Search Results (255)

Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. In mice, TH treatment causes photoreceptor degeneration, which is accompanied by an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in the retina. Here, we investigated the contribution of RIPK3/necroptosis to TH-induced photoreceptor degeneration using mice deficient in RIPK3 and the necroptotic mixed lineage kinase domain-like protein (MLKL). Wild-type (C57BL/6) and mutant mice at postnatal day 30 received triiodothyronine (T3, 20 µg/mL in drinking water) for four weeks, followed by the evaluation of photoreceptor survival/death and retinal function. Deletion of Ripk3 preserved photoreceptor integrity against T3-induced degeneration, evidenced by improved retinal morphology, increased cone density, improved retinal light responses, and reduced cell death. This protection was observed in both global and photoreceptor-specific Ripk3 knockout mice. In contrast, the deletion of Mlkl did not protect photoreceptors. This work supports the view that RIPK3, but not MLKL, contributes to TH-induced photoreceptor degeneration. The lack of protection from Mlkl deletion suggests that RIPK3’s action is likely mediated via a necrosome-independent mechanism. These findings provide significant insight into how TH signaling induces photoreceptor degeneration and implicate RIPK3 as a potential therapeutic target. Full article

Galectin-9 (Gal-9, LGALS9) is a member of the family of carbohydrate-binding lectins known as galectins. Galectins bind a diverse repertoire of galactose-bearing glycoprotein receptors expressed across multiple cell types. These interactions elicit a broad spectrum of pleiotropic effects important in both normal physiology and disease pathogenesis. Gal-9 contains two separate carbohydrate recognition domains with overlapping yet also divergent binding affinities for distinct glycostructures. This tandem repeat motif enables fine-tuning of its various biological functions. Additional control of Gal-9 activity is provided via multiple gene variants, protein isoforms, tissue distribution, and cell type-associated glycoprotein binding profiles. Within the tumor microenvironment, Gal-9 interacts with immune, non-immune, and cancer cells to influence malignant progression. Its binding of the premier immune checkpoint glycoreceptors, T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3) and programmed cell death protein 1 (PD-1), places Gal-9 apart as a burgeoning target for immunotherapy. In this review, we delve into important aspects of Gal-9 immunobiology in tumorigenesis, including glycobiological and lineage-dependent functions. We further examine Gal-9 as a promising new glyco-immune checkpoint target for cancer therapy. Full article

Perinatal hypoxic–ischemic encephalopathy (HIE) is a condition resulting from oxygen deprivation around the time of birth and may be associated with death, brain damage, and disability. Alongside this, studies have shown that HIE may result in visual impairment. Previously, this was thought to be due to damage to the visual pathways in the brain, in a condition known as cerebral visual impairment. However, recent studies suggest that direct injury to the retina may occur after HIE. Of note, the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome is thought to play a role in perpetuating inflammatory damage in the brain after hypoxia–ischemia (HI). As such, this study aimed to characterize retinal inflammation and the role of the NLRP3 inflammasome after HI using a modified Rice-Vannucci model in postnatal day 10 (P10) rat. Eighteen Sprague-Dawley rats were allocated evenly to three groups. Two groups received surgery to ligate the right common-carotid artery and induce HI, while another group received only sham surgery. Rats exposed to HI received subcutaneous injections of tonabersat (HI + Ton) or saline (HI + vehicle) at 1, 24 and 48 h after HI, and were culled at P17 for analysis. The results showed that the protein expression of GFAP, Iba-1, NLRP3, caspase-1 and connexin43 increased in the retina at 7 d after HI-vehicle compared with sham surgery, much more so in the ipsilateral = than the contralateral retina. Furthermore, = inflammasome components NLRP3, cleaved caspase-1 and connexin43 were significantly upregulated in the ipsilateral retina following HI-vehicle compared to the sham surgery group. Treatment with a connexin43 hemichannel blocker, tonabersat, significantly decreased the expression of the inflammasome markers, cleaved caspase-1 and connexin43, and diminished Iba-1+ cell infiltration in the ipsilateral retina. These findings suggest that direct retinal damage and inflammation may occur after HI. Furthermore, these inflammatory changes are likely mediated and propagated by activation of the NLRP3 inflammasome. Importantly, inhibition of the inflammasome by tonabersat may be able to inhibit retinal inflammation and damage, potentially preventing visual impairment after HI. Further investigation in humans is required to determine the efficacy of tonabersat in treating hypoxic–ischemic injuries to the brain and eye. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1–2% of pancreatic cancers, with an incidence of ≤1 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain–associated protein), ATRX (alpha thalassemia/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies. Full article

Polygoni Multiflori Radix Praeparata (PMRP), a processed root of Polygonum multiflorum Thunb. (known as Zhiheshouwu in Chinese medicine), exhibits anti-aging properties and is used to improve ovarian aging. However, its therapeutic mechanism against premature ovarian insufficiency (POI) remains unclear. This study investigates whether PMRP alleviates POI by inhibiting PANoptosis—a cell death pathway characterized by the concurrent occurrence and interplay of pyroptosis, apoptosis, and necroptosis. POI was induced in rats using tripterygium glycosides. We evaluated the estrous cycle, serum hormone levels (follicle-stimulating hormone [FSH], estrogen [E₂], anti-Müllerian hormone [AMH]), follicular development, and the ultrastructure of granulosa cells. PANoptosome assembly (apoptosis-associated speck-like protein containing a CARD [ASC]/caspase-8/receptor-interacting protein kinase 3 [RIPK3] co-localization) and key effectors of PANoptosis (caspase 3, cleaved caspase 3, gasdermin D [GSDMD], cleaved GSDMD, GSDME, RIPK1, mixed-lineage kinase domain-like protein [MLKL], and p-MLKL) were analyzed. PMRP restored the estrous cycle, lowered FSH levels, and increased E₂ and AMH levels in POI rats. It reduced follicular atresia, preserved primordial follicles, and suppressed PANoptosis-like death in granulosa cells. Mechanistically, PMRP disrupted PANoptosome assembly and downregulated key effectors of PANoptosis. PMRP alleviates POI by inhibiting PANoptosis in granulosa cells, overcoming the previous limitations of targeting single death pathways and providing novel insights into the pathogenesis and treatment strategies for POI. Full article

The global burden of liver diseases continues to rise, encompassing diverse pathologies such as viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In recent years, TNFR1-associated death domain protein (TRADD), a pivotal adaptor molecule in the TNF signaling pathway, has been found to play a dual regulatory role in the pathogenesis of liver diseases. Through its death domain, TRADD binds to TNFR1 and dynamically recruits downstream factors (e.g., TRAF2, RIPK1, FADD) to form Complex I or IIa, thereby activating pro-survival or pro-apoptotic signals that dictate hepatocyte fate and modulate the inflammatory microenvironment. This review systematically summarizes the molecular structure and functional networks of TRADD, along with its mechanistic roles in liver diseases: in HCC, TRADD expression correlates with tumor differentiation and is regulated by miRNA targeting; in ALD and MASLD, TRADD-mediated apoptosis is closely linked to fibrotic progression; and in acute liver injury, TRADD signaling is modulated by factors such as HO-1 to mitigate damage. Furthermore, TRADD inhibitors and antisense oligonucleotides demonstrate therapeutic potential. This review highlights the clinical translational value of TRADD as a diagnostic, therapeutic, and prognostic biomarker for liver diseases, providing a theoretical foundation for future precision medicine strategies. Full article

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) 4 alone or in combination with other drugs, has led to unexpected positive results in some tumors but not all. Several other molecules inhibiting lymphocyte antitumor effector subsets have been discovered in the last 30 years. Herein, we focus on the leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1/CD305). LAIR1 represents a typical immunoregulatory molecule expressed on almost all leukocytes, unlike other regulatory receptors expressed on discrete leukocyte subsets. It bears two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the intracytoplasmic protein domain involved in the downregulation of signals mediated by activating receptors. LAIR1 binds to several ligands, such as collagen I and III, complement component 1Q, surfactant protein D, adiponectin, and repetitive interspersed families of polypeptides expressed by erythrocytes infected with Plasmodium malariae. This would suggest LAIR1 involvement in several cell-to-cell interactions and possibly in metabolic regulation. The presence of both cellular and soluble forms of LAIR would indicate a fine regulation of the immunoregulatory activity, as happens for the soluble/exosome-associated forms of PD1 and CTLA4 molecules. As a consequence, LAIR1 appears to play a role in some autoimmune diseases and the immune response against tumor cells. The finding of LAIR1 expression on hematological malignancies, but also on some solid tumors, could open a rationale for the targeting of this molecule to treat neoplasia, either alone or in combination with other therapeutic options. Full article

Chronic kidney disease (CKD) represents a major and widespread global health challenge. It affects over 800 million people worldwide, which is approximately 13% of the world’s population. Over the past 20 years, it has consistently ranked among the leading causes of death. As a result of its typically painless and asymptomatic presentation in the early stages of the disease, CKD is frequently diagnosed late, when the patient is already suffering from serious complications. In recent years, studies have identified novel biomarkers associated with the pathophysiology of CKD, including chronic inflammation, tubular injury, and CKD-related outcomes such as bone and mineral metabolism disorders, cardiovascular events, and all-cause mortality. Identifying and using these emerging biomarkers—like kidney injury molecule, N-acetyl–D-glucosaminidase, ficolins, the NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasome, soluble suppression of tumorigenicity-2, galectin-3, growth differentiation factor-15, soluble urokinase-type plasminogen activator receptor, sclerostin, the Dick-kopf proteins, and indexes such as the systemic inflammation response index—may lead to a significant advancement in early diagnosis, risk stratification, and personalized treatment strategies for CKD patients. Despite their potential, the routine clinical use of these novel biomarkers remains limited due to challenges such as high costs and the lack of standardized testing methods. There is still considerable room for advancement in both the diagnosis and management of CKD. Hopefully, increasingly more new biomarkers will become usable in clinical practice, ultimately improving care quality and outcomes for patients with CKD. Full article

Mutations in the TP63 gene cause several syndromic disorders, including ankyloblepharon–ectodermal defects–cleft lip/palate (AEC) syndrome, characterized by severe skin erosions, cleft palate, and ectodermal dysplasia. These mutations often affect the carboxy-terminal sterile-α-motif (SAM) domain of the p63 protein, leading to domain misfolding, protein aggregation, and impaired transcriptional activity. To dissect the molecular mechanisms underlying AEC pathogenesis, we investigated primary keratinocytes derived from p63L514F mutant mice, which carry a SAM domain mutation associated with AEC syndrome. p63L514F keratinocytes exhibited significantly reduced proliferation compared to wild-type controls, as indicated by decreased 5-ethynyl-2′-deoxyuridine (EdU) incorporation, decreased Cyclin D1 and Cyclin D2 expression, and an increase in the cell-cycle inhibitors p21 and p27. Furthermore, p63L514F keratinocytes showed increased cell death, elevated reactive oxygen species (ROS) levels, and a decreased reduced (GSH) and oxidized (GSSG) glutathione (GSH/GSSG) ratio, indicating oxidative stress. This stress response was accompanied by a marked reduction in Solute Carrier Family 7 Member 11 (Slc7a11), a critical regulator of antioxidant defense. We further identified Slc7a11 as a likely direct transcriptional target of p63: p63 depletion reduced Slc7a11 expression, and chromatin immunoprecipitation uncovered an evolutionary conserved p63-binding enhancer upstream of the Slc7a11 promoter. Together, our findings demonstrate that p63 mutations causative of AEC syndrome impair keratinocyte proliferation, promote cell death via oxidative stress, and compromised antioxidant defenses, revealing a dual role for p63 in sustaining skin homeostasis. Full article

Fungal phytopathogens employ effector proteins and secondary metabolites to subvert host immunity. Effector proteins have attracted widespread interest in infection, especially for unknown, unreported genes. However, the type of protein remains much less explored. Here, we combined transcriptome analysis and functional validation to identify virulence-associated genes in Fusarium graminearum during fungi infection. A unique secreted protein, FGSE02, was significantly upregulated in the early infection stage. Proteomic characterization revealed that the protein contains a functional signal peptide but lacks known domains. The transient expression of FGSE02 in Nicotiana benthamiana induced rapid cell death, while gene knockout stains reduced fungal virulence without affecting growth. Our findings highlight FGSE02 as a key virulence factor, offering potential targets for disease control. Taken together, the results of this study identify a pathogenic factor and provide new insights into the development of green pesticides. Full article

Ovarian clear cell carcinoma (OCCC) represents a distinct histological subtype with a high prevalence in Asian populations and poor chemotherapy response. This study investigated molecular interactions between phosphatase and tensin homolog (PTEN), AT-rich interactive domain 1A (ARID1A), programmed death-ligand 1 (PD-L1), and mismatch repair (MMR) proteins in Asian patients with OCCC. Immunohistochemical analysis was performed on tissue microarrays from 69 OCCC cases. The expression of PTEN, ARID1A, PD-L1, and four MMR proteins was evaluated alongside clinical data. A high prevalence of PTEN loss (78.3%) and ARID1A deficiency (48.8%), with PD-L1 expression in 26.1% and MMR deficiency in 10.1% of cases, was observed. All PD-L1-positive tumors demonstrated concurrent PTEN loss (p = 0.007). MMR deficiency was significantly associated with ARID1A loss (p = 0.049). PTEN loss correlated with worse progression-free survival (PFS) in early-stage disease (p = 0.039). PTEN and ARID1A alterations represent early pathogenic events in Asian OCCC, with PTEN loss significantly impacting PFS in early-stage disease. The correlation between PTEN loss and PD-L1 expression, alongside ARID1A-MMR deficiency association, provides insights into OCCC’s immunological landscape and therapeutic vulnerabilities. Full article

The combination of immunotherapy and radiotherapy has demonstrated synergistic potential, especially when a combination of immune checkpoint inhibitors (ICIs) is administered. Cytotoxic T-Lymphocyte-Associated Protein-4 (CTLA-4) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors or Programmed Cell Death Protein 1 (PD-1) inhibitors have been assessed in both clinical and preclinical studies; the addition of radiotherapy activates immunomodulatory mechanisms materialized by an effect similar to “in situ” vaccination or the “abscopal” distant response of lesions outside the irradiation field. The new therapeutic targets (T cell immune-receptor with Ig and ITIM domains (TIGIT), Lymphocyte activating gene 3 (LAG-3), and T cell Ig- and mucin-domain-containing molecule-3 (TIM-3)) associated with traditional ICIs and radiotherapy open new perspectives to the concept of immuno-radiotherapy. The dynamic evaluation of T lymphocyte expression involved in the antitumor immune response, both in the tumor microenvironment (TME) and in the tumor itself, could have biomarker value in assessing the response to combination therapy with traditional and new ICIs in association with irradiation. Preclinical data justify the initiation of clinical trials in various tumor pathologies to explore this concept. Full article

Research on functional recovery after ischemic stroke has primarily focused on non-invasive brain stimulation and motor rehabilitation therapies, while direct pharmacological interventions are relatively underexplored. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationship between 191 resting-state functional magnetic resonance imaging (rs-fMRI) features and post-ischemic stroke functional recovery (PISFR). Significant rs-fMRI phenotypes were identified, and Mendelian randomization was employed to determine their associated proteins. Bidirectional Mendelian randomization identified four rs-fMRI phenotypes potentially associated with functional recovery after ischemic stroke. Subsequent MR analysis, using pheno12 as the outcome and plasma protein as the exposure, highlighted Fas-Associated protein with Death Domain (FADD) as a significant protein. Further exploration within the protein–protein interaction (PPI) network identified FADD, Cysteinyl Aspartate Specific Proteinase 8 (CASP8), and Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) as potential drug targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these proteins are involved in the extrinsic apoptotic pathway, providing new insights for pharmacological strategies in post-ischemic stroke recovery. This study offers genetic evidence linking rs-fMRI to functional recovery post-ischemic stroke and identifies potential drug targets that may facilitate therapeutic interventions to enhance recovery after ischemic stroke. Full article

1′-Acetoxychavicol acetate (ACA) is a natural compound derived from rhizomes of the Zingiberaceae family that suppresses the nuclear factor κB (NF-κB) signaling pathway; however, the underlying mechanisms remain unclear. Therefore, the present study investigated the molecular mechanisms by which ACA inhibits the NF-κB signaling pathway in human lung adenocarcinoma A549 cells. The results obtained showed ACA decreased tumor necrosis factor (TNF)-α-induced intercellular adhesion molecule-1 (ICAM-1) expression in A549 cells. It also inhibited TNF-α-induced ICAM-1 mRNA expression and ICAM-1 promoter-driven and NF-κB-responsive luciferase reporter activities. Furthermore, the TNF-α-induced degradation of the inhibitor of NF-κB α protein in the NF-κB signaling pathway was suppressed by ACA. Although ACA did not affect TNF receptor 1, TNF receptor-associated death domain, or receptor-interacting protein kinase 1 protein expression, it selectively downregulated TNF receptor-associated factor 2 (TRAF2) protein expression. The proteasome inhibitor MG-132, but not inhibitors of caspases or lysosomal degradation, attenuated ACA-induced reductions in TRAF2 expression. ACA also downregulated TRAF2 protein expression in human fibrosarcoma HT-1080 cells. This is the first study to demonstrate that ACA selectively downregulates TRAF2 protein expression. Full article

The impact of pathogenic Vibrio on bivalves is expected to be aggravated by global warming, posing a growing threat to aquaculture. Clam production has been particularly vulnerable, with significant losses attributed to the lack of pathogen-resistant strains. In this study, the mantle cavity of the grooved carpet shell clam Ruditapes decussatus (Linnaeus, 1758) was injected with Vibrio splendidus at 18 °C, 22 °C, and 24 °C and the transcription of the phagelysozyme, Cu-Zn superoxide dismutase (Cu-Zn sod), tumor necrosis factor receptor associated factor 6 (traf6), inhibitor of NF-κB (IκB), and Fas-associated protein with death domain (fadd) genes were assessed during a 20-day period. Additionally, the coding sequences of lysozyme, fadd, and IκB in Ruditapes decussatus were characterized for the first time, and SNPs were identified. Some SNPs showed significantly different distributions between infection-resistant and infection-susceptible individuals. Infected clams experienced increased mortality at elevated temperatures. Lysozyme mRNA was upregulated in infected groups across all temperatures. The sustained increase on day 20, coinciding with elevated traf6 mRNA, suggests a prolonged activation of the immune response. Cu-Zn sod transcription at 18 °C and 22 °C peaked on day 7 and returned to control levels by day 20, indicating an effective immune response, while at 24 °C, infected animals showed a continuously increased transcription. IκΒ and traf6 transcription, reflecting NF-κB pathway activity, varied with temperature and showed transient stimulation at higher temperatures. The pattern of fadd expression indicated a late induction of apoptosis, particularly at 18 °C and 24 °C. Overall, this study illustrates the involvement of five key genes in host–pathogen interactions and identifies potential markers for selection for Vibrio resistance in Ruditapes decussatus. However, given the weak correlation observed, further research is needed on the link between these polymorphisms and pathogen resilience. Full article