Search Results (7,433)

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy. Full article

Cortex Lycii Radicis, a medicinal plant, has been reported to inhibit epithelial–mesenchymal transition (EMT) and exhibit anti-lung cancer properties. Our previous study identified its major compound, Kukoamine B (KuB), as an inhibitor of membrane PD-1/PD-L1 interaction, thereby restoring T-cell function. However, the effect of KuB on EMT and the underlying mechanism thereof remain unknown. Herein, we show that PD-L1 overexpression enhances the proliferation, migration, and EMT of LUAD cells, upregulating N-cadherin and Vimentin, while downregulating E-cadherin. Mechanistically, PD-L1 directly binds phosphorylated p65 (p-p65) and facilitates p65 nuclear translocation, an interaction confirmed by molecular simulations. We found that KuB disrupts the PD-L1/p65 complex, impedes p65 nuclear translocation, and suppresses EMT, proliferation, and migration in LUAD cells. These inhibitory effects were reversed by PD-L1 overexpression. We therefore conclude that KuB suppresses EMT in LUAD by targeting intracellular PD-L1, blocking PD-L1–p65 interaction and nuclear translocation of p65. Full article

Introduction: Isolated pelvic nodal metastasis from carcinoma of unknown primary origin (CUP) is rare. Evaluation should prioritize gynecological and anorectal sites based on pelvic lymphatic drainage. Although spontaneous regression of these primary lesions is exceptional, regressed lesions can present as CUP, necessitating diagnostic caution. Case presentation: Here, we report the case of a 40-year-old woman with a solitary, intensely fluorodeoxyglucose F-18 avid left obturator lymph node and a subtle endocervical abnormality on pelvic magnetic resonance imaging. Loop electrosurgical excision revealed a Nabothian cyst only. Excisional nodal biopsy by polymerase chain reaction revealed metastatic squamous cell carcinoma with diffuse block-type p16 and human papillomavirus (HPV) 16. Considering the potential for a primary cervical tumor along the obturator drainage pathway, the patient underwent hysterectomy with pelvic lymph node dissection. No residual invasive carcinoma was found; however, HPV16 was detected in the cervix with a low-grade squamous intraepithelial lesion, supporting a regressed cervical focus. She received adjuvant cisplatin-based chemoradiotherapy and has remained disease-free for 56 months. Conclusions: This case highlights the diagnostic value of integrating lymphatic anatomy with the molecular profile of HPV. Cervical squamous cell carcinoma rarely regresses and presents solely as an isolated nodal disease. Full article

Osteosarcoma, the most common malignant bone tumor in young individuals, often exhibits poor outcomes due to MDM2-mediated suppression of the p53 pathway. Whereas conventional MDM2 inhibitors block the p53–MDM2 interaction but frequently induce compensatory MDM2 upregulation, proteolysis-targeting chimeras (PROTACs) directly degrade MDM2 and bypass this limitation. Here, we investigated the anticancer efficacy of two MDM2-targeting PROTAC compounds, CL0144 and CL0174, in osteosarcoma models. In Saos-2 and U2OS cells, both PROTACs efficiently induced MDM2 degradation, leading to activation of p53 or p73 signaling, increased reactive oxygen species production, apoptotic cell death, and marked reductions in viability. PROTAC treatment also significantly suppressed proliferation, colony formation, sphere formation, migration, and invasion. In vivo, xenograft assays demonstrated robust tumor growth inhibition following PROTAC administration. Collectively, these findings demonstrate that MDM2-targeting PROTACs exert strong antitumor effects by degrading MDM2 and disrupting downstream oncogenic pathways, supporting their potential as a promising therapeutic strategy for osteosarcoma. Full article

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, ultimately releasing the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it regulates gene expression. This review mainly aims to evaluate γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, with a focus on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard therapies. Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following PRISMA guidelines. The review included preclinical in vitro and in vivo studies, as well as clinical trials, investigating GSIs, either as monotherapy or in combination with other treatments, in TNBC, metastatic melanoma, PDAC, gastric cancer, and NSCLC. Exclusion criteria included duplicates, non-English articles, studies published before 2010, studies on non-cancer conditions, research unrelated to NOTCH signaling, and studies outside the selected cancer types. Overall, 69 articles were included and categorized into the five types of cancer analyzed (20 on NSCLC, 22 on TNBC, 11 on metastatic melanoma, 7 on GC, and 9 on PDAC). Of these, 60 studies corresponded to preclinical research in the types of cancer, and 9 studies corresponded to clinical trials in the types of cancer except for GC. Two independent authors screened and extracted relevant data, with disagreements resolved by the corresponding author. Findings were synthesized qualitatively across cancer types under study. Results. This review summarizes therapeutic advances involving GSIs in cancers driven by oncogenic NOTCH signaling, based on the 69 articles included. Preclinical studies show that GSIs synergize with chemotherapy and radiotherapy, particularly in NSCLC, melanoma, and TNBC, and block EMT, overcome therapeutic resistance, and improve prognosis. Commonly used GSIs include DAPT and RO4929097, which enhance the efficacy of agents, such as gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib, and crizotinib (NSCLC), and 5-FU (gastric cancer, TNBC). Promising strategies include combining GSIs with SAHA, ATRA, CB-103, and other NOTCH signaling targeting molecules, either alone or with chemo- and radiotherapy. Clinical trials with GSIs, however, remain limited. RO4929097 is the most extensively tested GSI in clinical settings. PDAC trials combining GSIs with gemcitabine showed no benefit; melanoma trials yielded modest outcomes; and TNBC trials demonstrated partial responses to GSIs but overall low efficacy and significant adverse events. Discussion and Conclusions. Despite encouraging preclinical evidence, clinical trials with GSIs have underperformed, largely due to tumor heterogeneity, dosing limitations, and the non-selective nature of γ-secretase inhibition. Other NOTCH inhibitors, such as DLL4 antibodies, also resulted in partial responses and secondary effects. Future strategies should prioritize receptor-specific NOTCH inhibitors, patient stratification based on NOTCH pathway activation, and optimized combination regimens. Emerging approaches include integrating immunotherapy with advanced technologies such as CRISPR, CAR-T cells, and bispecific antibodies, as well as targeted delivery systems to enhance efficacy and reduce toxicity. Additional research directions include addressing the tumor microenvironment and EMT-driven resistance, elucidating the mechanisms of immune evasion, and inhibiting tumor angiogenesis. Finally, leveraging artificial intelligence and big-data-driven personalized medicine, including sex-specific considerations, will be essential for improving patient outcomes. Full article

The present study evaluated the effects of sugarcane-derived polyphenol nutritional supplement on milk production, milk composition, and somatic cell count (SCC) in lactating Holstein cows. A second objective was to evaluate the quality and stability of yogurt produced with milk from supplemented cows. Sixteen cows (20 ± 2 L/d milk, 120 ± 21 days in milk, 550 ± 82 kg body weight) were assigned to either a control group or a polyphenol-supplemented group in a randomized block design for a six-week evaluation period. Milk yield and individual milk samples for composition analysis (fat, protein, lactose, non-fat solids, casein, free fatty acids, and milk urea nitrogen) were recorded weekly, and only SCC was monitored three times per week. Yogurt was produced from pooled milk of each treatment and evaluated for fermentation parameters (pH, titratable acidity), shelf life, and sensory attributes were evaluated using a triangle test (discriminative sensory analysis). Polyphenol supplementation did not significantly affect milk yield or composition (p > 0.05), but reduced SCC considerably (238 × 10³ vs. 593 × 10³ cells/mL; p < 0.01). Yogurt fermentation and storage parameters were not significantly affected by supplementation, although pH and titratable acidity changed considerably over time (p < 0.01). Sensory analysis indicated that only 37.3% of panelists correctly identified differences between yogurts, which did not differ from chance expectation in the triangle test. These results demonstrate that polyphenol supplementation can improve udder health, evidenced by reduced SCC, without compromising milk yield, composition, or yogurt quality. Polyphenols thus represent a promising nutritional supplement for enhancing dairy cow health and maintaining product quality. Full article

Complement and pathogenic antibodies act independently and together to mediate the pathology of many autoimmune diseases. To address these drivers of disease, we generated a monoclonal antibody (mAb), CSL305, that binds and inhibits both complement and the neonatal Fc (fragment crystallizable) receptor FcRn. The fragment antigen binding (Fab) portion of CSL305 was engineered to bind both human C2 (huC2) zymogen and the active fragment huC2b to inhibit the classical and lectin complement pathways in vitro, and C3b deposition on primary lung endothelial cells using a 3-dimensional microvascular model system. Engineering of a triple amino acid mutation (“YPY” motif) into the Fc region of CSL305 increased its affinity to FcRn at both acidic and neutral pH, allowing it to also act as a potent FcRn antagonist. Intracellular trafficking experiments demonstrated that CSL305, but not the wild-type (WT) mAb lacking the YPY motif, was able to block immunoglobulin G (IgG) recycling in vitro. The generation of a high resolution 2.6Å crystal structure of CSL305 Fab region bound to huC2b showed that the epitope lies directly over the huC2b catalytic triad, providing evidence of its complement mechanism of action as a neutralising mAb. Early pharmacokinetic (PK)/pharmacodynamic (PD) studies using CSL305 in cynomolgus monkeys demonstrated both complement inhibition and FcRn antagonism in vivo, with reductions in complement classical pathway activity and endogenous IgG observed following single intravenous (IV) administration. CSL305 thus represents a dual-functional mAb as a potential therapeutic candidate. Full article

Photovoltaic double-skin façades (PV-DSFs) can block solar radiation heat, mitigate air heat transfer, facilitate ventilation cooling, and generate electricity, making them a high-performance building envelope suitable for hot southern regions in summer. The thermal performance of DSFs is relatively well understood; however, with the addition of photovoltaic glass panels, the influence of design parameters is altered due to thermoelectric coupling effects. Then, the influence of design parameters on their thermoelectric performance remains unclear, hindering their design optimization. This paper establishes a mathematical model for DSFs with MATLAB (R2023a) to analyze their thermoelectric performance and the impact of design parameters. The results indicate that the daily power generation of PV-DSFs is primarily influenced by the solar radiation on the west-facing vertical surface. The wall exterior surface gains heat via longwave radiation during the day and loses heat at night, while convective heat dissipation occurs throughout the entire day, with radiative heat flux being the dominant mechanism. The power generation of photovoltaic cells is significantly influenced by their coverage ratio, while the impact of other factors can be neglected. The temperature of the wall’s exterior surface is significantly influenced by the heat storage of the outer cladding panel, the solar absorptivity of the exterior surface, and the emissivity of the interior surface. Among these factors, the heat storage of the outer cladding panel primarily affects the attenuation and delay of peak values and temperature fluctuations on the exterior surface. Meanwhile, the solar absorptivity of the exterior surface and the emissivity of the interior surface mainly influence the peak temperature of the wall’s exterior surface, with the effect becoming more pronounced when the interior surface emissivity is lower. Full article

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial–Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA’s suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer. Full article

Teosinte branched1/cycloidea/proliferating cell factor (TCP) transcription factors are key regulators of plant growth and stress adaptation. However, their evolutionary history and functional divergence in rye (Secale cereale L.) remain unclear. Here, 26 ScTCP genes were identified from the reference rye genome. Phylogenetic and collinearity analyses with six representative cereals (Secale cereale, H. vulgare, O. sativa, T. aestivum, Z. mays, and A. tauschii Coss) revealed that segmental duplication, rather than tandem repetition, drove ScTCP expansion, with ScTCP2 located in a conserved syntenic block shared across the Poaceae family. Promoter analysis identified numerous hormone- and stress-responsive cis-elements, while a predicted protein–protein interaction network indicated extensive cross-talk with ERF and MYB transcription factors. Expression profiling of 12 representative ScTCP genes using qRT-PCR across different organs, developmental stages, six abiotic stress conditions, and three hormone treatments showed that ScTCP6 plays an important role in rye development and in responses to hormonal signals and abiotic stresses. Therefore, this study provides the first genome-wide characterization of the TCP gene family in rye and contributes to a broader understanding of the evolution and functional diversification of the TCP superfamily in higher plants. Full article

Maintaining a membrane electrical potential of biological cells is a dynamic process, as some cells have a continually changing potential, like pacemaker cells, while other cells may function with large or small changes in the membrane potential. Additionally, some cells may change their electrical potential when stimulated or inhibited by electrical signals, chemical compounds, or both—either simultaneously or episodically. The persistent leak of K⁺ through two-pore-domain potassium channels (K2P) and of Na⁺ through Na⁺ leak channels (NALCNs) and the action of pumps and exchangers are primarily responsible for maintaining a resting potential. Ca²⁺ ions are known to block the NALCNs and result in a more hyperpolarized membrane potential, with a reduction in Ca²⁺ resulting in a depolarized state. Using the larval muscles of Drosophila, the membrane potentials were monitored as Ca²⁺ and Mg²⁺ concentrations were altered. Changes as large as 20 mM of Mg²⁺ had only small effects (1 to 2 mV) on the membrane potential compared to 3–5 mM changes in Ca²⁺ having larger effects (5–10 mV). Although, it appears raised [Mg²⁺] may dampen the changes induced by Ca²⁺. Simulations of the G-H-K equation estimate the changes in permeability of Na+ (pNa). These experiments are significant, as the clinical severity of hypocalcemia and hypercalcemia may also depend on Mg²⁺ levels. Full article

Huwentoxin-XI (HWTX-XI) is a 55-amino acid peptide belonging to the family of spider Kuntiz-type toxins (KTTs), isolated from the venom of the Chinese tarantula Cyriopagopus schmidti. Under whole-cell voltage-clamp conditions, HWTX-XI was found to block Kv1.1 potassium channels but had no effect on other potassium channel subunits (Kv1.4, Kv2.1, Kv3.1 and Kv4.2), sodium channels or calcium channels. In the present study, it was found that the substitution of Tyr379 by the valine in the filter region significantly decreased the affinity of toxin HWTX-XI by about 90-fold, indicating that the Kv1.1 filter region is a critical determinant of HWTX-XI potassium channel activity. After intrathecal or intraplantar injections, HWTX-XI decreased the mechanical nociceptive threshold (hyperalgesia) for a long-lasting period. HWTX-XI also significantly increased the firing frequency in mouse DRG neurons. The novel function of HWTX-XI makes it a new tool for studying the relationship between spider toxins and Kv1.1 channels and suggests that Kv1.1 channels might be a novel potential target for preventing and/or treating neuropathic pain. Full article

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE. Full article

Porphyra-334 (PPR-334) is one of the species of mycosporine-like amino acids (MAAs), known as biological UV protection ingredients. In this study, we developed a large-scale purification process to extract PPR-334 from Saccharomyces cerevisiae and confirmed the previously identified efficacy of PPR-334, while also demonstrating its efficacy under UV-independent conditions. PPR-334 scavenged reactivity oxygen species (ROS) and increased catalase (CAT) gene expression in human epidermal keratinocyte cells (HEKa). In both HEKa and normal human dermal fibroblast cells (NHDF), PPR-334 suppressed the gene expression of matrix metalloproteinase-1 (MMP-1). NHDF treated with PPR-334 showed increased collagen expression and proliferation, while advanced glycation end-product (AGE) production was decreased. It was confirmed that the efficacy in vitro was also reproduced in human artificial skin tissue models. Above all, the antioxidant efficacy mechanism of PPR-334 through nuclear factor erythroid 2-related factor 2 (NRF2) and Caspase-9 signals was identified. It was determined that the proliferation efficacy of PPR-334 was due to factors related to the cell cycle. These results demonstrate the anti-aging efficacy of PPR-334 independent of UV irradiation, while enhancing the UV-blocking and antioxidant effects. Thus, we suggest the potential of PPR-334 as a sunscreen agent as well as a dual- or multifunctional material. Full article

Necroptosis is a regulated form of programmed cell death that helps the body defend itself against infections and cellular stress, especially when apoptosis is blocked. At the center of this process is mixed lineage kinase domain-like (MLKL) protein, the final effector of necroptosis, which is activated downstream of receptor-interacting protein kinase 3 (RIPK3). Once phosphorylated, MLKL changes shape, assembles into oligomers, moves to cellular membranes, and disrupts membrane integrity, ultimately causing cell death. While this RIPK3-MLKL pathway has been well described, it is becoming increasingly clear that MLKL regulation is more complex than originally thought. Recent findings show that MLKL can be modified and activated through alternative mechanisms, even in the absence of RIPK3, and that post-translational modifications such as ubiquitination further fine-tune its activity. Notably, deleting RIPK3 or MLKL does not consistently resolve inflammatory phenotypes in experimental models, suggesting that MLKL has context-dependent functions that extend beyond its role in necroptosis. In line with this idea, MLKL has been implicated in inflammatory signaling, interferon responses, and innate immunity, and is frequently targeted by viruses seeking to evade host defenses. Beyond infections, aberrant MLKL activation contributes to a wide range of chronic diseases, including atherosclerosis, cardiometabolic disorders, liver disease, neurodegeneration, and cancer. In these settings, sustained MLKL-mediated membrane damage and release of danger signals drive ongoing inflammation and tissue injury rather than protective cell elimination. In this review, we provide an overview of MLKL structure, activation, and regulation in both necroptotic and non-necroptotic contexts. We also discuss emerging therapeutic strategies aimed at targeting MLKL activation, membrane engagement, and stability, and highlight key unanswered questions that must be addressed to translate MLKL biology into effective clinical interventions. Full article