Explore the vast range of titles available.

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.

The trapping of pathogenic ligands can potentially be used to prevent signal transduction mediated by catabolic factor expression in osteoarthritis (OA). Although vaspin is known to function as a pathogenic ligand and represents a novel adipokine, little is known about its function and the impact of its nebulization-based administration in OA. Here we provide a report on the function of vaspin in articular chondrocytes and OA model mice. RNA sequencing analysis and ingenuity pathway analysis demonstrated that vaspin upregulation in chondrocytes triggers OA development-related signaling. Vaspin is upregulated in the injured cartilage of patients with OA and DMM (Destabilization of the Medial Meniscus) mice, and its overexpression induces catabolic factor expression in vitro under OA-mimicked conditions. Col2a1–vaspin Tg (Transgenic) animals showed extensive cartilage degradation, whereas vaspin −/− (knockout) mice exhibited decreased OA development. Furthermore, in silico and biochemical analyses showed that vaspin activates the p38 and JNK signaling pathways to regulate AP-1-driven catabolic factor production and cartilage breakdown. Finally, we identified and characterized a vaspin-targeting nanobody, vas nanobody, and showed that intraarticularly injected vas nanobody could effectively block the vaspin–AP-1 axis to treat OA in DMM mice. Together, our results suggest that blockade of the vaspin–AP-1 axis could be an effective therapeutic approach for preventing OA development. Vaspin blockade offers new hope for osteoarthritis treatment Osteoarthritis (OA) is a common joint disease that causes pain and stiffness. This study explores the role of a protein called vaspin in OA. Researchers collected cartilage samples from humans and mice to study vaspin’s effects. They found that vaspin levels were higher in damaged cartilage, suggesting it may worsen OA. To test this, they used mice genetically modified to produce more or less vaspin. Mice with more vaspin had worse OA symptoms, while those with less had milder symptoms. The team also developed a small antibody called a nanobody to block vaspin. When injected into mice with OA, this nanobody reduced cartilage damage and pain without causing side effects. The study concludes that targeting vaspin could be a promising new approach for treating OA. Future research may focus on developing nanobody treatments for human use. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

The TGF-β signaling pathway is initiated when the type II receptor phosphorylates the type I receptor (ALK5) upon TGF-β binding. While E3 ubiquitin ligases regulate TGF-β receptor degradation, their role in modulating receptor catalytic activity via ubiquitination remains largely unexplored. Here, we demonstrate that the E3 ubiquitin ligase MARCH2 enhances ALK5 catalytic activity by conjugating K63-linked ubiquitin chains to lysines 342/343 (K342/343), primarily at endosomes following TGF-β-induced endocytosis. Mutations of ALK5 at K342/343 (K342/343R) abolish its catalytic activity for SMAD2 phosphorylation, leading to impaired TGF-β responses and reduced cell migration in A549 cells. In a mouse model, expression of the ALK5 K342/343 R mutant significantly decreases lung metastasis compared to wild-type ALK5. TCGA analysis further revealed a strong positive correlation between MARCH2 expression and TGF-β target gene expression. Collectively, these findings establish ALK5 ubiquitination at K342/343 by MARCH2 as a crucial regulatory mechanism for ALK5 catalytic activity, TGF-β signaling, and metastasis.

Osteoarthritis (OA) is an age-related degenerative disease for which an effective disease-modifying therapy is not available. Natural compounds derived from plants have been traditionally used in the clinic to treat OA. Over the years, many studies have explored the treatment of OA using natural extracts. Although various active natural extracts with broad application prospects have been discovered, single compounds are more important for clinical trials than total natural extracts. Moreover, although natural extracts exhibit minimal safety issues, the cytotoxicity and function of all single compounds in a total extract remain unclear. Therefore, understanding single compounds with the ability to inhibit catabolic factor expression is essential for developing therapeutic agents for OA. This review describes effective single compounds recently obtained from natural extracts and the possibility of developing therapeutic agents against OA using these compounds.

In East Asia, anguillid eels are commercially important. However, unlike other species, they have not been successfully cultivated throughout their lifecycle. Facing population decline due to overharvesting and environmental pressures, the industry is turning to alternatives, such as Anguilla bicolor pacifica (short-finned eel). However, genomic data for short-finned eels are unavailable. Here, we present in-depth whole-genome sequencing results for short-finned eel obtained using two sequencing platforms (PacBio Revio, and Illumina). In this study, we achieved a highly contiguous genome assembly of the short-finned eel, comprising 19 pseudochromosomes encompassing 99.76% of the 1.087 Gb genome sequence with an N50 of 16.88 and 61.07 Mb from contig and scaffold, respectively. Transcripts from four different tissues led to the annotation of 23,095 protein-coding genes in the eel genome, 98.66% of which were functionally annotated. This high-quality genome assembly, along with the annotation data, provides a foundation for future functional genomic studies of short-finned eels.

Bromodomains are epigenetic readers that modulate gene expression linked to inflammation and cartilage degeneration. Emerging evidence suggests their dysregulation plays a pivotal role in osteoarthritis (OA) pathogenesis, making them promising therapeutic targets. We evaluated the therapeutic efficacy of a novel carboxamide derivative bromodomain inhibitor (NCD) as a potentially safer alternative for preventing OA progression. The inhibitory effects of NCD were assessed through both in vitro and in vivo models. In vitro , mouse primary chondrocytes were stimulated with IL-1β, and the effects of NCD treatment were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. In vivo , destabilization of the medial meniscus (DMM) surgery was performed in 12-week-old male C57BL/6 mice, followed by either oral administration or intra-articular (IA) NCD injection. Cartilage integrity was assessed by histology. We analyzed changes in the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways to elucidate the mechanism of NCD. NCD treatment significantly suppressed IL-1β-induced expression of matrix metalloproteinases (Mmp3 and Mmp13) and cyclooxygenase-2 (Cox2) in mouse chondrocytes. In the DMM mouse model, both oral IA administration of NCD alleviated OA-related cartilage destruction. Mechanistically, NCD inhibited IκB degradation and reduced Erk and Jnk phosphorylation, indicating suppression of the NF-κB and MAPK signaling pathways. This study demonstrates that targeting bromodomains with a novel carboxamide-based inhibitor effectively attenuates OA cartilage destruction by suppressing these signaling pathways. These findings support the therapeutic potential of epigenetic modulation in mitigating OA pathogenesis.

Background: A large proportion of patients with inflammatory bowel disease (IBD) relapse after drug discontinuation despite achieving a stable state of infliximab-induced clinical remission. Resuming the use of the same tumor necrosis factor-alpha (TNF-α) inhibitors in patients who relapse following TNF-α inhibitor discontinuation was suggested as a treatment strategy. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of infliximab retreatment in patients with IBD. Methods: A systematic literature search to shortlist relevant studies was conducted using the MEDLINE, Embase, CINAHL, and SCOPUS databases for studies published from inception to August 2020. Results: Nine studies were included in the meta-analysis. The pooled clinical remission rate of infliximab retreatment in patients with IBD was 85% (95% confidence interval (CI), 81–89%) for induction treatment and 73% (95% CI, 66–80%) for maintenance treatment. A clinical remission rate following infliximab reintroduction was achieved in a greater proportion of patients with Crohn’s disease (87%; 95% CI, 83–91%) than in those with ulcerative colitis (78%; 95% CI, 61–91%) for induction treatment, but the difference was not statistically significant. Infusion-related reactions after infliximab retreatment occurred in 9% of patients with IBD (95% CI, 3–16%). Conclusion: Infliximab retreatment showed high clinical remission rates with tolerable infusion-related reactions in patients with IBD who achieved remission with initial infliximab treatment but relapsed after its discontinuation. We suggest infliximab as a viable alternative in patients with IBD who previously responded well to infliximab treatment.

Prussian blue (PB) is a metal cluster nanoparticle (NP) of cyanide-bridged iron(II)–iron(III) and exhibits a characteristic blue color. Its peroxidase-, catalase-, and superoxide-dismutase-like activities effectively remove excess reactive oxygen species that induce inflammation and tumorigenesis. However, the dispersion of PB NPs is not sufficiently stable for their application in the biomedical field. In this study, we developed Pluronic-stabilized Prussian blue nanoparticles (PB/Plu NPs) using a series of Pluronic triblock copolymers as a template material for PB NPs. Considering the hydrophilic–lipophilic balance (HLB) values of the Pluronic series, including F68, F127, L35, P123, and L81, the diameters of the PB/Plu NPs decreased from 294 to 112 nm with decreasing HLB values. The smallest PB NP stabilized with Pluronic P123 (PB/PP123 NP) showed the strongest antioxidant and anti-inflammatory activities and wound-healing efficacy because of its large surface area. These results indicated that the spatial distribution of PB NPs in the micelles of Pluronic greatly improved the stability and reactive oxygen species scavenging activity of these NPs. Therefore, PB/Plu NPs using U.S.-FDA-approved Pluronic polymers show potential as biocompatible materials for various biomedical applications, including the treatment of inflammatory diseases in the clinic.

Understanding the intrahepatic protective immune systems against acetaminophen (APAP)-induced acute liver injury (ALI) is currently limited. Here we reveal that Gram-positive gut-microbiota-derived pathogen-associated molecular patterns promote the CCL2-dependent infiltration of hepatotoxic Ly6C hi monocytes into the APAP-damaged liver, thus inducing APAP-ALI. Conversely, Gram-negative bacterial pathogen-associated molecular patterns activate hepatic CD103⁺ cDC1s to produce IL-15, which in turn expands intrahepatic tissue-resident memory CD8⁺ T (T RM ) cells and promotes protective immunity against APAP-derived liver injury. APAP-ALI was further exacerbated in Batf3-knockout and Rag1-knockout mice owing to an increased population of intrahepatic Ly6C hi monocytes in both knockout strains. The adoptive transfer of hepatic CD8 + T cells or hepatic CD103 + cDC1s from wild-type mice ameliorated APAP-ALI in both knockout mice. Notably, CD44 + CD69 + T RM cells within hepatic CD8 + T cells, when activated by IL-15/IL-15Rα from hepatic CD103 + cDC1s of APAP mice, played a crucial role in inducing apoptosis of liver-infiltrating monocytes through direct cell-to-cell interactions and granzyme B secretion. Human results supported these animal findings. Our findings underscore the existence of an intrahepatic protective immune system, the hepatic CD103 + cDC1/CD8 + T RM axis, which regulates APAP-ALI by controlling pathogenic monocytes. Gut microbiota shapes liver immunity against acetaminophen injury Acetaminophen is a common pain reliever, but an overdose can cause severe liver damage, known as acute liver injury. Researchers found that gut bacteria influence how immune cells respond to this damage. Signals from Gram-positive bacteria encouraged harmful monocytes to enter the liver and worsen injury, whereas signals from Gram-negative bacteria activated a protective immune pathway. In this pathway, a special liver immune cell type called cDC1s released the molecule IL-15, which stimulated CD8⁺ tissue-resident memory T cells to destroy the harmful monocytes. This CD103⁺ cDC1/IL-15/CD8⁺ tissue-resident memory T cell ‘protective immune axis’ helped limit liver damage in mice, and similar results were supported by human data. The study highlights a promising new therapeutic direction for treating acetaminophen-induced liver injury by strengthening the liver’s own protective immune system. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by “reading” the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire’s nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire’s two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.