Search Results (42)

Thyroid hormones (thyroxine, T₄, and triiodothyronine, T₃) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T₄) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T₃, which can also be generated extrathyroidally by T₄ deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG locus. Secretory ChEL acquires Golgi-type glycans and is properly delivered to the thyroid follicle lumen, where T₃ is first formed. Homozygous knock-in mice are capable of thyroidal T₃ synthesis but largely incompetent for T₄ synthesis such that T₄-to-T₃ conversion contributes little. Instead, T₃ production is regulated thyroidally by thyrotropin (TSH). Compared to cog/cog mice with conventional hypothyroidism (low serum T₄ and T₃), the body size of ChEL-knock-in mice is larger; although, these animals with profound T₄ deficiency did exhibit a marked elevation of serum TSH and a large goiter, despite normal circulating T₃ levels. ChEL knock-in mice exhibited a normal expression of hepatic markers of thyroid hormone action but impaired locomotor activities and increased anxiety-like behavior, highlighting tissue-specific differences in T₃ versus T₄ action, reflecting key considerations in patients receiving thyroid hormone replacement therapy. Full article

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons. Full article

Objectives: This study engineered a colon-targeted drug delivery system (CTDS) using the dual pharmaceutical and edible properties of Pueraria lobata to encapsulate Lactobacillus paracasei for Type 2 diabetes mellitus (T2DM) therapy. Methods: The CTDS was designed as a core–shell composite through microwave–hydrothermal engineering, comprising the following: (1) a retrograded starch shell with acid/enzyme-resistant crystallinity to protect probiotics from gastric degradation; (2) a porous cellulose core derived from Pueraria lobata’s natural microstructure, serving as a colonization scaffold for probiotics. Results: Structural characterization confirmed the shell’s resistance to acidic/pancreatic conditions and the core’s hierarchical porosity for bacterial encapsulation. pH/enzyme-responsive release kinetics were validated via fluorescence imaging, demonstrating targeted probiotic delivery to the colon with minimal gastric leakage. In diabetic models, the CTDS significantly reduced fasting blood glucose and improved dyslipidemia, while histopathological analysis revealed restored hepatic and pancreatic tissue architecture. Pharmacologically, the system acted as both a probiotic delivery vehicle and a microbiota modulator, selectively enriching Allobaculum and other short-chain fatty acid (SCFA)-producing bacteria to enhance SCFA biosynthesis and metabolic homeostasis. The CTDS further exhibited direct compression compatibility, enabling its translation into scalable oral dosage forms (e.g., tablets). Conclusions: By integrating natural material engineering, microbiota-targeted delivery, and tissue repair, this platform bridges the gap between pharmaceutical-grade probiotic protection and metabolic intervention in T2DM. Full article

Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child–Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications. Full article

The S1 subunit of SARS-CoV-2 Spike is crucial for ACE2 recognition and viral entry into human cells. It has been found in the blood of COVID-19 patients and vaccinated individuals. Using BioGRID, I identified 146 significant human proteins that interact with S1. I then created an interactome model that made it easier to study functional activities. Through a reverse engineering approach, 27 specific one-to-one interactions of S1 with the human proteome were selected. S1 interacts in this manner independently from the biological context in which it operates, be it infection or vaccination. Instead, when it works together with viral proteins, they carry out multiple attacks on single human proteins, showing a different functional engagement. The functional implications and tropism of the virus for human organs/tissues were studied using Cytoscape. The nervous system, liver, blood, and lungs are among the most affected. As a single protein, S1 operates in a complex metabolic landscape which includes 2557 Biological Processes (GO), much more than the 1430 terms controlled when operating in a group. A Data Merging approach shows that the total proteins involved by S1 in the cell are over 60,000 with an average involvement per single biological process of 26.19. However, many human proteins become entangled in over 100 different biological activities each. Clustering analysis showed significant activations of many molecular mechanisms, like those related to hepatitis B infections. This suggests a potential involvement in carcinogenesis, based on a viral strategy that uses the ubiquitin system to impair the tumor suppressor and antiviral functions of TP53, as well as the role of RPS27A in protein turnover and cellular stress responses. Full article

Inflammation plays a crucial role in atherosclerosis and nonalcoholic fatty liver disease (NAFLD). We previously engineered a recombinant Lactococcus lactis strain expressing the Ling-Zhi immunomodulatory protein (L. lactis-LZ8). This study investigated the anti-atherosclerotic effects of L. lactis-LZ8 in rabbits fed a high-fat diet (HFD). Changes in body weight, serum lipid profiles, and liver function were monitored. The aorta and liver tissues were analyzed for gross pathology and histopathology. Eight-week administration of L. lactis-LZ8 with HFD ameliorated atherosclerosis by downregulating protein and gene expression associated with lipid metabolism and inflammation in the aortas. The rabbits receiving L. lactis-LZ8 exhibited a significant dose-dependent reduction in hepatic fat accumulation. RNA sequencing of the livers revealed that inflammatory genes in the L. lactis-LZ8 groups were downregulated compared to the HFD group. Disease ontology enrichment analysis indicated that these genes were involved in atherosclerosis. Gene set enrichment analysis plots revealed significant enrichment in the gene sets related to cholesterol homeostasis. CIBERSORT immune cell fraction analysis indicated significant infiltration by regulatory T cells, CD8+ T cells, activated dendritic cells, and natural killer cells in the L. lactis-LZ8 group. Our studies underscore LZ8’s role in precision nutrition, providing a potential solution to the current challenges in modifying atherosclerosis and NAFLD. Full article

Background: Biomedical engineering, especially tissue engineering, is trying to provide an alternative solution to generate functional organs/tissues for use in various applications. These include beyond the final goal of transplantation, disease modeling and drug discovery as well. The aim of this study is to comprehensively review the existing literature on hydrogel-based vascularized organ (i.e., liver, pancreas, kidneys, intestine, stomach and spleen) tissue engineering of the abdominal organs. Methods: A comprehensive literature search was conducted on the Scopus database (latest search 1 September 2024). The research studies including hydrogel-based vascularized organ tissue engineering in the organs examined here were eligible for the review. Results: Herein, 18 studies were included. Specifically, 10 studies included the liver or hepatic tissue, 5 studies included the pancreas or pancreatic islet tissue, 3 studies included the kidney or renal tissue, 1 study included the intestine or intestinal or bowel tissue, 1 study included the stomach or gastric tissue, and 0 studies included spleen tissue. Conclusion: Hydrogels are biocompatible materials with ideal characteristics for use as scaffolds. Even though organ tissue engineering is a rapidly growing field, there are still many obstacles to overcome to create a fully functional and long-lasting organ. Full article

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term “liver–brain axis” vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver–brain axis and its role in metabolic homeostasis. Full article

Cadmium (Cd) is recognized as being linked to several liver diseases. Currently, due to the limited spectrum of drugs available for the treatment of Cd intoxication, developing and designing antidotes with superior detoxification capacity and revealing their underlying mechanisms remains a major challenge. Therefore, we developed the first next-generation probiotic E. coli 1917-pSK18a-MT that delivers metallothionein (MT) to overcome Cd-induced liver injury in C57BL/6 mice by utilizing bacterial surface display technology. The results demonstrate that E. coli 1917-pSK18a-MT could efficiently express MT without altering the growth and probiotic properties of the strain. Moreover, we found that E. coli 1917-pSK18a-MT ameliorated Cd contamination-induced hepatic steatosis, inflammatory cell infiltration, and liver fibrosis by decreasing the expression of aminotransferases along with inflammatory factors. Activation of the Nrf2-Keap1 signaling pathway also further illustrated the hepatoprotective effects of the engineered bacteria. Finally, we showed that E. coli 1917-pSK18a-MT improved the colonic barrier function impaired by Cd induction and ameliorated intestinal flora dysbiosis in Cd-poisoned mice by increasing the relative abundance of the Verrucomicrobiota. These data revealed that the combination of E. coli 1917 and MT both alleviated Cd-induced liver injury to a greater extent and restored the integrity of colonic epithelial tissues and bacterial dysbiosis. Full article

Understanding the final fate of nanomaterials (NMs) in the liver is crucial for their safer application. As a representative two-dimensional (2D) soft nanomaterial, graphene oxide (GO) has shown to have high potential for applications in the biomedical field, including in biosensing, drug delivery, tissue engineering, therapeutics, etc. GO has been shown to accumulate in the liver after entering the body, and thus, understanding the GO–liver interaction will facilitate the development of safer bio-applications. In this study, the hepatic clearance of two types of PEGylated GOs with different lateral sizes (s-GOs: ~70 nm and l-GOs: ~300 nm) was carefully investigated. We found that GO sheets across the hepatic sinusoidal endothelium, which then may be taken up by the hepatocytes via the Disse space. The hepatocytes may degrade GO into dot-like particles, which may be excreted via the hepatobiliary route. In combination with ICP-MS, LA-ICP-MS, and synchrotron radiation FTIR techniques, we found that more s-GO sheets in the liver were prone to be cleared via hepatobiliary excretion than l-GO sheets. A Raman imaging analysis of I_D/I_G ratios further indicated that both s-GO and l-GO generated more defects in the liver. The liver microsomes may contribute to GO biotransformation into O-containing functional groups, which plays an important role in GO degradation and excretion. In particular, more small-sized GO sheets in the liver were more likely to be cleared via hepatobiliary excretion than l-GO sheets, and a greater clearance of s-GO will mitigate their hepatotoxicity. These results provide a better understanding of the hepatic clearance of soft NMs, which is important in the safer-by-design of GO. Full article

Aortic and visceral aneurysms affect large arterial vessels, including the thoracic and abdominal aorta, as well as visceral arterial branches, such as the splenic, hepatic, and mesenteric arteries, respectively. Although these clinical entities have not been equally researched, it seems that they might share certain common pathophysiological changes and molecular mechanisms. The yet limited published data, with regard to newly designed, novel therapies, could serve as a nidus for the evaluation and potential implementation of such treatments in large artery aneurysms. In both animal models and clinical trials, various novel treatments have been employed in an attempt to not only reduce the complications of the already implemented modalities, through manufacturing of more durable materials, but also to regenerate or replace affected tissues themselves. Cellular populations like stem and differentiated vascular cell types, large diameter tissue-engineered vascular grafts (TEVGs), and various molecules and biological factors that might target aspects of the pathophysiological process, including cell-adhesion stabilizers, metalloproteinase inhibitors, and miRNAs, could potentially contribute significantly to the treatment of these types of aneurysms. In this narrative review, we sought to collect and present relevant evidence in the literature, in an effort to unveil promising biological therapies, possibly applicable to the treatment of aortic aneurysms, both thoracic and abdominal, as well as visceral aneurysms. Full article

The liver is a vital organ responsible for metabolic and digestive functions, protein synthesis, detoxification, and numerous other necessary functions. Various acute, chronic, and neoplastic disorders affect the liver and hamper its biological functions. Most of the untreated liver diseases lead to inflammation and fibrosis which develop into cirrhosis. The human amniotic membrane (hAM), the innermost layer of the fetal placenta, is composed of multiple layers that include growth-factor rich basement membrane, epithelial and mesenchymal stromal cell layers. hAM possesses distinct beneficial anti-fibrotic, anti-inflammatory and pro-regenerative properties via the secretion of multiple potent trophic factors and/or direct differentiation into hepatic cells which place hAM-based therapies as potential therapeutic strategies for the treatment of chronic liver diseases. Decellularized hAM is also an ideal scaffold for liver tissue engineering as this biocompatible niche provides an excellent milieu for cell proliferation and hepatocytic differentiation. Therefore, the current review discusses the therapeutic potential of hAM and its derivatives in providing therapeutic solutions for liver pathologies including acute liver failure, metabolic disorders, liver fibrosis as well as its application in liver tissue engineering. Full article

In recent studies, liver decellularized extracellular matrix (dECM)-based bioinks have gained significant attention for their excellent compatibility with hepatocytes. However, their low printability limits the fabrication of highly functional liver tissue. In this study, a new liver dECM–gelatin composite bioink (dECM gBioink) was developed to overcome this limitation. The dECM gBioink was prepared by incorporating a viscous gelatin mixture into the liver dECM material. The novel dECM gBioink showed 2.44 and 10.71 times higher bioprinting resolution and compressive modulus, respectively, than a traditional dECM bioink. In addition, the new bioink enabled stable stacking with 20 or more layers, whereas a structure printed with the traditional dECM bioink collapsed. Moreover, the proposed dECM gBioink exhibited excellent hepatocyte and endothelial cell compatibility. At last, the liver lobule mimetic structure was successfully fabricated with a precisely patterned endothelial cell cord-like pattern and primary hepatocytes using the dECM gBioink. The fabricated lobule structure exhibited excellent hepatic functionalities and dose-dependent responses to hepatotoxic drugs. These results demonstrated that the gelatin mixture can significantly improve the printability and mechanical properties of the liver dECM materials while maintaining good cytocompatibility. This novel liver dECM gBioink with enhanced 3D printability and resolution can be used as an advanced tool for engineering highly functional liver tissues. Full article

To investigate the potential of H2-calponin (CNN2) as a serum biomarker for hepatocellular carcinoma (HCC), this study employed the serological analysis of recombinantly expressed cDNA clone (SEREX) technique to identify the presence of CNN2 antibody in the serum of patients with HCC and other tumors. The CNN2 protein was produced through genetic engineering and used as an antigen to determine the positive rate of serum CNN2 autoantibodies via indirect enzyme-linked immunosorbent assay (ELISA). In addition, the mRNA and protein expressions of CNN2 in cells and tissues were evaluated using RT-PCR, in situ RT-PCR, and immunohistochemistry methods. The HCC group exhibited a significantly higher positive rate of anti-CNN2 antibody (54.8%) compared to gastric cancer (6.5%), lung cancer (3.2%), rectal cancer (9.7%), hepatitis (3.2%), liver cirrhosis (3.2%), and normal tissues (3.1%). The positive rates of CNN2 mRNA in HCC with metastasis, non-metastatic HCC, lung cancer, gastric cancer, nasopharyngeal cancer, liver cirrhosis, and hepatitis were 56.67%, 41.67%, 17.5%, 10.0%, 20.0%, 53.13%, and 41.67%, respectively. Meanwhile, the positive rates of CNN2 protein were 63.33%, 37.5%, 17.5%, 27.5%, 45%, 31.25%, and 20.83%, respectively. The down-regulation of CNN2 could inhibit the migration and invasion of liver cancer cells. CNN2 is a newly identified HCC-associated antigen that is implicated in the migration and invasion of liver cancer cells, making it a promising target for liver cancer therapy. Full article

New therapeutic options for liver cirrhosis are needed. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as a promising tool for delivering therapeutic factors in regenerative medicine. Our aim is to establish a new therapeutic tool that employs EVs derived from MSCs to deliver therapeutic factors for liver fibrosis. EVs were isolated from supernatants of adipose tissue MSCs, induced-pluripotent-stem-cell-derived MSCs, and umbilical cord perivascular cells (HUCPVC-EVs) by ion exchange chromatography (IEC). To produce engineered EVs, HUCPVCs were transduced with adenoviruses that code for insulin-like growth factor 1 (AdhIGF-I-HUCPVC-EVs) or green fluorescent protein. EVs were characterized by electron microscopy, flow cytometry, ELISA, and proteomic analysis. We evaluated EVs’ antifibrotic effect in thioacetamide-induced liver fibrosis in mice and on hepatic stellate cells in vitro. We found that IEC-isolated HUCPVC-EVs have an analogous phenotype and antifibrotic activity to those isolated by ultracentrifugation. EVs derived from the three MSCs sources showed a similar phenotype and antifibrotic potential. EVs derived from AdhIGF-I-HUCPVC carried IGF-1 and showed a higher therapeutic effect in vitro and in vivo. Remarkably, proteomic analysis revealed that HUCPVC-EVs carry key proteins involved in their antifibrotic process. This scalable MSC-derived EV manufacturing strategy is a promising therapeutic tool for liver fibrosis. Full article