Search Results (2,436)

Background/Objectives: The COVID-19 pandemic resulted in 675 million cases and 6.9 million deaths by 2022. Despite substantial declines in case fatalities following widespread vaccination campaigns, the threat of future coronavirus outbreaks remains a concern. Current treatments for COVID-19 have been repurposed from existing therapies for other infectious and non-infectious diseases. Emerging evidence suggests a role for genetic factors in both susceptibility to SARS-CoV-2 infection and response to treatment. However, comprehensive studies correlating clinical outcomes with genetic variants are lacking. The main aim of our study is the identification of host genetic biomarkers that predict the clinical outcome of COVID-19 pharmacological treatments. Methods: In this study, we present findings from GWAS and candidate gene and pathway enrichment analyses leveraging diverse patient samples from the Spanish Coalition to Unlock Research of Host Genetics on COVID-19 (SCOURGE), representing patients treated with immunomodulators (n = 849), corticoids (n = 2202), and the combined cohort of both treatments (n = 2487) who developed different outcomes. We assessed various phenotypes as indicators of treatment response, including survival at 90 days, admission to the intensive care unit (ICU), radiological affectation, and type of ventilation. Results: We identified significant polymorphisms in 16 genes from the GWAS and candidate gene studies (TLR1, TLR6, TLR10, CYP2C19, ACE2, UGT1A1, IL-1α, ZMAT3, TLR4, MIR924HG, IFNG-AS1, ABCG1, RBFOX1, ABCB11, TLR5, and ANK3) that may modulate the response to corticoid and immunomodulator therapies in COVID-19 patients. Enrichment analyses revealed overrepresentation of genes involved in the innate immune system, drug ADME, viral infection, and the programmed cell death pathways associated with the response phenotypes. Conclusions: Our study provides an initial framework for understanding the genetic determinants of treatment response in COVID-19 patients, offering insights that could inform precision medicine approaches for future epidemics. Full article

Fatty degenerative osteonecrosis of the jaw (FDOJ) is a chronic, aseptic inflammatory condition that is characterized by molecular disruptions in bone metabolism and necrotic bone marrow within the jawbone cavities. In contrast to the overt clinical signs typically observed in osteopathies, FDOJ frequently presents with a “silent inflammation” phenotype. The electronic databases PubMed, Scopus, and Embase were searched using appropriate search terms, and the methodology was performed according to PRISMA-ScR guidelines. The elevated expression of inflammatory mediators, particularly C-C motif Chemokine Ligand-5/Regulated on Activation, Normal T Cell Expressed and Secreted (CCL5/RANTES), fibroblast growth factor-2, and interleukin-1 receptor antagonist, distinguishes FDOJ at the molecular level and links it to systemic inflammatory and autoimmune diseases. These immunohistochemical markers play a pivotal role in the pathogenesis of chronic inflammation, immune response regulation, and abnormal bone remodeling. Advanced diagnostic tools, such as conebeam computed tomography and trans-alveolar ultrasonography, facilitate the detection of pathological changes that are not easily discernible with conventional radiography. Surgical intervention remains the primary treatment modality, often complemented by therapies that target these molecular pathways to modulate chronic inflammation. This article underscores the importance of integrating molecular diagnostics, advanced imaging, and clinical data for effective FDOJ detection and management. Full article

Stem cells are essential for the proper functioning of tissues, replacing damaged, senescent cells to ensure tissue regeneration. However, as age advances, the number of these stem cells can change, and their self-renewal abilities can become impaired, leading to disruption of homeostasis, loss of regenerative capacity, and, ultimately, deterioration of tissue function. In Drosophila testis, in addition to the germline and somatic cells involved in spermatogenesis, there are immune cells (hemocytes) with macrophage function. In our study, we aimed to investigate the role of hemocytes in maintaining germline stem cells throughout their lifespan. Our results show that in the absence of plasmatocytes and crystal immune cells, the number of germline stem cells (GSCs) and apoptotic germline cells also increases significantly during senescence, which may have detrimental effects on the differentiation processes of germline cells. The size of the hub increases in aged male testes. It is therefore conceivable that changes in the hub may induce dysfunction of differentiation processes. The fertility of aged immunodeficient animals is decreased. Furthermore, we show that the expression of the JAK/STAT signaling pathway, which is essential for the maintenance of the stem cell niche, is impaired in the lack of hemocytes. We found an increased expression of Socs36e, an inhibitor of JAK-STAT, which correlates with decreased JAK-STAT activity. Overexpression of Socs36e in the apical part of the germline led to a phenotype similar to the immunodeficient aged germline, where an increased GSC number and hub size were also observed. However, spermatogenesis was also disturbed in this case. Our study shows that hemocytes are required to regulate the number of GSCs. This regulation could be mediated through the JAK-STAT signaling pathway. These results may help to provide a more complex insight into the relationships between immune cells and stem cells. Full article

New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or “targeting kinesins”, holds great potential as an effective strategy for treating lung cancer. Full article

Objectives: This retrospective study examines midkine, an inflammatory cytokine, as a potential serological biomarker to distinguish dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Identifying such a biomarker is crucial for effective treatment of these two entities. Methods: The study included 54 patients with heart failure, reduced left ventricular systolic function, and suspected cardiac inflammation. Endomyocardial biopsies were obtained from all 54 patients to differentiate between DCM and DCMi. Blood sera were collected from these patients the same day the endomyocardial biopsy was performed and compared with those of 13 age-matched healthy individuals for different measurements such as midkine and NT-proBNP. Patients were followed up to a median of 194 days after the baseline visit. Results: Endomyocardial biopsies from patients with DCMi were associated with more infiltrating immune cells such as CD68⁺ macrophages and CD3⁺ T cells and a more frequent presence of a viral genome than those from patients with DCM. Both groups showed similar improvements in LV function and dimensions over time. MK serum levels were significantly higher in DCM/ DCMi patients than in healthy individuals but did not differ significantly between DCM and DCMi. MK levels did not significantly correlate with NYHA class, NT-proBNP, LVEDD, or LVEF, except for a weak correlation with LVEF at follow-up. Conclusions: Midkine serum levels were significantly higher in patients with a DCM phenotype and severely reduced systolic function. However, these levels could not distinguish between DCM and DCMi and showed no correlation with baseline or follow-up parameters. Therefore, midkine cannot be used as a biomarker to distinguish between DCM and DCMi. Full article

Background: Elevated estrogen has been found to contribute to the pathological development of endometrial cancer (EC), potentially through alterations in the tumor inflammatory immune microenvironment. However, the exact mechanisms underlying this process remain unclear. Methods: Bioinformatics was used to identify differentially expressed genes, analyze pathway enrichment, and assess their correlation with immune cell infiltration. Ishikawa cells and ECC-1 cells were stimulated with estradiol (E2) or the selective estrogen receptor modulator Arzoxifene, and qPCR was performed to measure gene expression changes. CCK8 and FACS assays were used to analyze cell cycle alterations, while Western blotting (WB) was used to evaluate apoptosis. Results: ZNF626 and SLK were highly expressed in EC tissues, whereas RFWD3 expression was downregulated. Immune cell infiltration analysis revealed a positive correlation between ZNF626 and M2 macrophages, while SLK was negatively correlated with M1 macrophages, memory B cells, and plasma cells. RFWD3 showed more complex correlations with multiple immune cell phenotypes, including T cells. E2 stimulation resulted in the increased expression of ZNF626 and SLK, while RFWD3 expression decreased. This was accompanied by enhanced cell proliferation and suppressed apoptosis. In contrast, Arzoxifene stimulation produced the opposite effects. Conclusions: Estrogen promotes cell proliferation and inhibits apoptosis by upregulating ZNF626 and SLK, while downregulating RFWD3. Furthermore, estrogen induces a shift in the tumor microenvironment, characterized by a reduction in memory CD4+ T cells and a transition from M1 to M2 macrophage phenotypes, thus facilitating the onset and progression of EC. Full article

Several etiologic factors for the development of acute leukemias have been suggested; however, none is applicable to all cases. We isolated a certain mycovirus-containing Aspergillus flavus (MCAF) from the home of a patient with acute lymphoblastic leukemia. Repeated electron microscopic evaluations proved the existence of mycovirus in this organism. According to chemical analysis, this organism does not produce any aflatoxin, possibly due to its infestation with mycoviruses. We reported that using the ELISA technique, forty pediatric patients with acute lymphoblastic leukemia (ALL) uniformly had antibodies to the products of MCAF. In contrast, three separate groups of controls, consisting of normal blood donors, individuals with solid tumors, and patients with sickle cell disease, were negative. In vitro exposure of mononuclear blood cells from patients with ALL, in full remission, to the products of MCAF induced redevelopment of cell surface phenotypes and genetic markers characteristic of ALL. The controls were negative. The incubation of normal and ALL cell lines with the products of MCAF resulted in significant cellular apoptosis, changes in the cell cycle, and the downregulation of transcription factors, including PAX-5 and Ikaros (75 and 55 kDa). Fungi are widespread in nature, and many contain mycoviruses. Normally, an individual inhales 1 to 10 fungal spores per minute, while farmers can inhale up to 75,000 spores per minute. It is known that farmers and foresters, who are more exposed to fungi, have a higher rate of acute leukemia. In contrast, asthmatics, most of whom are allergic to fungal agents, and individuals working in office settings have a lower rate. One of the theories for the development of acute leukemia suggests a genetic predisposition followed by exposure to an infectious agent. With the above findings, we propose that mycovirus-containing Aspergillus flavus may have an etiological role in leukemogenesis in immune-depressed and genetically susceptible individuals. Full article

Background and Objectives: As a key mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, inflammation triggered by chronic liver injury and immune cells with macrophages enables MASLD to progress to an advanced stage with irreversible processes such as fibrosis, cell necrosis, and cancer in the liver. The complexity of MASLD, including crosstalk between multiple organs and the liver, makes developing a new drug for MASLD challenging, especially in single-drug therapy. It was reported that upregulation of Notch1 is closely associated with the function of pro-inflammatory macrophages. To leverage this signaling pathway in treating MASLD, we developed a combination therapy. Materials and Methods: We chose Notch1 siRNA (siNotch1) to block the Notch pathway so that phenotypic regulation and functional recovery can be achieved in macrophages, combining with small molecule drug AMD3100. AMD3100 can cut off the migration of inflammatory cells to the liver to impede the development of inflammation and inhibit the CXCL12/CXCR4 biological axis in liver fibrosis to protect against the activation of HSCs. Then, we investigated the efficacy of the combination therapy on resolving inflammation and MASLD. Results: We demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release. The restored macrophages further regulate HSC and neutrophils. In in vivo pharmacodynamic studies, combination therapy exhibits a superior therapeutical effect over monotherapy in MASLD models. Conclusions: These results constitute an siRNA therapeutical approach combined with a small molecule drug against inflammation and liver injury in MASLD, offering a promising therapeutic intervention for MASLD. Full article

Near-infrared light (NIR)-responsive metal-based nanoparticles (NPs) could be used for tumour therapy. We examined how platinum (Pt), gold (Au), and core-shell Pt-Au NPs affect the viability of human hepatocellular carcinoma (HCC) cell lines (Hep3B, HepG2, and Huh7D-12) alone and in combination with NIR exposure. In addition, the expression of immune checkpoint molecules (ICMs) on the tumour cells was analysed. We revealed that the cytotoxicity and programmed cell death induction of Au and Pt-Au NPs toward HCC cells could be enhanced by NIR with 960 nm in a different way. Pt-Au NPs were the only particles that resulted in an additional temperature increase of up to 2 °C after NIR. Regarding the tumour cell immune phenotype, not all of the cells experienced changes in immune phenotype. NIR itself was the trigger of the alterations, while the NPs did not significantly affect the expression of most of the examined ICMs, such as PD-L1, PD-L1, HVEM, CD70, ICOS-L, Ox40-L, and TNFRSF9. The combination of Pt-Au NPs with NIR resulted in the most prominent increase of ICMs in HepG2 cells. We conclude that the thermotherapeutic effect of Pt-Au NP application and NIR could be beneficial in multimodal therapy settings in liver cancer for selected patients. Full article

Silver carp is a critically significant species in freshwater aquaculture in China, characterized by its limited tolerance to hypoxia. In this study, a significant SNP locus at Chr8: 29647765 (T/C) associated with hypoxia tolerance traits was identified in Changfeng silver carp, and the homozygotic CC genotype exhibited higher hypoxic tolerance than the homozygotic TT and heterozygotic TC genotypes. Under hypoxic conditions, the hemoglobin concentration increased, with the CC genotype demonstrating a significantly higher level compared with the TT genotype; the activities of antioxidant enzymes including catalase and superoxide dismutase were significantly higher in the CC genotype than in the other genotypes; the area of the gill lamellae was significantly smaller in the CC genotype than in the TT and TC genotypes; and the number of apoptotic cells in the brain was significantly lower in the CC genotype than in the TT and TC genotypes. Sequence analysis showed that this SNP was located in the promoter region of the cathepsin C (CTSC) gene. The expression levels of the CTSC gene were analyzed across the three genotypes, revealing that the CC genotype exhibited significantly lower expression compared with the TT and TC genotypes under hypoxia. This finding suggests that the SNP associated with the CC genotype leads to reduced CTSC expression, which may facilitate better physiological adaptation to hypoxia. Analysis of the promoter region of CTSC found a unique predicted hypoxia-inducible factor 1-alpha (HIF-1α) binding site (CGTG) in the T genotype, implying that the differential expression of CTSC among the three genotypes under hypoxic stress may be regulated by HIF-1α, a transcription factor integral to hypoxia adaptation, thereby affecting hypoxia tolerance, which further affects the immune response of the Changfeng silver carp in response to the hypoxic environment. Although SNPs represent significant genetic determinants, their phenotypic effects are predominantly mediated through complex interactions within gene regulatory networks and environmental influences. This study identified an effective SNP site in Changfeng silver carp, providing valuable guidance for future selective breeding and the development of new hypoxia-tolerant varieties. Full article

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells’ invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma. Full article

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) requires lifelong glucocorticoid replacement to manage cortisol deficiency and excessive androgen production. Conventional circadian treatment (CT) tries to mimic natural cortisol rhythms, whereas reverse-circadian treatment (RC) prioritizes the suppression of adrenal androgen excess overnight through evening dosing. Limited data exist on the immunological impact of these regimens. A bi-centric study was conducted, including 41 pediatric and adolescent CAH patients. Peripheral blood samples were collected from patients on conventional treatment (n = 38) or RC (n = 16), with 11 RC patients switching to conventional treatment. Immune cell phenotypes, cytokine profiles, and natural killer (NK) cell cytotoxicity were assessed. Patients receiving RC showed lower percentages of CD4+CD25+ T cells (p = 0.0139). After the switch, patients with RC presented with a higher percentage of non-classical monocytes (p = 0.0255) and a lower percentage of Th17 cells (p = 0.0195). A lower expression of CD107 was observed with RC (p < 0.0001), as well as a higher percentage of NKp30 (p = 0.0189). Comparing patients after the switch from RC to HC, patients with RC presented with a lower NKG2D expression (p = 0.0420). Both conventional treatment and RC exhibited distinct immunological impacts, with CT showing modest advantages in normalizing immune phenotypes. These findings suggest that CT may offer immunological benefits for managing young patients with congenital adrenal hyperplasia. Full article

The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer’s disease (AD). Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGSs) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGSs in both the overall sample and a subgroup of older participants (>60 years). While we did not find any significant associations between immune cell subtypes and ALS and AD PGSs when controlling for the false discovery rate (FDR = 0.05), we observed several nominally significant results (p < 0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p = 0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naïve CD57+ CD8+ T cells and mature NKG2A+ natural killer cells showed nominally significant associations. We did not observe major immune cell changes in individuals at high genetic risk of ALS or AD, suggesting they may arise later in disease progression. Additional studies are required to validate our nominally significant findings. Full article

The serine protease prostasin on the surface of the exosomes released from epithelial cells can interact with ectopically over-expressed cell-surface serine protease matriptase in cancerous B cells to initiate the prostasin–matriptase proteolytic activation cascade. Matriptase activation and the ensuing self-activation result in its removal from cancer cells, reducing cell proliferation and migration. In this study, we tested the hypothesis that the matriptase in the lymphoid cells could be removed by the prostasin-initiated activation and self-activation using genetically engineered autologous cells carrying prostasin. In co-cultures with the prostasin-positive cells, the matriptase on the prostasin-negative vector-control cells was removed in a dose-dependent manner, as determined by flow cytometry. This paracrine phenotype requires the active sites of both proteases. In silico analysis of the RNA-seq profiles indicated an imbalanced expression of high matriptase and low prostasin, and their cognate protease inhibitors in B-cell lymphoma patient specimens. The impact of exosomal prostasin on the cluster of differentiation molecules in activated human peripheral blood mononuclear cells was investigated by flow cytometry, revealing candidate mechanisms for prostasin’s role in regulating cellular adaptive immunity. This autologous paracrine prostasin–matriptase interaction could be exploited as a method for targeting over-expressed matriptase in diseases such as B-cell lymphoma. Full article

The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16 ^INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level. The P16-3MR mouse model harbors the p16^INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo identification of p16 ^INK4a activation at the cellular level and the consequences of selective elimination of p16^INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16^INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry. Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD. Full article