Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo . Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro . The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A–induced tissue injury in vivo , which was strongly associated with reduced liver cell apoptosis. In vitro , CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo . Conclusion: The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis.

Abstract Climate change significantly impact plant growth and development, prompting researchers to explore effective strategies to stabilize agricultural plant performance under environmental stresses. Strigolactones (SLs) are integral to regulating plant responses to both abiotic and biotic stresses, in addition to influencing various stages of plant growth and development. SLs interact with a network of other phytohormones, such as auxins, cytokinins, abscisic acid, gibberellins, and ethylene, to form a coordinated signaling system that regulates SLs biosynthesis and mediates stress responses. This review present an in-depth overview of SLs biosynthesis and highlights the emerging understanding of their specific roles in modulating plant adaptation to environmental stressors. The complex interactions between SLs and various phytohormones highlith their potential in enhancing plant resilience in response to climate change.

Crocetin protected human hepatocyte LO cell from TGF--induced oxygen stress and apoptosis but

The Beatles formed in Liverpool are one of the most famous music groups in the history of pop considered as the best-selling artists in the category "band," with the highest amount of claimed record sales. With their foremost pioneering activities in songwriting, artistic presentation, and recording, the band revolutionized many aspects of music industry and impacted social developments. Although active as a foursome in the 1960s, their music and films still attract new generations all over the world. Similar to former periods, the popularity of the Beatles and the fanaticism toward the band (i.e., "Beatlemania") has an ongoing impact on society and culture. Mostly unknown, Beatles songs inspire scientists in daily work and are part of clinical studies investigating aspects of human health and disease. This review briefly discusses the influence of The Beatles on Life Sciences, highlights the "better than the Beatles problem" affecting new drug development, and discusses several examples in which The Beatles impacted progression in Medicine. Finally, it is discussed if the meteoric success of the band contributed to the rapid progress in modern radiology.

Mast cells develop from the myeloid lineage and are released from the bone marrow as immature cells, which then differentiate at the destination tissue based on cues from the local environment. In the liver, mast cells are recruited in diseased states to fibrogenic surroundings rich in TGF-β1. The aim of this study was to investigate TGF-β1 signaling in primary and permanent mast cells to identify common and unique mechanisms. The TGF-β receptor repertoire is similar among mast cells, with high expression of type I and type II receptors and very low expression of type III receptors (Betaglycan and Endoglin). Downstream, TGF-β1 activates the SMAD2/3 signaling axis and also SMAD1/5 with target genes Smad6 and Id1 in a transient manner. Initially, TGF-β1 upregulates the transcription of mucosal mast cell effectors Mcpt1 and Mcpt2 in all analyzed mast cells. This upregulation is reduced in the presence of IL-3, which promotes proliferation. Inhibition of ERK1/2 activation reduces proliferation and mitigates the negative effect of IL-3 on Mcpt1 mRNA and protein expression in the immortalized mast cell line PMC-306 but not in bone marrow-derived mast cells. Therefore, extracellular signal-regulated kinases ERK1/2 are identified as a mutual switch between IL-3-driven proliferation and TGF-β1-promoted mucosal mast cell differentiation in PMC-306. In conclusion, TGF-β1 promotes a mucosal gene signature and inhibits proliferation in mast cells, with these effects being counter-regulated by IL-3/ERK1/2.

The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved crystal structures. They have a variety of functions, including acting as carrier proteins, transporting retinol, participating in olfaction, and synthesizing prostaglandins. Importantly, they also play a critical role in human diseases, including cancer. Additionally, they are involved in regulating cellular homeostasis and immune response and dispensing various compounds. This comprehensive review provides information on the lipocalin family, including their structure, functions, and implications in various diseases. It focuses on selective important human lipocalin proteins, such as lipocalin 2 (LCN2), retinol binding protein 4 (RBP4), prostaglandin D2 synthase (PTGDS), and α1-microglobulin (A1M).

Background: The excessive consumption of free sugars is mainly responsible for the high prevalence of obesity and metabolic syndrome in industrialized countries. More and more studies indicate that fructose is involved in the pathophysiology and also in the degree of disease of non-alcoholic fatty liver disease (NAFLD). In epidemiologic studies, energy-adjusted higher fructose consumption correlates with NAFLD in overweight adults. In addition to glucose, fructose, as an equivalent component of conventional household sugar, appears to have negative metabolic effects in particular due to its exclusive hepatic metabolism. Liver-related mortality is strictly associated with the degree of fibrosis, whereas the most common cause of death in patients suffering from NAFLD and non-alcoholic steatohepatitis (NASH) are still cardiovascular diseases. In this review article, we have summarized the current state of knowledge regarding a relationship between fructose consumption, liver fibrosis and life expectancy in NASH. Method: Selective literature search in PubMed using the keywords ‘non-alcoholic fatty liver’, ‘fructose’, and ‘fibrosis’ was conducted. Results: The rate of overweight and obesity is significantly higher in both, adult and pediatric NASH patients. The consumption of free sugars is currently three times the maximum recommended amount of 10% of the energy intake. The current literature shows weight gain, negative effects on fat and carbohydrate metabolism and NASH with hypercaloric intake of fructose. Conclusions: Excessive fructose consumption is associated with negative health consequences. Whether this is due to an excess of energy or the particular metabolism of fructose remains open with the current study situation. The urgently needed reduction in sugar consumption could be achieved through a combination of binding nutritional policy measures including taxation of sugary soft drinks. Previous studies suggest that diet-related fructose intake exceeding the amount contained in vegetables and fruits lead to an increase of hepatic lipogenesis. Thus, further studies to clarify the protective contribution of low-fructose intake to positively influence NAFLD in industrial population are urgently required.

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in order to enable tooth movement. hPDLF involvement in the early phase-OTM compression side was investigated for a 72-h period through a well-studied in vitro model. Changes in the morphology, cell proliferation and cell death were analyzed. Specific markers of the cell cycle were investigated by RT-qPCR and Western blot. The study showed that the morphology of hPDLF changes towards more unstructured, unsorted filaments under mechanical compression. The total cell numbers were significantly reduced with a higher cell death rate over the whole observation period. hPDLF started to recover to pretreatment conditions after 48 h. Furthermore, key molecules involved in the cell cycle were significantly reduced under compressive force at the gene expression and protein levels. These findings revealed important information for a better understanding of the preservation and remodeling processes within the periodontium through Periodontal Ligament Fibroblasts during orthodontic tooth movement. OTM initially decelerates the hPDLF cell cycle and proliferation. After adapting to environmental changes, human Periodontal Ligament Fibroblasts can regain homeostasis of the periodontium, affecting its reorganization.

Programmed cell death protein 1 (PD-1)/PD-ligand (L)1, the immune checkpoint inhibitors have emerged as a promising strategy for the treatment of various diseases including chronic liver diseases (CLDs) such as hepatitis, liver injury and hepatocellular carcinoma (HCC). The role of PD-1/PD-L1 has been widely inspected in the treatment of viral hepatitis and HCC. PD-1 is known to play a crucial role in inhibiting immunological responses and stimulates self-tolerance by regulating the T-cell activity. Further, it promotes apoptosis of antigen-specific T-cells while preventing apoptosis of T reg cells. PD-L1 is a trans -membrane protein which is recognized as a co-inhibitory factor of immunological responses. Both, PD-1 and PD-L1 function together to downregulate the proliferation of PD-1 positive cells, suppress the expression of cytokines and stimulate apoptosis. Owing to the importance of PD-1/PD-L1 signaling, this review aims to summarize the potential of PD-1/PD-L1 inhibitors in CLDs along with toxicities associated with them. We have enlisted some of the important roles of PD-1/PD-L1 in CLDs, the clinically approved products and the pipelines of drugs under clinical evaluation.

The accumulation of extracellular matrix proteins is the hallmark of liver fibrosis associated with all chronic liver disease (CLD) types. Liver fibrosis results from repeated bouts of liver injury, which trigger the wound-healing response, ultimately disrupting the normal hepatic architecture. Over time, fibrosis can progress to cirrhosis, portal hypertension, liver failure, and hepatocellular carcinoma, worsening patient outcomes. Biological modifiers, such as sex and socio-cultural constructs like gender, influence the development of liver fibrosis through various genetic, hormonal, immunological, metabolic, and lifestyle-related factors, including alcohol consumption, diet, sedentary behavior, and hormonal therapy. Moreover, liver fibrosis is significantly modulated by age, reproductive status, and the etiology of CLD. This review aims to summarize the most well-characterized pathomechanisms underlying sex and gender differences in hepatic fibrogenesis as well as liver-related complications (cirrhosis, portal hypertension, hepatic encephalopathy, liver failure, and hepatocellular carcinoma) and extra-hepatic correlates of liver fibrosis (sarcopenia, cardiovascular disease, diabetes, chronic kidney disease, and dementia) across various types of CLD due to viral-related, autoimmune, drug-induced and metabolic etiologies. Understanding these disease modifiers and their mechanisms is crucial for developing innovative treatment strategies and precision medicine approaches in this field.

Background/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 hours, 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.

<br><b> Measurement of % of body weight changes , White blood cells, and clinical chemistry parameters at the4-day in sera of male mice treated with L-asparaginase.</b><br><br>

Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.

Excess calorie intake and a sedentary lifestyle have made non-alcoholic fatty liver disease (NAFLD) one of the fastest growing forms of liver disease of the modern world. It is characterized by abnormal accumulation of fat in the liver and can range from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis as well as development of hepatocellular carcinoma (HCC). Biopsy is the golden standard for the diagnosis and differentiation of all NAFLD stages, but its invasiveness poses a risk for patients, which is why new, non-invasive ways of diagnostics ought to be discovered. Lipocalin-2 (LCN2), which is a part of the lipocalin transport protein family, is a protein formally known for its role in iron transport and in inflammatory response. However, in recent years, its implication in the pathogenesis of NAFLD has become apparent. LCN2 shows significant upregulation in several benign and malignant liver diseases, making it a good candidate for the NAFLD biomarker or even a therapeutic target. What makes LCN2 more interesting to study is the fact that it is overexpressed in HCC development induced by chronic NASH, which is one of the primary causes of cancer-related deaths. However, to this day, neither its role as a biomarker for NAFLD nor the molecular mechanisms of its implication in NAFLD pathogenesis have been completely elucidated. This review aims to gather and closely dissect the current knowledge about, sometimes conflicting, evidence on LCN2 as a biomarker for NAFLD, its involvement in NAFLD, and NAFLD-HCC related pathogenesis, while comparing it to the findings in similar pathologies.