Search Results (4,338)

The LAP2–emerin–MAN1-domain (LEM-D) proteins constitute a family of inner nuclear membrane proteins that play essential roles in the spatial regulation of intranuclear signaling. Defined by the conserved LEM domain, these proteins interact with chromatin, nuclear lamins, and barrier-to-autointegration factor (BAF), thereby linking nuclear architecture to signal-dependent transcriptional control. This review summarizes current knowledge on the structural features and molecular functions of representative LEM-D proteins, including LAP2, emerin, and MAN1, with a particular focus on their emerging roles as regulators of intranuclear signaling pathways. We discuss how these proteins modulate the activity of transcription factors involved in Hedgehog, Wnt/β-catenin, STAT3, Notch, and transforming growth factor-β (TGF-β) signaling by temporally retaining them at the inner nuclear membrane and controlling their access to chromatin. Furthermore, this review highlights the physiological and pathological relevance of LEM-D-mediated signaling regulation, especially in the context of muscle development, regeneration, and nuclear envelope-associated diseases such as muscular dystrophies. By integrating structural, signaling, and disease-related perspectives, this review proposes a conceptual framework in which LEM-D proteins function as critical intranuclear signaling hubs. Understanding these mechanisms provides new insights into nuclear signal transduction and suggests potential therapeutic targets for diseases associated with nuclear envelope dysfunction. Full article

The Janus Kinase (JAK) and Signal Transducers and Activators of Transcription (STAT) pathways regulate a range of biological processes, including immune response and hematopoiesis. While a major research focus has been on somatic human mutations in disease, less is known about the heritability of germline variants and their physiological impact. This study addresses an important issue in population genetics: the context-dependent effects and incomplete penetrance of rare genetic variants in immune pathways. Here we identify the rare JAK3^P151R, JAK3^R925S, STAT5A^V494L, and STAT6^Q633H variants in an extended family spanning three generations, integrate in silico analyses and AlphaFold 3 structural predictions, and investigate the immune transcriptomes in probands carrying one or more variants. All four variants are inherited through the germline without any evident clinical or physiological manifestations in the carriers. As individual variants, not all persons carrying a specific variant showed the same immune transcriptome. The presence of activated basal transcriptomes was limited to some, but not all, individuals carrying the above variants. A next step in understanding the role of germline variants will be to understand how and why other factors, including both other germline variants and environmental and developmental factors, influence the likelihood of expression of an activated basal transcriptome. Full article

Regulatory T cells (Tregs), particularly their phenotypically distinct subpopulations, are critical for the establishment of maternal immune tolerance during embryo implantation. Despite advances in assisted reproductive technologies, implantation failure remains a frequent and often unexplained clinical challenge. Variations in Treg frequency and phenotype have been proposed to influence implantation success, particularly under differing hormonal conditions. This study aimed to investigate peripheral blood Treg levels and their subpopulations on the day of blastocyst transfer in both stimulated in vitro fertilization (IVF/ICSI) cycles involving controlled ovarian hyperstimulation (COH) and true natural cycles with frozen embryo transfer (FET), and to examine their associations with systemic hormone levels and anti-Müllerian hormone (AMH). A prospective observational study was conducted including women undergoing IVF/ICSI with fresh embryo transfer (ET) and women undergoing natural cycle FET. Peripheral blood samples were collected on the day of ET and analyzed using 13-colour flow cytometry, enabling detailed subdivision of Tregs into multiple subpopulations based on the expression of differentiation and chemokine markers, including CXCR5. In addition, because common $\gamma$-chain cytokines may influence pregnancy success by modulating the balance between suppressive Treg and non-Treg subsets, intracellular STAT5 signaling was assessed using phospho-specific flow cytometry. Serum estradiol, progesterone, FSH, LH, and AMH levels were measured in parallel. Significant differences were observed in Treg subpopulation distributions between women who conceived and those who did not. Higher frequencies of naïve CXCR5⁻ Tregs were associated with clinical pregnancy, independent of age, and correlated with serum progesterone levels. Moreover, both naïve Treg frequency and enhanced IL-7-dependent STAT5 signaling in naïve Tregs from women undergoing COH were associated with AMH levels, suggesting a link between ovarian reserve and Treg homeostasis mediated by signal transducer and activator of transcription 5 (STAT5) signaling. In conclusion, Treg subpopulations, particularly CXCR5⁻ naïve Tregs, appear to play a central role in implantation success following ET. Their distribution differs between stimulated and natural cycles and is influenced by systemic progesterone levels and STAT5 signaling. These findings suggest that peripheral Treg profiling may represent a potential biomarker of implantation competence and could inform personalized approaches in assisted reproduction. Full article

Early prevention of pathological changes underlying gastric cancer (GC) development is a critical strategy, offering the most effective opportunity to limit malignant progression and improve patient outcomes. We have previously demonstrated that Helicobacter pylori (Hp) (cagA⁺vacA⁺) contributes to GC development by activating gastric fibroblasts toward CAF-like phenotype, eliciting aggressive, cancer stem cells (CSCs)-related malignant transformation of LGR5⁺ normal epithelial cells. A key mediator of these processes appears to be the NF-κB/STAT3 axis. Therefore, our aim was to investigate the protective role of hydrogen sulfide (H₂S) as a potential novel strategy for counteracting Hp-induced fibroblast reprogramming. Human fibroblasts were infected with Hp (cagA+vacA+) for 120 h. The fast-releasing H₂S donor NaHS (50, 100, 200 and 400 µM) was added every 24 h. Activation markers, corresponding signaling pathways, H₂S release and activities of H₂S-metabolizing enzymes were determined. NaHS reduced Hp-induced fibroblast activation and their pro-inflammatory, pro-tumorigenic markers, which was associated with the inhibition of NF-κB/STAT3 axis and Twist expression. Additionally, it modulated sulfur metabolism while preserving sulfur-enzyme homeostasis. NaHS limited Hp adhesion (high doses), reduced reinfection-induced activation and increased sensitivity of Hp to metronidazole. These findings suggest that H₂S signaling may represent a modulatory factor of NF-κB/STAT3-driven inflammatory responses during Hp infection and warrant further investigation. Full article

Objective: This study aimed to investigate the association between time to admission (TTA) and long-term mortality in patients with hip fractures, enabling surgeons to assess individual risks and prevent adverse outcomes. Methods: Demographic and clinical data of patients with hip fractures were obtained from medical records in our hospital. Patients aged 65 years or older were included. TTA was defined as the time from injury to first presentation at our institution. The primary outcome was long-term all-cause mortality. The regular multivariate Cox regression, restricted cubic spline, and two-piecewise model were used to explain the linear and curvilinear association between TTA and long-term mortality. The analyses were performed using EmpowerStats and R. Results: A total of 2361 patients were included in our study. There were 743 males and 1618 females, with a mean age of 79.44 ± 6.71 years. There were 1745 intertrochanteric fractures and 616 femoral neck fractures. We divided the patients into four groups according to TTA distribution: TTA ≤ 6 h, 6 h < TTA ≤ 12 h, 12 h < TTA ≤ 24 h, and TTA > 24 h, and the corresponding long-term mortality rates were 254 (25.53%), 85 (32.20%), 127 (32.56%), and 267 (37.50%). A curvilinear association was observed between TTA delay and long-term mortality in geriatric hip fractures, with 24 h serving as an inflection point. When TTA was less than 24 h, every one-hour increase in TTA was associated with a 1.6% increase in long-term mortality (HR = 1.016, 95% CI: 1.008–1.024; p < 0.001). When TTA exceeded 24 h, the long-term mortality risk showed no significant further increase with TTA (HR = 1.000, 95% CI: 1.000–1.000; p = 0.531). Conclusions: This study suggests that delayed admission is associated with a worse prognosis, and the mortality risk increases by approximately 1.6% per hour of delay within the first 24 h, after which the risk appears to stabilize. The first 24 h post-injury may represent a critical window for intervention. Full article

Background: Organ transplant offers patients a second chance at life, yet chronic rejection remains a formidable barrier to long-term success. Unlike the instantaneous storm of acute rejection, chronic rejection is a slow, unremitting process that silently remodels vessels, scars tissues, and diminishes graft function. At the center of this process are macrophages, immune “shapeshifters” that can heal or harm depending on their cues. Methods: This manuscript systematically reviews and synthesizes the current evidence from experimental studies and clinical observations, as well as molecular insights, to unravel how macrophages orchestrate chronic rejection. It travels over macrophage origins alongside their dynamic polarization into pro-inflammatory (M1) or pro-repair yet fibrotic (M2) states. The discussion integrates mechanisms of recruitment, antigen presentation, vascular injury, and fibrosis, while highlighting the molecular pathways (NF-κB, inflammasomes, STAT signaling, metabolic rewiring) that shape macrophage fate. Results: Macrophages play a central role in chronic rejection. Resident macrophages, once tissue peacekeepers, amplify inflammation, while recruited monocyte-derived macrophages fuel acute injury or dysfunctional repair. Together, they initiate transplant vasculopathy through cytokines, growth factors, and matrix metalloproteinases, slowly narrowing vessels and starving grafts. Donor-derived macrophages, often overlooked, act as early sentinels and long-term architects of fibrosis, blurring the line between donor and host immunity. At the molecular level, macrophages lock into destructive programs, perpetuating a cycle of inflammation, vascular remodeling, and scarring. Conclusions: Macrophages are not passive bystanders but pivotal decision makers in chronic rejection. Their plasticity, while a source of pathology, also opens therapeutic opportunities. Emerging strategies like macrophage-targeted drugs, immune tolerance approaches, gene and exosome therapies currently offer ways to reprogram these cells and preserve graft function. By shifting the macrophage narrative from saboteurs to guardians, transplantation medicine may transform chronic rejection from an inevitability into a preventable complication, extending graft survival from fleeting years into enduring decades. Full article

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP–PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS–STING pathways to engage a coordinated network of IRFs—including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9—that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies. Full article

Thymic carcinoma (TC) is a rare and aggressive malignancy with poor prognosis, and its genomic landscape remains incompletely defined. Identifying the somatic alterations that shape TC biology is essential for improving diagnostic precision, developing targeted therapies, and informing early detection strategies. We performed a retrospective genomic analysis of 141 TC tumor specimens from 134 patients using de-identified data from the American Association for Cancer Research (AACR) Project GENIE^® database. Somatic mutations and copy number alterations (CNAs) were characterized, and statistical analyses were conducted to evaluate associations with patient demographics (sex, race) and tumor site (primary vs. metastatic). The cohort was predominantly male (56.7%) and White (56.7%). The most frequently altered genes were TP53 (27.7%), CYLD (17.6%), and CDKN2A (12.1%). Recurrent homozygous deletions at chromosome 9p21.3 involving CDKN2A and CDKN2B were common. Sex-stratified analysis revealed several significant male-specific alterations. Although the Pacific Islander subgroup was small (n = 2), preliminary analysis suggested enrichment of alterations in key cancer-associated genes, including TP53, BRCA1, and STAT5B, underscoring the need for diverse representation in TC genomics. Notably, MTOR mutations were significantly enriched in a subset of local recurrences and lymph node metastases (n = 3; q = 0.013), suggesting a potential role in disease progression. This large-scale genomic analysis reinforces the central involvement of TP53, cell-cycle control, and chromatin-modifying pathways in TC. The identification of sex-associated and race-associated mutational patterns, together with the enrichment of MTOR alterations in recurrent and metastatic disease, highlights biologically plausible mechanisms of progression and potential therapeutic vulnerabilities. These findings support the value of comprehensive genomic profiling in TC and emphasize the need for prospective, multi-omic studies to validate these observations and guide the development of more personalized treatment strategies. Full article

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells. Full article

Worldwide, prostate cancer (PC) has a rising incidence and is the sixth leading cause of death globally, especially with increasing cases in developing countries. Risk factors for PC include genetic predisposition, family history, race/ethnicity, and various occupational factors like diet, obesity, smoking, and transmitted diseases. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can be activated by hormones, cytokines, and growth factors, and it plays a role in many vital biological processes such as cell growth, differentiation, immune regulation, and apoptosis. Dysregulation of JAK/STAT3 can lead to cancer, inflammation, diabetes, and neurodegenerative disorders. In cancers, including PC, STAT3 promotes cell survival, progression, angiogenesis, and metastasis. Inhibitors targeting JAK and STAT3 tested in vivo have shown potential to inhibit malignant cell growth. Additionally, flavonoids are bioactive plant compounds that are important in preventing inflammation, oxidative stress, and cancer. Research indicates that natural flavonoids can be developed into cancer-preventive and therapeutic agents. Experimental studies have demonstrated that some flavonoids can inhibit PC development. The main goal of this review is to present the incidence and risk factors of PC, the JAK/STAT3 pathway and its inhibitors, and how flavonoids may influence this pathology. Full article

Activation of JAK/STAT and MAPK/ERK1,2 signalling pathways has been shown to increase the production of reactive oxygen species (ROS) in multiple cell types involved in cardiovascular diseases (CVDs), including vascular smooth muscle cells (VSMCs). However, these have not yet been studied in human saphenous vein SMCs (HSVSMCs) responsible for the maladaptive remodelling leading to saphenous vein graft failure (VGF), to which patients with type 2 diabetes mellitus (T2DM) are more susceptible. Therefore, this study aimed to evaluate the contributions of the JAK/STAT and MAPK/ERK1,2 pathways towards production of mitochondrial ROS (mROS) in HSVSMCs from T2DM patients versus non-diabetic controls. HSVSMCs explanted from surplus HSV tissues from consenting patients undergoing coronary artery bypass graft surgery were stimulated in vitro with mitogenic stimuli known to be involved in neointimal hyperplasia (NIH) and VGF, which are known activators of the JAK/STAT and the MAPK/ERK1,2 signalling pathways. Flow cytometry was then used to analyse the production of mROS (superoxide) in MitoSOX-stained HSVSMCs. Additionally, we examined the effect of ruxolitinib and trametinib, selective inhibitors of JAK1/2 and MEK1/2 signalling pathways, respectively, on mROS levels in these cells. From our findings, mROS production was significantly higher in HSVSMCs from T2DM patients versus non-diabetic controls. Activation of either the JAK/STAT or MAPK/ERK1,2 signalling pathways did not significantly alter the production of mROS in HSVSMCs from both T2DM and non-diabetic patients. However, inhibition of JAK/STAT and MAPK/ERK1,2 signalling pathways with ruxolitinib and trametinib, respectively, resulted in a significant reduction in mROS in HSVSMCs from both T2DM and non-diabetic patients. Our findings demonstrate a JAK/STAT- and MAPK/ERK1,2-mediated production of mROS in HSVSMCs. Hence, they are potential targets for drug development to limit ROS production in ROS-driven proliferation and migration of HSVSMCs responsible for VGF. Full article

Background/Objectives: Osteoporosis is a multifactorial skeletal disorder in which chronic inflammation, dysregulated cytokine signaling, and metabolic imbalance contribute to excessive bone resorption and impaired bone formation. Asiatic acid has demonstrated bone-protective effects, but its molecular mechanisms in osteoporosis remain incompletely understood. This study aimed to investigate the anti-osteoporotic mechanisms of asiatic acid using an integrative in silico strategy. Methods: Network pharmacology analysis was performed to identify osteoporosis-related molecular targets of asiatic acid. Molecular docking was used to predict the binding modes and affinities between asiatic acid and its target proteins. Molecular dynamics simulation was used to assess the structural stability and interaction persistence of the asiatic acid–protein complex. Results: Network pharmacology identified 135 overlapping targets between asiatic acid and osteoporosis, with IL-6, STAT3, PPARG, and NFKB1 emerging as key hubs. KEGG analysis indicated the PPAR signaling pathway as a potential mechanism underlying the anti-osteoporotic effect. Molecular docking showed strong binding energies of asiatic acid with all predicted target proteins, with the highest affinity observed for IL-6, involving key residues ASN61, LEU62, GLU172, LYS66, and ARG168. Consistently, molecular dynamics simulation confirmed stable binding of asiatic acid to IL-6, with persistent interactions with ASN61, LYS66, LEU62, LEU64, and GLN154 mediated by hydrogen bonds, water bridges, and hydrophobic interactions. Conclusions: This integrative in silico study provides mechanistic insight into the potential anti-osteoporotic actions of asiatic acid, implicating IL-6 as a plausible upstream molecular target. These results establish a robust mechanistic framework for future translational studies exploring asiatic acid as a natural therapeutic candidate for osteoporosis. Full article

Abdominal fat deposition in chickens significantly impacts production efficiency and is influenced by complex genetic and molecular mechanisms. This review summarizes current genomic and transcriptomic research on the regulation of adipogenesis and fat accumulation in chickens, highlighting key genes and loci identified through genome-wide association studies as well as other candidates involved in lipogenesis, lipolysis, and transcriptional regulation. Major metabolic pathways, including MAPK, AMPK, PI3K/AKT/mTOR, TGFβ1/Smad3, FoxO, JAK–STAT, Wnt/β-catenin, and Sonic Hedgehog signaling, are examined for their roles in fat deposition. The regulatory functions of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, are discussed, focusing on their interactions with target mRNAs and signaling networks that control lipid metabolism, adipocyte differentiation, and energy balance. Integrating insights from both avian and human studies, this review emphasizes the molecular mechanisms underlying adipogenesis and highlights potential strategies for genetic selection aimed at reducing excessive abdominal fat and improving poultry productivity. Full article

BslA (Biofilm surface layer protein A), a highly hydrophobic lipoprotein from Bacillus spp., self-assembles at fluid interfaces to form a crystalline film that reduces surface tension. In this study, we selected Pichia pastoris as a eukaryotic system for expressing recombinant BslA identified in Bacillus paralicheniformis BL-1. The secretory expression of recombinant BslA in the P. pastoris GS115 strain under the AOX1 promoter was confirmed in shake-flask cultivation. Next, two fed-batch fermentation strategies, constant dissolved oxygen strategy (DO-stat) and oxygen-limited fed-batch (OLFB) strategy, in a 5 L scale, were compared. The DO-stat process led to late-stage cell death and product degradation, limiting yields. Switching to the OLFB process by removing the glycerol feeding phase mitigated this issue, allowing extended fermentation and increasing the final recombinant BslA concentration to 657 mg/L. This study establishes P. pastoris with an OLFB strategy as an effective system for secreting recombinant BslA protein, providing a basis for future industrial-scale production. Full article

In mammals, CD22 is a member of the Siglec family and plays essential roles in B-cell activation, signal transduction, and immune regulation. However, its functions in teleost fish remain largely unclear. In this study, a CD22 homolog designated On-CD22 was identified and cloned from Nile tilapia (Oreochromis niloticus). On-CD22 transcripts were highly expressed in the head kidney and peripheral blood of healthy fish and showed significant expression changes following infection with Streptococcus agalactiae, Aeromonas hydrophila, or stimulation with poly(I:C). Subcellular localization analysis indicated that On-CD22 is predominantly localized to the plasma membrane. Luciferase reporter assays performed in heterologous cell systems showed that overexpression of On-CD22 was associated with changes in the basal transcriptional activities of NF-κB, IFN1, IFN3, and STAT1 responsive promoters under unstimulated conditions. Furthermore, single-cell transcriptomic analysis revealed that On-CD22 expression was mainly confined to the B-cell population within head-kidney leukocytes. Collectively, these findings suggest that On-CD22 may be involved in immune regulatory processes in Nile tilapia. Full article