Search Results (953)

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane, leading to viral infection. Several mutations in S1-RBD in SARS-CoV-2 variants are known to enhance infection through an increased affinity for ACE2. While many reports are available describing the SARS-CoV-2 infection mechanism, there is a dearth of studies towards understanding the initial interaction of the S1-RBD with ACE2 on living host cells and the role of endocytosis and cytoskeleton in the process. Here, we reconstituted the interaction between S1-RBD- and ACE2-expressing host cells in a hybrid live cell-supported lipid bilayer (SLB) platform enabling live monitoring of the interaction between S1-RBD on SLBs and the ACE2 receptor on living cells and showed that cells depleted Omicron S1-RBD from SLB corrals, likely through endocytosis. Specifically, interaction of living host cells with S1-RBD-functionalized SLB substrates resulted in the enrichment of S1-RBD and ACE2 at the cell–SLB interface. Interaction of host cells with wild type (WT), Omicron, and Omicron Revertant S1-RBD functionalized on micron-scale SLB corrals, which mimic viral membranes but are flat, also resulted in their enrichment. However, cells interacting with Omicron S1-RBD revealed a depletion of the protein from many corrals, which was generally not observed with the WT S1-RBD and was reduced with the Omicron Revertant, which contains the Q493R mutation reversion, S1-RBD. Further, S1-RBD depletion coincided with the localization of the early endosomal marker EEA1. Importantly, treatment of cells with the clathrin inhibitor, pitstop 2, but not the myosin II inhibitor, blebbistatin, significantly reduced Omicron S1-RBD depletion. Collectively, these observations suggest that the SARS-CoV-2 Omicron variant has evolved, through mutations in its S1-RBD, to take advantage of the cellular endocytic pathway for enhanced infection, which is not observed with the parental SARS-CoV-2 and appears to be lost in the Omicron Revertant variant. Additionally, these results underscore the significance of the hybrid live cell–SLB platform in studying SARS-CoV-2 S1-RBD-ACE2 interaction and the potential impact of mutations in the S1-RBD on adapting to a specific cellular entry mechanism. Full article

Testing medical countermeasures for SARS-CoV-2 transmission using vertebrates can be hindered by legislation regulating animal experimentation, high costs, and ethical concerns. To overcome these challenges, we propose a new Caenorhabditis elegans strain that constitutively expresses the human angiotensin-converting enzyme 2 receptor (ACE2). This resulted in significant impairment of reproduction and a defect in pharyngeal function compared to wild-type (WT) worms. SARS-CoV-2 infection was simulated by treating worms with the receptor-binding domain (RBD) of the spike protein, which caused dose-dependent and time-dependent pharyngeal impairment in ACE2 worms but not in WT worms. The toxicity of RBD was prevented by administering an anti-human ACE2 antibody, demonstrating that interactions with the ACE2 receptor are essential. The ACE2-expressing worm strain was further used for pharmacological research with Raloxifene. In vitro, 1–3 μM of Raloxifene reduced the entry of lentiviral particles carrying the Wuhan variant and B.1.1.7 UK and B.1.1.529 Omicron strains into HEK293-ACE2, in addition to particles expressing N501Y-mutated or P681H-mutated spike proteins. Raloxifene (0.1–1 μM) completely counteracted RBD toxicity in ACE2 worms, indicating that this strain offers a cost-effective in vivo screening platform for molecules with effects involving interactions with the ACE2 receptor. Full article

Chickpea protein hydrolysates have antihypertensive potential. However, neither the effect of their daily consumption on blood pressure (BP) nor their potential antihypertensive mechanisms has been evaluated. Thus, both the antihypertensive effect of an optimized chickpea protein hydrolysate (OCPH) and its potential mechanisms were assessed in spontaneously hypertensive rats. OCPH (50 mg/kg of body weight) was supplemented daily (5 weeks), BP levels were measured, and mRNA relative levels (angiotensin-converting enzyme-I (ACE1), renin, AT₁R receptor, ACE2 and Mas1) in the kidneys were determined. BP (systolic, diastolic, and mean) levels were lowered after five days of OCPH supplementation (p < 0.05 vs. control group) and the hypotensive effect was up to −39.80 mmHg (p < 0.05). Furthermore, the supplementation increased ACE2 (67.30%) and Mas1 (61.1%) mRNA levels (p < 0.05 vs. control group). ACE1, renin and AT₁R receptor mRNA levels were similar between groups (p > 0.05). A negative correlation of ACE2 mRNA levels with BP was found (p < 0.05). The findings support that OCPH activates the ACE2/Ang-(1–7)/Mas1 pathway of the renin–angiotensin–aldosterone system, maintaining a reduction in BP after daily supplementation. Further studies to evaluate the potential of the OCPH for functional food and nutraceutical development are justified. Full article

This study investigated the interactive effects of dietary vitamin A (VA) and all-trans retinoic acid (ATRA) on growth performance and intestinal health in broilers. A total of 432 one-day-old male Arbor Acres chicks were assigned to a 2 × 3 factorial design with two VA levels (2000 and 6000 IU/kg) and three ATRA levels (0, 0.25, and 0.50 mg/kg). The maize–soybean meal basal diet contained 180 IU/kg VA without extra VA supplementation. Results showed that compared with 0 mg/kg ATRA, 0.50 mg/kg ATRA enhanced average daily gain (ADG) during days 1–21 (p < 0.05). Compared with 2000 IU/kg VA, 6000 IU/kg VA improved body weight on day 35 as well as ADG and feed intake during days 22–35 and reduced feed conversion ratio over the entire trial (p < 0.05). There were VA × ATRA interactions for the ratio of villus height (VH) to crypt depth (CD) in duodenum as well as VH and CD in ileum on day 21 (p < 0.05). The 0.25 mg/kg ATRA decreased duodenal VH/CD and ileal VH in broilers fed 2000 and 6000 IU/kg VA, respectively (p < 0.05). The 0.50 mg/kg ATRA increased ileal VH in broilers fed both 2000 and 6000 IU/kg VA (p < 0.05). When birds were fed 6000 IU/kg VA, 0.50 mg/kg ATRA increased ileal CD compared with 0.25 mg/kg CD (p < 0.05). On day 35, compared with 0 mg/kg ATRA, 0.25 mg/kg ATRA increased ileal VH while 0.50 mg/kg ATRA decreased ileal CD, and both of them increased ileal VH/CD (p < 0.05). The VA × ATRA interactions for mRNA expression of jejunal Mucin5ac on day 21 and jejunal Occludin, Claudin-1, Mucin 2, leucine-rich-repeat-containing G-protein-coupled receptor 5⁺ (Lgr5⁺), zinc and ring finger 3 (Znrf3), and secreted phosphoprotein 1 (SPP1) on day 35 were detected (p < 0.05). Dietary 0.50 mg/kg ATRA up-regulated jejunal Mucin5ac expression in broilers fed 6000 IU/kg VA on day 21 as well as Claudin-1, Znrf3, and SPP1 expression broilers fed 2000 IU/kg VA on day 35 (p < 0.05). The 0.25 mg/kg ATRA down-regulated Occludin expression in broilers fed 6000 IU/kg VA on day 35 (p < 0.05). The 0.25 mg/kg ATRA decreased and increased Lgr5⁺ expression on day 35 in broilers fed 2000 and 6000 IU/kg VA, respectively (p < 0.05). Both 0.25 and 0.50 mg/kg ATRA down-regulated Mucin-2 expression in broilers fed 2000 IU/kg VA on day 35 (p < 0.05). The VA × ATRA interactions were observed for jejunal retinol dehydrogenase 10 (RDH10), cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), retinoic acid receptor (RAR) α, and RARβ expression on days 21 and 35 (p < 0.05). Both 0.25 and 0.50 mg/kg up-regulated RDH10, CYP26A1, and RARβ expression in broilers fed 6000 IU/kg VA (p < 0.05). The RARα expression was up-regulated by 0.50 and 0.25 mg/kg ATRA on days 21 and 35, respectively (p < 0.05). Plasma metabolomics identified 269 VA- and 185 ATRA-associated differential metabolites, primarily enriched in lipid metabolism, vitamin digestion and absorption, and bacterial infection pathways. In conclusion, dietary 0.50 mg/kg ATRA and 6000 IU/kg VA enhanced growth performance, intestinal integrity, and VA metabolism, partly through activation of retinoic acid receptors and modulation of plasma lipid metabolism. Full article

COVID-19 severity is frequently linked to exacerbated inflammation, with the inflammasome pathway playing a key role in activating inflammatory interleukins. This observational post-mortem study evaluated the expression of inflammasome-associated molecules in patients who died from COVID-19 during the second wave. Minimally invasive autopsies were performed on patients from the first (n = 24) and second (n = 18) waves. Lung tissue samples underwent immunohistochemical staining for ACE-2, TLR-4, NF-κB, TNF-α, NOX4, NLRP3, ASC, CASPASE-1, IL-1β, IL-18, GSDMD, and CASPASE-9. Additionally, genetic polymorphisms within inflammasome-related genes were assessed via real-time polymerase chain reaction. Lung tissue expressions of TLR-4, NLRP3, and IL-18 were significantly higher in patients from the second wave compared to those from the first, with expression levels of 26.3 versus 12.1, 13.9 versus 6.4, and 25.6 versus 3.8, respectively. The A allele at rs4648090 of NFKB1 and the T allele at rs317155 of NOX4 were associated with increased corresponding protein expression by factors of 5.1 and 8.9, respectively. Notably, IL-18 demonstrated substantial immunological relevance, correlating strongly with elevated expression linked to these genetic variants in second wave cases. These findings suggest that the inflammasome pathway harbors biologically meaningful molecules implicated in severe COVID-19, meriting further investigation for their potential as diagnostic or therapeutic targets. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Next-generation cancer immunotherapy increasingly combines tumor-targeting antibodies or antibody–drug conjugates (ADCs) with immune effector cells to enhance therapeutic precision. However, many existing approaches rely on genetic modification or complex manufacturing, limiting their clinical scalability and rapid deployment. To address this issue, we developed an antibody capture protein (ACP)-based surface engineering platform that enables the rapid, reversible, and non-genetic functionalization of NK cells with therapeutic antibodies or ADCs. This approach uses a DMPE-PEG-lipid conjugate to anchor thiolated protein A (ACP) to the NK cell membrane via hydrophobic insertion, thereby stably and selectively binding to the Fc region of IgG molecules. Using this strategy, we developed ACP-modified NK cells (AC-NKs) that can selectively capture therapeutic antibodies (trastuzumab (TZ), trastuzumab-emtansine (T-DM1), and sacituzumab (SZ)) pre-bound to each target antigen on tumor cells and induce antigen-specific cytotoxic responses. The resulting AC-NKs exhibited enhanced tumor recognition and cytotoxicity against HER2-positive and Trop-2-positive cancer cells in vitro. Compared with conventional combination therapies, AC-NKs enhanced immune activation, as demonstrated by effective delivery of cytotoxic agents, enhanced cancer cell engagement, and upregulation of CD107a expression. Notably, the system supports multiple antigen targeting and tunable antibody loading, enabling adaptation to tumor heterogeneity and resistant phenotypes. This platform might also provide a simple, scalable, and safe method for rapidly developing programmable immune cell therapies without genetic modification. Its versatility supports multi-antigen targeting and broad applicability across NK and T cell therapies, offering a promising path toward personalized, off-the-shelf chemoimmunotherapy. Full article

Despite numerous research efforts and several effective vaccines and therapies developed against coronavirus disease 2019 (COVID-19), drug repurposing remains an attractive alternative approach for treatment of SARS-CoV-2 variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of two polyamine metabolism-targeting drugs, an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), and a non-steroidal anti-inflammatory drug (NSAID), Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in the human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. In the infected human cell lines, the DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The Sulindac alone and DFMO/Sulindac combination treatments also suppressed the expression of the viral Spike protein and the host angiotensin-converting enzyme 2 (ACE2). In K18-hACE2 mice, the antiviral activity of DFMO and Sulindac as single agents and in combination was tested as prophylaxis (drug supplementation started 7 days before infection) or as treatment (drug supplementation started 24 h post-infection) at the doses equivalent to patient chemoprevention trials (835 ppm DFMO and 167 ppm Sulindac). The drugs’ antiviral activity in vivo was evaluated by measuring the clinical (survival rates and clinical scores), viral (viral load and virus infectivity), and biochemical (plasma polyamine, Sulindac, and Sulindac metabolite levels) endpoints. Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p = 0.01 and p = 0.027, respectively), and the combination was effective in the aged male mice (p = 0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p = 0.001) and the DFMO/Sulindac combination (p = 0.018), while aged female mice did not benefit significantly from any intervention. Treatment of SARS-CoV-2-infected animals with DFMO or/and Sulindac did not significantly improve their survival rates. Overall, our studies demonstrated that DFMO and Sulindac administration as the prophylaxis regimen provided strong protection against the lethal outcome of SARS-CoV-2 infection and that male mice benefited more from the polyamine-targeted antiviral treatment than female mice. Our findings underscore the importance of evaluation of the antiviral activity of the drugs in the context of sex and age. Full article

Driven by the concept of sustainable aquaculture, natural feed additives with growth-promoting, antioxidant, and immune-enhancing properties have become a key research focus. This study assessed the effects of dietary red pepper powder (Capsicum annuum) supplementation at 0%, 0.5%, 1.0%, and 2.0% over 50 days on the growth, digestive function, immune and antioxidant capacities, intestinal microbiota, and gene expression in Strongylocentrotus intermedius (S. intermedius). The results indicated that red pepper powder significantly promoted growth and decreased the feed conversion ratio (FCR) (p < 0.05), with the 1.0% group showing the highest growth rate. Additionally, supplementation improved gonadal coloration and increased crude protein and lipid contents in the gonads, particularly in the 1.0% and 2.0% groups (p < 0.05). Supplementation with 1.0% and 2.0% red pepper powder enhanced digestive, immune, and antioxidant enzyme activities, while reducing malondialdehyde (MDA) levels, indicating lower lipid peroxidation. α-diversity analysis revealed the highest ACE, Chao, and Shannon indices and the lowest Simpson index in the 1.0% group, indicating greater microbial diversity. Community analysis revealed that in the red pepper powder treatment groups, beneficial bacteria, such as Firmicutes and Unclassified_f__Rhodobacteraceae, increased in relative abundance, while potential pathogens like Arcobacter, and Epsilonbacteraeota were less abundant. Red pepper powder supplementation upregulated key immune- and antioxidant-related genes while downregulating pro-inflammatory and stress-associated genes. Overall, optimal dietary supplementation of red pepper powder, particularly at 1.0%, enhanced antioxidant and immune functions, optimized intestinal microbiota, mitigated oxidative stress, and consequently promoted growth, improved gonadal quality, and strengthened overall health in S. intermedius. Full article

Phlorizin (PHZ) is a glucoside of phloretin, belonging to the dihydrochalcone class within flavonoids; It is one of the active ingredients of the plant Cynomorium, and it has been shown that PHZ can regulate lipid metabolism disorders as well as having anti-aging properties. However, no studies have investigated whether PHZ ameliorates Aβ-induced toxicity in Alzheimer’s disease (AD) by regulating fatty acid β-oxidation. This study aims to investigate the effects of PHZ on the regulation of fatty acid β-oxidation and resistance to Aβ-associated toxicity on the AD Caenorhabditis elegans and the mechanisms of action. Wild-type N2 and AD model CL4176 C. elegans were used; lifespan, heat stress resistance, chronic paraquat stress, reactive oxygen species (ROS), behavioral performance, and lipofuscin accumulation assays were examined to evaluate the anti-aging effects; and non-esterified fatty acid (NEFA), triglyceride (TG) and lipidomic contents were quantified after PHZ treatment. The detection of genes related to fatty acid β-oxidation pathways was performed using qRT-PCR. nhr-49 knockout mutant RB1716; and GFP-binding mutants PMD150 WBM170 were used to observe the effect of PHZ on NHR-49 pathways, and molecular docking studies were performed by combining PHZ with NHR-49 proteins. Results showed that PHZ improved worms’ survival and delayed senescence, as demonstrated by enhanced performance in lifespan, heat stress, ROS, and paraquat assays and chronic paraquat assays; PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway, and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2, and cpt-5, and can be tightly coupled to NHR-49 targets. PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through the NHR-49—related pathway and anti-aging in AD worms. Full article

Background/Objectives: Ulcerative colitis (UC) pathogenesis involves gut barrier dysfunction, dysregulated immune responses, and gut microbiota imbalance. Alfalfa polysaccharide (APS), a bioactive compound with immunomodulatory potential, remains underexplored in intestinal inflammation. While APS exhibits anti-inflammatory properties in vitro, its in vivo efficacy, mechanisms, and ability to restore gut microbiota and barrier integrity in UC are unclear. This study aims to investigate the treatment effect of APS on dextran sulfate sodium (DSS)-induced colitis in mice and confirm its prebiotic potential. Methods: A mouse model of ulcerative colitis was induced by DSS. RNA sequencing, Western blotting, the terminal deoxynucleotidyl transferase dUTP nick end labeling technique, and an immuno-histochemical technique were used to study the mechanism of action by which APS at different dosages relieves DSS-induced colitis. Results: The findings show that APS alleviated the symptoms of colitis in mice given DSS, improved the gut morphology, heightened goblet cells production, increased the levels of IL-10 and IL-22, decreased the levels of TNF-α, IL-1β, and IL-6, and prevented the activation of the TLR4/MyD88/NF-κB pathways. Additionally, they maintained the integrity of the intestine by enhancing the expression of the mucins MUC2 and MUC5AC and by increasing the amounts of ZO-1, Occludin, and Claudin-1 proteins. Moreover, APS supported the growth of probiotic bacteria, including unclassified_f_lachnospiraceae, Parabacteroides, Alistipes, and Mucispirillum, and in particular, Parabacteroides distasonis, which is strongly associated with decreased pro-inflammatory cytokine through the inhibition of the TLR4-MyD88-NFκB pathways. Conclusions: APS can be used as a new type of prebiotic to improve UC by regulating intestinal flora and enhancing intestinal barrier function against the TLR4-MyD88-NFκB pathway. Full article

Chronic inflammatory conditions often involve the dysregulation of key enzymes, including serine proteases such as transmembrane serine protease 2 (TMPRSS2) and the angiotensin converting enzyme 2 (ACE2), which are key proteins implicated in the cellular entry mechanism of SARS-CoV-2. It remains uncertain whether the gastrointestinal symptoms observed in COVID-19 patients result from direct viral infection of the gastrointestinal tract, a process that may be exacerbated by altered expression of ACE2 or TMPRSS2. In this review, we explore the interplay among ACE2 and TMPRSS2 in the context of inflammatory bowel disease (IBD), including their roles in disease pathology and response to therapy. We also examine methodological approaches for assessing whether protease alterations contribute to increased susceptibility to infection, considering that TMPRSS2 exists in inactive (zymogen) and active forms. Furthermore, while membrane-bound ACE2 facilitates viral entry, soluble ACE2 fragments may act as decoys, preventing virus–receptor interaction. Therefore, the interpretation of changes in full-length versus cleaved forms of ACE2 and related enzymes is critical for understanding vulnerability to SARS-CoV-2 infection. Full article

Fermented liquid feed (FLF) is a microbiologically fermented, highly nutritious and easily digestible feed. This study investigated the effects of FLF on growth performance, carcass traits, meat quality, antioxidant capacity, and intestinal microbes of Yuedong black pigs. The pigs were divided into a control group and FLF group. Compared with the control, FLF increased (p < 0.05) the ADG and body weight of Yuedong black pigs. FLF increased (p < 0.05) the loin muscle area, and reduced cooking loss and meat color brightness (L*) of longissimus thoracis. Furthermore, FLF reduced (p < 0.05) the contents of bitter amino acids, including histidine and arginine. The expression of MYH4 (a fast glycolytic fiber gene) and TNNI1 (an inhibitor of muscle contraction) was increased (p < 0.05) in longissimus thoracis from the fermentation group. FLF increased (p < 0.05) the lipogenesis-related gene expression of FABP4, CEBPα, and PPARγ and the protein level of FATP4. Moreover, FLF increased (p < 0.05) serum T-AOC and GPx activity. In addition, FLF improved colonic microbial diversity and increased (p < 0.05) the abundance of Fibrobacterota (Phylum)-degrading cellulose and Lachnospiraceae-AC2044-group (genus)-generating butyric acid. In conclusion, FLF has a broad perspective for improving growth performance, meat quality, antioxidant capacity, and intestinal microbiota composition of Yuedong black pigs. Full article

Polynucleotide (PN), a high-molecular-weight DNA fragment derived from salmon and other fish sources, shows promising anti-aging and regenerative effects on the skin. This study investigated how PN enhances collagen synthesis, focusing on its effect on phosphoenolpyruvate carboxykinase 1 (PCK1) in senescent macrophages and its downstream effects on fibroblasts. Using in vitro senescent cell models and in vivo aged animal models, PN significantly upregulated the adenosine 2A receptor (A2AR), adenylate cyclase (AC), cyclic AMP (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) in senescent macrophages. This led to increased PCK1 expression, which reduced oxidative stress and promoted M2 macrophage polarization, associated with elevated levels of interleukin-10 and tumor growth factor-β. Conditioned media from PN-treated macrophages enhanced SMAD family member 2 and signal transducer and activator of transcription 3 phosphorylation in senescent fibroblasts, increasing collagen I and III synthesis and reducing nuclear factor-κB activity. In vivo, PN administration elevated expression of the A2AR/AC/PKA/CREB/PCK1 pathway, reduced oxidative stress, increased M2 macrophage markers, and significantly improved collagen density and skin elasticity over time. Use of a PCK1 inhibitor attenuated these effects, highlighting the pivotal role of PCK1. Overall, PN modulates macrophage-fibroblast interactions via the CREB/PCK1 axis, enhancing collagen synthesis and counteracting age-related skin changes. PN has emerged as a promising therapeutic agent for skin rejuvenation by targeting cellular senescence and promoting extracellular matrix restoration. Full article

Introduction: Bovine leukemia virus is a single-stranded RNA virus that targets B cell CD5⁺ lymphocytes in cattle. Only a tiny percentage of individuals develop malignant lymphoproliferative disorders, while most remain healthy carriers or experience persistent lymphocytosis. The exact mechanisms leading to lymphoma development are complex and not fully understood. RNA-seq analysis of cows’ peripheral blood leukocytes (PBLs) with and without Bovine leukemia virus (BLV) antibodies was conducted to gain a deeper understanding of molecular events beyond BLV infection. Method: Eighteen samples were selected, and their RNA was sequenced. For gene expression analysis and protein–protein network interactions, three groups were selected, including healthy negative samples (CT, n = 7), asymptomatic carriers (AC, n = 5), and persistent lymphocytosis (PL, n = 6), to provide the differentially expressed gene (DEG) and protein–protein interaction network (PPIN) outputs. Results: Our results demonstrated that in comparison to CT, ACs upregulated TLR7 and transcription activation factors. In the CT vs. PL group, MHC class II, transcription activation factors, and anti-inflammatory cytokines increased, while the acute-phase proteins, antiviral receptors, and inflammatory cytokines decreased. Additionally, antiviral receptors, acute-phase proteins, and inflammatory receptors were downregulated in the PL versus the AC groups. Moreover, PPINs analysis suggested that nuclear receptor corepressor 1 (NCOR1), serine/arginine repetitive matrix 2 (SRRM2), LUC7 like 3 pre-mRNA splicing factor (LUC7L3), TWIST neighbor (TWISTNB), U6 small nuclear RNA and mRNA degradation associated (LSM4), eukaryotic translation elongation factor 2 (EEF2), ubiquitin C (UBC), CD74, and heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNP A2B1) are possible hub gene candidates in the PL group. Conclusions: Our results suggest that innate and cellular immune responses are more loose in severe BLV infectious conditions, while the PPINs revealed that new protein interactions are necessary for oncogenesis. Full article