Search Results (1,595)

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

Novel coronavirus (SARS-CoV-2) is highly infectious and pathogenic. Novel coronavirus infection can not only cause respiratory diseases but also lead to multiple organ damage through direct or indirect mechanisms, in which the liver is one of the most frequently affected organs. It has been reported that 15–65% of coronavirus disease 2019 (COVID-19) patients experience liver dysfunction, mainly manifested as mild to moderate elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Severe patients may progress to liver failure, develop hepatic encephalopathy, or have poor coagulation function. The mechanisms underlying this type of liver injury are complex. Pathways—including direct viral infection (via ACE2 receptors), immune-mediated responses (e.g., cytokine storm), ischemic/hypoxic liver damage, thrombosis, oxidative stress, neutrophil extracellular trap formation (NETosis), and the gut–liver axis—remain largely speculative and lack robust clinical causal evidence. In contrast, drug-induced liver injury (DILI) has been established as a well-defined causative factor using the Roussel Uclaf Causality Assessment Method (RUCAM). Treatment should simultaneously consider antiviral therapy and liver protection therapy. This article systematically reviewed the mechanism, clinical diagnosis, treatment, and management strategies of COVID-19-related liver injury and discussed the limitations of current research and the future directions, hoping to provide help for the diagnosis and treatment of such patients. 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

Cancer-induced cardiac dysfunction has become a major clinical challenge as advances in cancer therapies continue to extend patient survival. Once regarded as a secondary concern, cardiotoxicity is now recognized as a leading contributor to morbidity and mortality among cancer patients and survivors. Its pathophysiology is multifactorial, involving systemic inflammation (e.g., TNF-α, IL-6), oxidative stress driven by reactive oxygen species (ROS), neurohormonal imbalances (e.g., angiotensin II, endothelin-1), and metabolic disturbances. These mechanisms collectively promote cardiomyocyte apoptosis, atrophy, mitochondrial dysfunction, and impaired cardiac output. Cardiac complications may arise directly from cancer itself or as adverse effects of oncologic therapies such as anthracyclines, trastuzumab, and immune checkpoint inhibitors. These agents have been linked to heart failure (HF), systolic dysfunction, and cardiac atrophy, often progressing insidiously and underscoring the importance of early detection and careful monitoring. Current preventive and therapeutic strategies include pharmacological interventions such as ACE inhibitors, beta-blockers, statins, dexrazoxane, and endothelin receptor antagonists like atrasentan. Emerging compounds, particularly Withaferin A (WFA), have shown potential through their anti-inflammatory and cardiac protective properties. In addition, antioxidants and lifestyle modifications may provide supplementary cardioprotective benefits, while interventional cardiology procedures are increasingly considered in selected patients. Despite encouraging progress, standardized treatment protocols and robust long-term outcome data remain limited. Given the heterogeneity of cancer types and cardiovascular responses, a personalized and multidisciplinary approach is essential. Continued research and close collaboration between oncologists, cardiologists, and basic scientists will be the key to advancing care, reducing treatment-related morbidity, and ensuring that improvements in cancer survival are matched by preservation of cardiovascular health. Full article

Background: There are no comparative trials between the two most common schemes in HER2-positive early breast cancer treatment; BERENICE (with anthracyclines) and TRAIN-2 (without anthracyclines). In this study, we investigated the pathological complete response (pCR) and safety events achieved with each. Methods: This analytical retrospective observational study included 111 patients with early and locally advanced HER-2-positive breast cancer who initiated neoadjuvant treatment with an anthracycline-based scheme (four cycles of doxorubicin and cyclophosphamide, followed by four cycles of taxane, trastuzumab, and pertuzumab = AC-THP) and a non-anthracycline scheme (carboplatin, weekly paclitaxel, trastuzumab, and pertuzumab for six–nine cycles = TCbHP) at the National Cancer Institute in Colombia, between April 2020 and December 2024. The primary endpoint was the pCR. Safety was analyzed in patients who received at least one treatment cycle. Results: A total of 51 patients received AC-THP and 60 TCbHP (89.6% of which received six cycles). The pCR was 58.3% in ACHTP and 60.4% in TCbHP (p = 0.84). As a descriptive analysis, with the anthracycline-based scheme, there was a trend toward a higher pCR in patients with T3-T4, positive nodal involvement (N+), and positive hormone receptor (HR+). Cardiac toxicity events during the neoadjuvant phase were 9.8% in ACTHP and 3.3% in TCbHP. Grade 2 neuropathy events were higher in patients with the TCbHP scheme, at 23.3%, versus 9.8% in ACTHP. Conclusions: We found similar pCR rates between the schemes with anthracyclines and without anthracyclines. It is still pertinent to discuss the risk–benefit of using anthracycline-based regimens in patients with HR+, T3-T4, and N+. The cardiac adverse events reported in our patients were similar to those reported in the BERENICE trial. Full article

The early stages of plant–microbe interaction are critical for establishing beneficial symbioses. We investigated how the endophytic fungus Fusarium solani strain FsK modulates tomato (Solanum lycopersicum) development and hormone pathways during in vitro co-cultivation. Seedlings were sampled at three early interaction stages (pre-contact, T1; initial contact, T2, 3 days post-contact, T3). Root traits and root and leaf transcripts for abscisic acid (ABA) and ethylene (ET) pathways were quantified, alongside fungal ET-biosynthesis genes. FsK altered root system architecture, increasing root area, lateral root number, root-hair length, and fresh biomass. These morphological changes coincided with tissue- and time-specific shifts. In leaves, FsK broadly affected ABA biosynthetic and homeostasis genes (ZEP1, NCED1, ABA2, AAO1, ABA-GT, BG1), indicating reduced de novo synthesis with enhanced deconjugation of stored ABA. ET biosynthesis was curtailed in leaves via down-regulation of ACC oxidase (ACO1–3), with isoform-specific changes in ACC synthase (ACS). The ET receptor ETR1 was transiently expressed early (T1–T2). FsK itself showed staged activation of fungal ET-biosynthesis genes. These results reveal coordinated fungal–plant hormone control at the transcriptional level that promotes root development during early interaction and support FsK’s potential as a biostimulant. Full article

Adipocytes can be infected by SARS-CoV-2, potentially contributing to the obesity-associated severity of COVID-19. Circumstantial evidence points to angiotensin-converting enzyme 2 (ACE2) as the necessary receptor for adipocyte infection, but this has not been demonstrated experimentally. Using differentiated immortalized human preadipocyte lines that we developed, we found that visceral adipocytes express higher levels of ACE2 and are more susceptible to SARS-CoV-2 spike (S)-mediated luciferase-VSV infection than subcutaneous adipocytes. Overexpression of ACE2 significantly increased infection, whereas knockout of ACE2 significantly decreased S-mediated infection. Visceral adipocytes at baseline were susceptible to infection by SARS-CoV-2 (Delta variant); however, increased levels of viral transcript with time were not apparent. ACE2 knockout significantly decreased the susceptibility of visceral adipocytes to SARS-CoV-2, whereas overexpression of ACE2 resulted in increased SARS-CoV-2 infection and was associated with increased viral transcript levels with time, as well as induction of IL6, a marker of the proinflammatory response. Our results demonstrate that ACE2 confers susceptibility to SARS-CoV-2 infection of visceral adipocytes. Higher levels of ACE2 in these cells may play a role in establishment of infection and a proinflammatory response, potentially leading to pathogenesis. Full article

DNA methylation holds promise for the early detection of tissue damage, making it crucial for identifying polycyclic aromatic hydrocarbon (PAH)-associated epigenetic biomarkers in childhood asthma. Sulforaphane (SFN), as a potential epigenetic modulator, can alleviate the adverse effects of environmental pollutants. This study quantified serum PAHs in 370 children via gas chromatography–mass spectrometry, assessed the methylation of target genes using bisulfite sequencing PCR (BSP), and performed mediation analysis to estimate the mediating effects of methylation levels between PAHs and childhood asthma. Murine models exposed to PAHs prenatally or postnatally, with offspring challenged with ovalbumin (OVA), were analyzed for lung DNA methylation. In vitro, HBE cells and HBSMCs treated with benzo(a)pyrene (BaP) and/or SFN were tested for inflammatory cytokines, methylation-related enzymes, and matrix metallopeptidase 9 (MMP9) modifications. The results showed total PAHs were associated with childhood asthma, with mediating effects of long interspersed nuclear element-1 (LINE-1) methylation. Prenatal PAH exposure enriched differentially methylated genes in the extracellular matrix (ECM)-receptor interaction pathway, while postnatal exposure enriched those in purine metabolism, and postnatal exposure also elevated Mmp9 expression via hypomethylation. BaP increased the expression of interferon gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A), transforming growth factor beta 1 (TGF-β), and ten-eleven translocation methylcytosine dioxygenases (TETs), and it upregulated MMP9 via enhancer hypomethylation and H3K27ac enrichment, while SFN reversed these effects by downregulating histone methyltransferase (HMT), leading to reduced H3K4me1 and subsequent H3K27ac depletion, thus suppressing MMP9 transcription. This study demonstrates that DNA methylation mediates PAH–childhood asthma associations, with distinct patterns in different exposure windows; MMP9 could serve as a crucial target for epigenetic modification during lung inflammation induced by PAH exposure, and SFN reverses PAH-induced epigenetic changes, aiding prevention strategies. Full article

Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective study aimed to assess [²²⁵Ac]Ac-DOTA-LM3 safety in advanced NEN patients (as monotherapy and with Lutetium-177 as TANDEM), survival, and follow-up duration. Thirty-five patients received a total of 57 [²²⁵Ac]Ac-DOTA-LM3 cycles (March 2022–September 2024): 24 monotherapies and 33 TANDEM therapies. The pancreas was the most common primary site (n = 19). PRRT-related toxicity was assessed, focusing on hematological, renal, and hepatic toxicity (Common Terminology Criteria for Adverse Events—CTCAE v5.0). Therapy was generally well tolerated, with mostly mild acute adverse events (primarily nausea, n = 8). Some new grade 3/4 long-term adverse events were reported after treatment: anemia grade 3 (n = 2), leukocytopenia grade 4 (n = 1), absolute neutrophil count reduction grade 3 (n = 1), thrombocytopenia grade 3 (n = 7), acute myeloid leukemia (n = 1), nephrotoxicity grade 3 (n = 2), and hepatotoxicity grade 3 (n = 2). During follow-up, 13 patients died (survival range 5–30 months); 22 patients were alive (follow-up range 1–18 months). Our retrospective analysis shows that [²²⁵Ac]Ac-DOTA-LM3 PRRT is relatively safe concerning acute and long-term toxicity and bears promising survival outcomes in patients progressing after [¹⁷⁷Lu]Lu-DOTATATE or [¹⁷⁷Lu]Lu-DOTATOC PRRT. Full article

Heparan sulfate proteoglycans serve as initial attachment sites for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein that promote the interaction between the receptor-binding domain (S1-RBD) and the cellular angiotensin-converting enzyme 2 receptor (ACE2), thereby triggering the virus internalization process. The molecular details that drive this process, particularly the co-receptor role of heparan sulfate (HS), remain incompletely understood. The interaction between an HS hexasaccharide (hexa) and the N343 glycosylated S1-RBD of the wild-type (WT) and Omicron variant of SARS-CoV-2 was investigated. The conformational properties of hexa with these S1-RBDs in unbound and bound states are explored using multiple independent MD simulations; the protein binding epitope of hexa, as well as the details of its interaction with S1-RBD of the Omicron variant, are characterized by comparing experimental and theoretical ¹H STD NMR signals. This investigation identifies the role played by the glycosyl moiety at N343 in potentially affecting this interaction in both WT and Omicron S1-RBD, explaining the observed low specificity and multi-modal nature of the interaction between HS oligosaccharides and these S1-RBDs. Full article

Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate how these antibodies engage the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and influence its function. Our results reveal that neutralization efficacy arises from the interplay of direct interfacial interactions and allosteric effects. Group F1 antibodies (CR3022, EY6A, COVA1-16) primarily operate via classic allostery, modulating flexibility in RBD loop regions to indirectly interfere with the ACE2 receptor binding through long-range effects. Group F2 antibody DH1047 represents an intermediate mechanism, combining partial steric hindrance—through engagement of ACE2-critical residues T376, R408, V503, and Y508—with significant allosteric influence, facilitated by localized communication pathways linking the epitope to the receptor interface. Group F3 antibody S2X259 achieves potent neutralization through a synergistic mechanism involving direct competition with ACE2 and localized allosteric stabilization, albeit with potentially increased escape vulnerability. Dynamic network analysis identified a conserved “allosteric ring” within the RBD core that serves as a structural scaffold for long-range signal propagation, with antibody-specific extensions modulating communication to the ACE2 interface. These findings support a model where Class 4 neutralization strategies evolve through the refinement of peripheral allosteric connections rather than epitope redesign. This study establishes a robust computational framework for understanding the atomistic basis of neutralization activity and immune escape for Class 4 antibodies, highlighting how the interplay of binding energetics, conformational dynamics, and allosteric modulation governs their effectiveness against SARS-CoV-2. Full article

The Complement C3a Receptor (C3aR) plays a multifaceted role along the varying temporal phases of brain injury following cerebral ischemia. C3aR is a G-protein-coupled receptor (GPCR) that binds to its ligand, C3a an anaphylatoxin generated during activation of the complement cascade. During ischemia, complement is activated as part of the initial inflammatory response, with C3aRs playing a time-dependent role in both brain injury and repair mechanisms. In the acute phase (minutes to hours post-ischemia), C3aR activation promotes the recruitment of immune cells and the release of chemokines and cytokines, driving blood–brain barrier (BBB) permeability and brain edema. During the subacute phase (hours to days post-ischemia), C3aR continues to modulate immune cell activity, worsening secondary brain injury, although emerging evidence suggests that C3aR activation in this phase may also aid in the clearance of cellular debris and cell survival. In the chronic phase (days to weeks post-ischemia), chronically elevated C3aR activity can prolong neuroinflammation and impair recovery, whereas controlled C3aR signaling in the subacute/chronic phase can activate reparative pathways (e.g., microglial phagocytosis, astrocyte trophic support). As a result, targeting the C3aR requires careful timing to optimize its benefits. Given the dual impact of C3aR activation, which serves to exacerbate injury in the acute phase but supports repair beginning in the subacute and chronic phases, a targeted therapeutic approach should focus on context- and time-dependent modulation of the C3a/C3aR axis. This strategy would involve blocking the C3aR during the acute phase to reduce inflammation and BBB breakdown while controlling C3a signaling in later phases to promote tissue repair. Full article

Background/Objectives: This systematic review aimed to gather the most recent evidence regarding the link between genetic polymorphisms and physical performance in team sports, with a focus on the practical utility of this information for athlete selection, training personalization, and injury prevention. Methods: Sixteen studies published between 2018 and 2025 were analyzed and selected from six international databases, in accordance with the PRISMA guideline. Only English-language studies were included, which evaluated active athletes in team sports and investigated associations between genetic variations, such as Actinin Alpha 3 (ACTN3 R577X), Angiotensin I Converting Enzyme (ACE I/D), Peroxisome Proliferator-Activated Receptor Alpha (PPARA), Interleukin 6 (IL6), and Nitric Oxide Synthase 3 (NOS3), and physical performance parameters. The methodological quality of the studies was assessed using the Q-Genie tool, with all studies scoring over 45 across all 11 items, indicating high quality. Results: The ACTN3 and ACE genes stood out due to their consistent association with traits such as strength, speed, endurance, and recovery capacity. Other genes, such as PPARA, Fatty Acid Amide Hydrolase (FAAH), Angiotensinogen (AGT), and NOS3, complemented this genetic profile by being involved in the regulation of energy metabolism and injury predisposition. An increasing number of studies have begun to adopt cumulative genotype scores, suggesting a shift from a monogenic approach to complex predictive models. Conclusions: The integration of genetic profiling into the evaluation and management of athletes in team sports is becoming increasingly relevant. Although current evidence supports the applicability of these markers, robust future research conducted under standardized conditions is necessary to validate their use in sports practice and to ensure sound ethical standards. 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

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes Full article