Search Results (54,304)

Natural killer (NK) cells are effector cells of the innate immune system. The cytokine microenvironment influences NK cell function. Dysregulation of NK cell cytotoxicity can manifest in reproductive disorders and is also observed in tumor-transformed tissues. The search for immunotherapies capable of regulating NK cell activity is therefore relevant. This study aimed to evaluate the effect of the TGFβ signaling pathway inhibitor and the cyclin-dependent kinase (CDK) 7/12/13 inhibitor on the transcriptional profile of NK-92 cell line. In the study, the cytokines TGFβ1, IL-12, IL-15, IL-18, and TNFα, and the TGFβ receptor type 1 (TGFβR1) inhibitor LY3200882 and the CDK7/12/13 inhibitor THZ1 were used. The cells were cultured sequentially in the presence of inhibitors and cytokines, followed by assessment of the gene expression of NCR2, NCR3, AHR, NCAM1, B3GAT1, EOMES, GATA3, KLRC1, KLRC2, CCL5, IL10 and TBX21. We observed direct effects of the inhibitors on NK cells. LY3200882 increased the expression of KLRC1 and B3GAT1, and reduced NCAM1. THZ1 increased the expression of KLRC1, KLRC2, AHR and EOMES, while it reduced IL-10 and NCR2. IL-12, IL-15, IL-18, and TNFα modified the gene expression of some phenotypic and cytotoxic receptors and transcription factors. TGFβ1 increased the expression of KLRC1, NCAM1, and B3GAT1. Blocking TGFβ-dependent signaling with LY3200882 abolished TGFβ1 effects. We assessed CD56 presence on NK-92 cell membrane and found its increase in the presence of LY3200882. After LY3200882 treatment, in the presence of TGFβ1 and choriocarcinoma cell line JEG-3, the expression of CD56 receptor on NK cell membrane decreased. Pretreating NK cells with THZ1 decreased the expression of NCAM1, B3GAT1, and EOMES in the presence of TGFβ1. Thus, LY3200882 partially neutralized TGFβ1 effects on the expression of NK cell receptor genes. THZ1 followed by TGFβ1 treatment promoted NK cell transcriptional profile characteristic for CD56dim NK cells. Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered. Full article

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy. Full article

Adenomyosis is a benign gynaecological disorder in which endometrial glands and stroma enter the uterine myometrium with varying degrees of spreading. To analyse the presence of developmentally displaced endometrial glands and stroma in the foetal myometrium, a retrospective cohort of 420 foetal uteri, including one monozygotic twin pair, was histopathologically evaluated. The gestational age ranged between 18 and 37 weeks; the clinical characteristics included various foetal malformations with a predominantly normal karyotype, except in one case with trisomy 18. Ectopic endometrial tissue enclosed in the myometrium was discovered in twelve individual foetuses from the cohort (12/420). The investigation of the histogenetic attributes of the misplaced endometrial tissue in both monozygotic twins’ (MZ) foetal uteri revealed isolated glands and thin channels containing cords of endometrial-type glands penetrating the myometrium. Through immunohistochemistry, low levels of oestrogen receptors (ERs) were detected, whereas a moderate level of progesterone receptor (PR) expression was observed in the ectopic glandular and stromal cell nuclei in all cases. Additionally, the surrounding periglandular component consistently expressed the vimentin and CD10 stromal cell markers, while the myometrial smooth muscle cells revealed the strong expression of both alpha-Smooth Muscle Actin (α-SMA) and desmin marker proteins. Full article

Background/Objectives: While standard antiemetic regimens have evolved, breakthrough symptoms and anticipatory nausea persist. Lorazepam has historically been used as an adjunct, yet a comprehensive re-evaluation of its efficacy across historical trials is lacking. This study provides a synthesis of clinical evidence to re-evaluate the adjunctive therapeutic value of lorazepam, potentially addressing persistent gaps in emesis control, such as anticipatory and refractory symptoms. Methods: Following PRISMA guidelines, we analyzed eight randomized controlled trials (n = 864) published between 1989 and 1997. Primary endpoints included complete and improved responses for emesis and nausea. Results: Eight trials (n = 864), published between 1989 and 1997, met the inclusion criteria. Lorazepam-containing regimens significantly increased the complete response rate for overall emesis (OR = 1.55; 95% CI, 1.12–2.14; p = 0.008) and improved the response rate (OR = 1.50; 95% CI, 1.03–2.19; p = 0.04). Subgroup analysis of acute emesis showed consistent benefits (complete response OR = 1.77; 95% CI 1.23–2.55; p = 0.002). Nausea control also favored lorazepam, although the differences were not statistically significant. Sedation was more frequent with lorazepam (RR = 2.67; 95% CI 1.54–4.63), although no serious adverse events were reported. Conclusions: By revisiting decades of clinical evidence, this meta-analysis confirms that lorazepam provides a significant therapeutic advantage in controlling chemotherapy-related vomiting, particularly during the acute phase. While its direct efficacy alongside modern agents like NK1 receptor antagonists remains to be fully elucidated, the anxiolytic and amnestic properties of lorazepam remain a potential adjunct for managing complex CINV profiles. Careful dose titration is necessary to balance efficacy with sedation. Full article

Background/Objective: In lung cancer treatment, increasing the concentration of antitumor drugs at the tumor site, enhancing efficacy, and reducing systemic toxicity are significant challenges. This study aims to develop an intelligent responsive polymer micelle system (GPDD) that achieves efficient accumulation and controlled release of drugs at lung tumor sites through targeted and pH-responsive design. Methods: The GPDD system is formed by the self-assembly of GE11-PEG-hyd-DOX conjugates and co-loads free DOX. This system utilizes the targeting effect of the GE11 peptide with the epidermal growth factor receptor (EGFR) to accumulate at the tumor site, while the hydrazone bond serves as a pH-responsive linker that breaks in the acidic tumor microenvironment, triggering drug release. Experiments employed CCK-8 cytotoxicity assays and tumor-bearing nude mouse models (strain not specified) for in vitro and in vivo evaluations. Results: In vitro experiments showed that GE11-modified GPDD effectively inhibited tumor cell growth. In tumor-bearing nude mouse experiments, GPDD demonstrated more significant tumor suppression effects and lower systemic toxicity compared to free DOX and unmodified PDD. Conclusions: The GPDD nanocarrier integrates targeting and pH responsiveness, improving antitumor efficacy and reducing side effects, with translational potential. The novelty of the study lies in its dual-functional design and co-loading strategy, providing new insights for tumor-targeted delivery systems. Full article

Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, γδ T cells, which express alternative T cell receptors, have emerged as a key immune component. This study examined the roles of αβ and γδ T cells in arteriogenesis using a murine hindlimb model. While the absence of αβ T cells did not affect arteriogenesis, γδ T cell depletion markedly reduced vascular cell proliferation and perfusion recovery. Early phase analyses revealed impaired mast cell activation, whereas platelet–neutrophil aggregates and neutrophil extravasation were unaffected. In the later proliferative phase, γδ T cell depletion hindered perivascular M2-like (MRC1⁺) macrophage accumulation. Flow cytometric analysis of whole blood in wildtype mice revealed a temporal shift in γδ T cell populations from a CD27⁺/CD39⁻ phenotype, commonly associated with pro-inflammatory functions and IFNγ production, to CD39⁺ phenotypes, which have been linked to anti-inflammatory properties and IL-10 production. In rescue experiments, administration of IFNγ to γδ T cell-depleted mice restored mast cell activation, whereas IL-10 treatment reestablished M2-like (MRC1⁺) macrophage accumulation. These findings collectively identify γδ T cells as critical regulators of both early and late phases of arteriogenesis through coordinated inflammatory and regenerative mechanisms. Full article

Against the backdrop of the full implementation of “antibiotic ban” and “zinc restriction” policies in livestock and poultry breeding, and the growing consumer demand for safe livestock and poultry products, the development of natural and efficient green feed additives has become crucial for the sustainable development of the animal husbandry industry. Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa L., has attracted extensive attention in poultry production due to its various biological activities and safety. This paper thoroughly reviews the chemical structure and physicochemical properties of curcumin, and elaborates on its core molecular mechanisms of action, which mainly involve the regulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptor γ (PPAR-γ), and mitogen-activated protein kinase (MAPK) pathways to exert antioxidant, anti-inflammatory, antibacterial, immunomodulatory and lipid metabolism regulatory effects. It further clarifies the practical application value of curcumin in major poultry species including broilers, laying hens, ducks and quails, showing that curcumin can significantly improve poultry production performance, optimize meat and egg quality, protect intestinal health, and enhance the ability of poultry to resist stress and diseases. Meanwhile, the review notes curcumin’s current application limitations (low bioavailability, poor stability, unclear standardized dosage, and high industrialization cost) and proposes targeted future research directions to address these issues. In conclusion, curcumin is a promising green feed additive alternative to antibiotics, and its large-scale and standardized application in poultry production will effectively promote the green, healthy and sustainable development of the poultry industry. Full article

As a representative form of extreme weather, typhoons inflict widespread and systemic damage, posing a severe threat to the livestock industry. The stress they induce, typhoon stress (TS), is an unavoidable and complex environmental challenge that severely disrupts the ovarian function of Wenchang chickens. In this preliminary study, we employed a two-group comparison design (n = 6 per group) integrating behavioral observations, serum biochemical assays, histopathological examinations, and molecular analyses (qPCR, 16S rDNA sequencing, and transcriptome sequencing) to explore the role of the microbiota–gut–brain–ovarian axis (MGBOA) in this process. The findings revealed that TS markedly reduced water intake and locomotor activity, while it elevated serum corticosterone (CORT) and oxidative stress markers. It also induced shifts in gut microbiota composition, including a decrease in Bacteroides and an increase in Escherichia–Shigella. Furthermore, TS compromises duodenal intestinal barrier integrity, as evidenced by downregulation of the tight junction proteins TJP1 and CLDN1, structural damage to intestinal villi, and a reduced villus-to-crypt ratio. In the hypothalamus, VIP mRNA expression was upregulated, while GHSR expression was downregulated; the expression of the tight junction protein CLDN5 was also reduced. In the ovary, reproductive potential was suppressed, manifested by a reduction in follicle number and downregulation of STAR expression. Ovarian transcriptome analysis highlighted enrichments in pathways associated with inflammation (e.g., Toll-like receptor signaling) and lipid metabolism (e.g., PPAR signaling). These results support the hypothesis that TS impairs egg production via the MGBOA, providing preliminary mechanistic insights into how environmental stressors might disrupt animal productivity through MGBOA-mediated pathways. Full article

Background/Objective: This study is a cross-sectional investigation of long-term immune responses measured at different time intervals after COVID-19 infections, vaccinations, or combined exposure. The focus is on immune reactivity against recombinant spike (S) and nucleocapsid (N) protein antigens. Materials and Methods: Serum antibody levels were assessed up to four to four and a half years after infection or immunization, including virus-specific immunoglobulin G (IgG), IgA and IgM antibodies, as well as neutralizing antibodies against the S-protein. Cellular immunity was assessed by analyzing peripheral blood mononuclear cells (PBMC; n = 43 in first cohort, n = 32 in second cohort), including T-helper memory and cytotoxic subsets, and cytokine production after in vitro stimulation with recombinant SARS-CoV-2 proteins. A multiplex cytokine assay was used to analyze effector and regulatory immune responses. Results: Virus-specific IgG antibodies persisted for years after exposure to SARS-CoV-2, with IgG against the receptor-binding domain (RBD) correlating most strongly with neutralizing activity. Vaccinated individuals demonstrated higher IgA responses, whereas antibodies to the N-protein were associated with previous infection. No IgM antibodies were detected in any subjects, suggesting an immune response based on memory rather than ongoing infection. PBMCs from individuals with a history of both COVID-19 exposure and vaccination exhibited enhanced responsiveness, characterized by increased frequencies of memory T cells compared to vaccination alone. Stimulating with the S-protein induces higher cytokine production, including IFN-gamma, TNF-alfa, and IL-12(p70), compared with stimulation by the N-protein. Cytokines such as IL-10 and TGF-beta are also elevated, suggesting immune regulation rather than persistent inflammation. Conclusions: SARS-CoV-2 infection and vaccination are associated with persistent humoral and cellular immune responses detectable several years after exposure. Individuals with hybrid immunity exhibit broader and functionally enhanced immune reactivity, indicating more robust long-term immune memory. Future studies should focus on the long-term consequences of hybrid immunity and optimize other vaccine strategies, including recombinant antigen vaccines. Full article

Podocyte injury is a characteristic feature of focal segmental glomerulosclerosis (FSGS) that leads to the development of nephrosis as its loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium levels; an excess or shortage of calcium influx in these cells may result in foot process effacement, apoptosis, and nephron degeneration. A key protein responsible for the regulation of calcium flux is the canonical transient receptor potential 6 (TRPC6) expressed in podocytes. Several mutations in the TRPC6 gene have been associated with FSGS. Here we present a systematically optimized inducible FSGS model system in human induced pluripotent stem cells (hiPSCs). We generated and phenotypically characterized three transgenic hiPSC lines with regulatable overexpression of TRPC6 wild-type and FSGS-associated gain-of-function (GoF, P112Q) and loss-of-function (LoF, G757D) mutations. Moreover, these cell lines were differentiated into induced podocytes (ipodocytes). We assessed the impact of TRPC6 GoF and LoF mutants on calcium influx in combination with TRPC6 agonists and antagonists. Our data showed relative calcium responses consistent with the GoF and LoF phenotypes. Transgenic iPSC-based models, like the one presented here, are instrumental to studying disease mechanisms in vitro and investigating the outcomes of, and possible therapeutic interventions for, this complex disease. Full article

Background/Objectives: Glioblastoma remains the most lethal primary brain tumor in adults, and progress in oncolytic virotherapy is limited by the lack of immunocompetent models permissive to human-tropic viruses. Methods: Here, murine CT-2A and GL261 glioma and B16 melanoma cell lines were engineered to express human Coxsackievirus and Adenovirus Receptor (CXADR) fused to tagBFP, generating “humanized” tumors that preserve parental growth characteristics while acquiring high susceptibility to group B Coxsackieviruses (CVBs) and adenovirus serotype 5. Results: CXADR expression in CT-2A, GL261, and B16 cells markedly enhanced binding, internalization, and replication of CVBs in vitro, with the strongest effect observed for LEV14 (attenuated CVB5), which reached up to 10⁵-fold higher viral titers in humanized cells compared with parental cells. Unchanged sensitivity to vesicular stomatitis virus indicated receptor-specific effects. Humanized CT-2A-CXADR-BFP and GL261-CXADR-BFP cells initiated aggressive subcutaneous and intracranial tumors in syngeneic C57BL/6 mice without signs of immune rejection, and histology and MRI confirmed invasive high-grade glioma phenotypes. In intracranial CT-2A-CXADR-BFP tumors, repeated intratumoral LEV14 administration induced extensive tumor necrosis and prolonged survival despite the rapid development of neutralizing antibodies. Systemic intravenous LEV14 dosing produced strong oncolytic activity against subcutaneous CT-2A-CXADR-BFP tumors, as demonstrated by pronounced tumor growth inhibition, long-lasting regression in a subset of animals with gliomas, and improved overall survival. Conclusions: Collectively, these data establish CXADR-humanized models as versatile, immunocompetent platforms for evaluation of CXADR-dependent oncolytic enteroviruses. Full article

Obesity, a heterogeneous metabolic disease, is linked with severe comorbidities, prominently increasing morbidity and mortality. A weight loss between 5% and 10% is already sufficient to induce clinically relevant improvements in human health. Activation of energy expenditure through an impact on the brown and beige adipose tissues has recently become an interesting new target in obesity treatment. Obeticholic acid (OCA) is a semisynthetic derivative of the primary human bile acid, chenodeoxycholic acid. The compound is an agonist of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor (TGR5), activating the cellular pathways such as fibroblast growth factor-19, tissue-specific uncoupling protein 1, or type 2 iodothyronine deiodinase associated with energy expenditure and brown adipose tissue activity. So far, OCA has been approved to treat primary biliary cholangitis. Interestingly, the drug demonstrated therapeutic effects in animal models of obesity. Preliminary results from the human studies show that OCA administration holds potential as a treatment option in obesity, although some adverse effects may occur. Long-term administration of OCA might constitute an attractive therapeutic add-on approach, complementary to the currently approved treatments. The design of OCA derivatives targeting similar mechanisms, yet with a better pharmacological profile, seems to be an exciting pathway in the search of novel anti-obesity drugs. Further clinical trials involving larger cohorts of patients, with and without comorbidities, are warranted to confirm the benefits and safety of OCA administration. Full article

The use of colored LED lights is a tool for controlling the development of lymphoid organs and the immune system in general. This study aims to analyze the effects of using simple and combined colored LED lights throughout a 6 week period (1–42 days of age). In this study, 336 one-day-old chicks were used, separated randomly into four groups with different sex and lighting systems, with each group being divided into four separate replicates (4 × 21 birds). The chicks in the WL-Male and WL-Female were exposed to white LED light (WL, 400–760 nm) for 6 weeks, while the chicks in the G-GxB-BL-Male and G-GxB-BL-Female were exposed to a combination of monochromatic lights as follows: green (560 nm) from 1 to 14 days of age, green and blue (480–560 nm) for 15–28 days of age, and blue lights (480 nm) for 29–42 days of age. The use of a mixture of green and blue LED lights (G-GxB-BL) resulted in a significant decrease in the average daily feed intake and feed conversion ratio compared to white light, without causing changes in the body weight of the chicks, average daily gain, mortality rate, and coefficient of variability. G-GxB-BL lights also improved the morphological development of the bursa of Fabricius (BF) compared to white light by significantly increasing the organ index and the lymphoid follicle area. At the same time, G-GxB-BL light compared to white light improved B lymphocytes proliferation in the BF by significantly increasing the lymphocyte density in lymphoid follicles, as well as the number of PCNA-positive cells. This light treatment had these results due to the activation of melatonin receptors, which led to a significant increase in Mel1a-positive cells and a significant decrease in the number of RORα-positive cells. These results demonstrate that G-GxB-BL lights improved the growth performance and immune response in the BF of broiler chickens. Full article

For over a decade, non-integrating Sendai virus vectors have been the gold standard for induced pluripotent stem cell (iPSC) reprogramming. However, as the field shifts toward regenerative and precision medicine and large-scale biorepositories, Sendai virus workflow necessitates dedicated viral-clearance testing, specialized manufacturing controls, and heightened regulatory oversight, leading to increased cost. While mRNA-based reprogramming offers a non-viral alternative, traditional mRNA delivery methods like electroporation are often physiologically disruptive. This study evaluates an mRNA-reprogramming platform that delivers lipid nanoparticles (mRNA-LNPs) via receptor-mediated endocytosis. By utilizing both Sendai virus and mRNA-LNP approaches to reprogram PBMCs from the same donor, we established a genetically identical starting point. Results demonstrate that mRNA-LNP-reprogrammed iPSCs maintain genomic integrity, retain the donor KCNH2 c.2398+5G>T variant, and exhibit characteristic colony morphology, pluripotency markers, and trilineage differentiation capacity consistent with the Sendai-reprogrammed counterparts. The mRNA-LNP-reprogrammed iPSCs differentiate into iPSC-derived cardiomyocytes presenting sarcomeric structures and electrophysiological activity, recapitulating a disease-specific phenotype. Notably, the mRNA-LNP workflow reached these milestones in significantly fewer passages than the Sendai virus workflow, markedly shortening timelines and reducing costs. These findings highlight mRNA-LNP reprogramming as a potentially attractive and effective, virus-independent platform to support future regenerative and precision medicine initiatives and scalable biobanking. Full article

Many approved oral paediatric medicines continue to have poor taste acceptance, suggesting that the ingredient blends employed in these medicines are not adequately effective in taste-masking drugs with strongly aversive tastes. To address this inadequacy, this narrative review provides a comparative evaluation of taste-masking ingredients used by the pharmaceutical industry with those employed in the food industry, as well as food items used by caregivers to mask the unpalatable taste of medicines for young children. Information was sourced from academic databases, industry publications, and caregiver forums on informal social platforms. Ingredients were classified into sweeteners, salts, acids, fats, peptides/amino acids, flavourants, cyclodextrins and polymers, with their taste-masking mechanisms delineated into receptor-level interactions and the creation of physical barriers and alternative dominant taste. Their applications are compared across the regulated medicinal and consumer food products, and in home remedies. Sweeteners show the highest cross-domain convergence as they are used in medicinal and food products and are recommended by caregivers. Peptides, amino acids, salt and texture modifiers applied in food and home remedies may have translational potential in medicines. Challenges, including drug–food interactions, regulatory constraints, and the need for combination approaches, are addressed. A decision framework is also designed to guide the development of simple, acceptable, and effective ingredient-based taste-masking systems for drugs with aversive tastes. Full article