR regulators inositol-requiring enzyme 1 (IRE1) and c-Jun N-terminal kinase (JNK) significantly reduced thapsigargin-induced LCN2 RNA and protein expression, and luciferase promoter assays identified nuclear factor kappa B (NF-κB) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1–JNK-NF-κB–C/EBP axis is a major driver of LCN2 expression in MPN, and targeting UPR and LCN2 may represent a promising novel therapeutic approach in MPN.
How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin?Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs).Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment.Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses.However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr.Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures.This efficiently generated 94.1% ± 7.35% TBX3 + HNF4A + human liver bud progenitors and 81.5% ± 3.2% FAH + hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah -/-Rag2 -/-Il2rg -/-mouse model of liver failure.
Read moreBACKGROUND: Fibrosis, or fibrotic scarring, is the body's response to injury that leads to the formation of fibrous connective tissue. It impacts various illnesses and can contribute to mortality. Currently, there are no effective treatments targeting the release of extracellular matrix (ECM) from fibroblasts, highlighting the urgent need for new therapies. Medicinal plants and their derivatives may offer a promising alternative for treating fibrosis. PURPOSE: This review aims to summarize the findings from reports published between 2023 and 2025 on the role of natural substances derived from plants in the treatment of four major types of fibrosis: myocardial fibrosis (MF), liver fibrosis (LF), pulmonary fibrosis (PF), and renal fibrosis (RF). METHODS: Data were sourced from PubMed, Google Scholar, ScienceDirect, and Scopus using terms related to fibrosis, such as "diagnosis," "treatment," "plant extracts," and "phytochemicals." Information on antifibrotic plant extracts and formulations from 2023 to 2025 was compiled. RESULTS: This review presents essential information on four main types of fibrosis and documents 72 botanicals. These consist of 28 individual plants studied separately and 44 combined herbal formulations. The botanicals are categorized according to the different types of fibrosis: 21 for LF, 8 for MF, 23 for PF, and 20 for RF. The review provides detailed information on 10 polyherbal formulations, which include: Guizhi Fuling Wan (GFW), Jiawei Taohe Chengqi decoction (JTCD), Longdan Xiegan Tang (LXT), and Tao-Hong-Si-Wu-Tang (THSWT) for LF; Linggui Zhugan decoction (LGZGD) and Qili Qiangxin (QLQX) for MF; Sha-Shen Mai-Dong (SMT) and Xuanfei Baidu decoction (XFBD) for PF; and Huangqi-Danshen (HDD) and Jian-Pi-Yi-Shen (JPYS) for RF. Additionally, the document lists 35 phytochemicals, which include 19 terpenoids and 16 phenolic compounds. CONCLUSION: This work highlights that, over the past three years, numerous scientific publications have underscored the importance of medicinal plants in treating various types of fibrosis globally. To improve the management of fibrosis, it is essential to conduct both preclinical and clinical studies on these promising samples to identify potential drug candidates.
Read moreWilson disease was previously called hepatolenticular degeneration. It is a rare inherited disorder preventing the body from removing copper via bile. Accordingly, copper builds up in liver and spills over to other organs, i.e., the basal ganglia of the brain.
Read moreIntroduction: , is commonly used in nutritional interventions for T2DM. However, it remains unclear which type of T2DM patients are suitable for inulin intervention. The aim of this study was to predict the effectiveness of inulin treatment for T2DM using a machine learning model. Methods: Original data were obtained from a previous study. After screening T2DM patients, feature election was conducted using LASSO regression, and a machine learning model was developed using XGBoost. The model's performance was evaluated based on accuracy, specificity, positive predictive value, negative predictive value and further analyzed using receiver operating curves, calibration curves, and decision curves. Results: Out of the 758 T2DM patients included, 477 had their glycated hemoglobin (HbA1c) levels reduced to less than 6.5% after inulin intervention, resulting in an incidence rate of 62.93%. LASSO regression identified six key factors in patients prior to inulin treatment. The SHAP values for interpretation ranked the characteristic variables in descending order of importance: HbA1c, difference between fasting and 2 h-postprandial glucose levels, fasting blood glucose, high-density lipoprotein, age, and body mass index. The XGBoost prediction model demonstrated a training set accuracy of 0.819, specificity of 0.913, positive predictive value of 0.818, and negative predictive value of 0.820. The testing set showed an accuracy of 0.709, specificity of 0.909, positive predictive value of 0.705, and negative predictive value of 0.710. Conclusion: The XGBoost-SHAP framework for predicting the impact of inulin intervention in T2DM treatment proves to be effective. It allows for the comparison of prediction effect based on different features of an individual, assessment of prediction abilities for different individuals given their features, and establishes a connection between machine learning and nutritional intervention in T2DM treatment. This offers valuable insights for researchers in this field.
Read moreAbstract This commentary discusses the significant findings of a study on Jaboticaba peel phenolic extract (JPPE) and its protective effects against oxidative stress and liver fat accumulation in rabbits fed a high cholesterol diet. The research highlights JPPE's ability to reduce serum biomarkers associated with hepatic damages, prevent lipid peroxidation, and restore antioxidant enzyme activities in those animals. By emphasizing the underutilized potential of Jaboticaba peels, this commentary advocates for further exploration of phenolic compounds as natural therapeutic agents in the prevention and management of hepatic diseases induced by high cholesterol diet. Ultimately, it underscores the importance of integrating such functional foods into dietary practices for enhancing liver health. These findings suggest that supplementation of JPPE into human diets could offer a promising natural strategy for reducing the risk of metabolic dysfunction-associated steatotic liver disease and improving the overall liver health, particularly in populations at risk due to poor dietary habits. Graphical Abstract
Read moreINTRODUCTION: This special report highlights the transformative potential of advanced diagnostic technologies in modern healthcare, emphasizing their role in enhancing disease detection, treatment personalization, and patient outcomes. AREAS COVERED: Innovations such as Next-Generation Sequencing (NGS), liquid biopsy, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) -based diagnostics, Point-of-Care (PoC) testing, microbiome analysis, and Artificial Intelligence are reshaping the diagnostic landscape. These methods facilitate early identification of diseases, enable tailored therapies based on individual genetic profiles, and provide noninvasive monitoring options. Furthermore, telemedicine enhances access to care while reducing costs associated with traditional healthcare delivery. Despite these advancements, challenges remain regarding regulatory compliance, data privacy concerns, and disparities in access to diagnostic services. The report underscores the need for ongoing collaboration among stakeholders to address these limitations effectively. EXPERT OPINION: By prioritizing equitable access and continuously evaluating emerging technologies' impact on patient safety and health outcomes, the healthcare system can harness the full potential of modern diagnostics to improve global health.
Read moreInsulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in ‘metaflammation’, and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys. Additionally, we will discuss principles of drug treatment for IR and outline a research agenda in this field.
Read moreCurrently, there are few validated and standardized tests for drug screening in pregnant women. In these as-says, maternal and fetal tissues are taken for screening, including maternal and fetal blood, meconium, hair, urine, pieces of placental material, and umbilical cord. Screening methods use different techniques including enzyme-linked immunosorbent assays, spectrometry, gas chromatography, high-performance liquid chromatography coupled with other detection techniques such as mass spectrometry. Here a new method is described that detects qualitative medication, legal drugs and illicit drugs in prenatal, perinatal and postnatal matrices in order to elucidate and explain various disorders in early childhood such as neonatal abstinence syndrome. Important in this work was the question of the range and sensitivity of methods to detect the sub-stances.
Read moreObesity is a complex systemic condition with significant sexual dimorphism, increasing the risks of disorders such as type 2 diabetes mellitus, arterial hypertension, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, premature cardiovascular disease, and certain types of cancers. A recent publication by Christaki et al. on the comprehensive overview of obesity management in Innovative Medicines and Omics highlights the multifactorial nature of obesity, as well as the importance of lifestyle changes, alongside pharmacological treatments and bariatric surgery. This commentary advocates for precision medicine strategies to effectively address the challenges posed by obesity. By highlighting the potential health and economic benefits of reducing obesity, we call for a holistic approach that integrates behavioral, medical, and policy interventions. We also identify research gaps, suggesting that future studies explore endocrine connections in obesity and assess endoscopic techniques targeting the duodenum as adjunct therapies in the context of tailored care.
Read moreBACKGROUND/OBJECTIVES: Type 2 diabetes and obesity present escalating global health and economic challenges, highlighting the need for therapies that can effectively manage glycemic levels and reduce excess adiposity. Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist available in subcutaneous or oral formulation, has quickly evolved from a theoretical concept to a crucial component of modern metabolic care. This review explores the comprehensive development journey of semaglutide, drawing on evidence from medicinal chemistry, animal studies, initial human trials, the pivotal SUSTAIN and STEP programs, and real-world post-marketing surveillance. METHODS: We conducted a detailed analysis of preclinical data sets, Phase I-III clinical trials, regulatory documents, and pharmaco-epidemiological studies published between 2008 and 2025. RESULTS: Through strategic molecular modifications, such as specific amino-acid substitutions and the addition of a C18 fatty-diacid side chain to enhance albumin binding, the half-life of the peptide was extended to approximately 160 h, allowing for weekly dosing. Studies in rodents and non-human primates showed that semaglutide effectively lowered blood glucose levels, reduced body weight, and preserved β-cells while maintaining a favorable safety profile. Phase I trials confirmed consistent pharmacokinetics and tolerability, while Phase II trials identified 0.5 mg and 1.0 mg once weekly as the most effective doses. The extensive SUSTAIN program validated significant reductions in HbA1c levels and weight loss compared to other treatments, as well as a 26% decrease in the relative risk of major adverse cardiovascular events (SUSTAIN-6). Subsequent STEP trials expanded the use of semaglutide to chronic weight management, revealing that nearly two-thirds of patients experienced a body weight reduction of at least 15%. Regulatory approvals from the FDA, EMA, and other regulatory agencies were obtained between 2017 and 2021, with ongoing research focusing on metabolic dysfunction-associated steatohepatitis, cardiovascular events, and chronic kidney disease. CONCLUSIONS: The trajectory of semaglutide exemplifies how intentional peptide design, iterative translational research, and outcome-driven clinical trial design can lead to groundbreaking therapies for complex metabolic disorders.
Read moreHintergrund: In Zellkultur, im Tiermodell und an humanem Biopsiematerial wurde ein kausaler Zusammenhang zwischen der Leberfibrose und einer erhöhten Expression von TIMP–1 belegt. Eine Bindung und Inaktivierung von TIMP–1 würde die natürliche proteolytische Aktivität des fibrotischen Gewebes fördern und so eine weitere Akkumulation von extrazellulärer Matrix verhindern. Ziel unserer Arbeiten ist eine spezifische Antagonisierung von TIMP–1 durch drei neue, proteolytisch inaktive MMP–9 Mutanten, die als gentherapeutische Vektoren im murinen Fibrosemodell (CCl4/BALB/c) analysiert wurden.
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