Search Results (536)

Background: The FDA-cleared antimicrobial quaternary ammonium silane K21 is recognized for its antimicrobial properties. This study explored potential applications of the K21 molecule in human health protection, disease prevention, and treatment using the zebrafish model. Method: A multi-dimensional approach was utilized to assess the toxicity, tolerance, and optimal dosage of K21 through serial dilutions at various concentrations. Acute and chronic exposure studies were performed at different developmental stages (embryonic, larval, juvenile, and adult) to evaluate its efficacy and toxicity in wild-type (WT), Casper (transparent skin mutant), and transgenic zebrafish lines. Results: Significant weight gain was observed in the F1 generation following K21 treatment, a trend that continued into the F2 and F3 generations. The effects of K21 on lipopolysaccharide-induced inflammation were also examined in Casper NFkB:GFP transgenic lines. Treatment with K21 reduced inflammation, indicating anti-inflammatory properties. Improved hatching rates, accelerated larval development, an increased adult mass, and modest reductions in embryonic motility (less than 20%) suggested positive developmental influences. Single-cell RNA sequencing further validated the biological impacts of K21, revealing the potential activation of a novel pathway that accelerates zebrafish growth. Summary and Conclusions: These findings position K21 as a promising candidate for biomedical applications and aquaculture, warranting further investigation into its underlying molecular mechanisms. Our additional study on the effect of K21 on the artemia (brine shrimp) hatching process provide strong evidence of better hatching ratio of 90% for brine shrimp in the group with K21 drug treatment as compared to 70% in the group without the K21 drug at 24 h of treatment; the K21 drug helps the early hatching process, as observed the 90% hatching rate in 20 h K21 treatment group hatching while in the group without K21, only 40% of brine shrimps hatched. Full article

The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction. Full article

Alcoholic beverages play a significant role in social engagement worldwide. Excessive alcohol causes a variety of health complications. Alcohol-induced liver disease (ALD) is responsible for the bulk of linked fatalities. The activation of immune mechanisms has a crucial role in developing ALD. No effective medication promotes liver function, shields the liver from harm, or aids in hepatic cell regeneration. Alcohol withdrawal is one of the most beneficial therapies for ALD patients, which improves the patient’s chances of survival. There is a crucial demand for safe and reasonably priced approaches to treating it. Exploring naturally derived phytochemicals has been a fascinating path, and it has drawn attention in recent years to modulators of inflammatory pathways for the prevention and management of ALD. In this review, we have discussed the roles of various immune mechanisms in ALD, highlighting the importance of intestinal barrier integrity and gut microbiota, as well as the roles of immune cells and hepatic inflammation, and other pathways, including cGAS-STING, NLRP3, MAPK, JAK-STAT, and NF-kB. Further, this review also outlines the possible role of phytochemicals in targeting these inflammatory pathways to safeguard the liver from alcohol-induced injury. We highlighted that targeting immunological mechanisms using phytochemicals or herbal medicine may find a place to counteract ALD. Preclinical in vitro and in vivo investigations have shown promising results; nonetheless, more extensive work is required to properly understand these compounds’ mechanisms of action. Clinical investigations are very crucial in transferring laboratory knowledge into effective patient therapy. Full article

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. These lesions are the result of the aberrant cell signaling step proteins, which normally regulate cell proliferation. Mitogen-activated protein kinase (MAPK) pathways and tyrosine kinase receptors are involved in tumorigenesis of low-grade gliomas. High-grade gliomas may carry similar mutations, but loss of epigenetic control is the dominant molecular event; it can occur either due to histone mutations or inappropriate binding or unbinding of DNA on histones. Therefore, despite the absence of genetic alteration in the classic oncogenes or tumor suppressor genes, uncontrolled transcription results in tumorigenesis. Isocitric dehydrogenase (IDH) mutations do not predominate compared to their adult counterpart. Embryonic tumors include medulloblastomas, which bear mutations of transcription-regulating pathways, such as wingless-related integration sites or sonic hedgehog pathways. They may also relate to high expression of Myc family genes. Atypical teratoid rhabdoid tumors harbor alterations of molecules that contribute to ATP hydrolysis of chromatin. Embryonic tumors with multilayered rosettes are associated with microRNA mutations and impaired translation. Ependymomas exhibit great variability. As far as supratentorial lesions are concerned, the major events are mutations either of NFkB or Hippo pathways. Posterior fossa tumors are further divided into two types with different prognoses. Type A group is associated with mutations of DNA damage repair molecules. Lastly, germ cell tumors are a heterogeneous group. Among them, germinomas manifest KIT receptor mutations, a subgroup of the tyrosine kinase receptor family. Full article

Excessive ammonia accumulation poses a significant threat to aquatic species. Potamocorbula ustulata, known for its burrowing behavior and high population density, may experience elevated ammonia levels in its environment. However, its ammonia stress response mechanisms remain unclear. This study investigates the physiological and molecular responses of P. ustulata to acute ammonia exposure. Antioxidant enzyme activity was significantly altered in the gills and hepatopancreas, with GS, GDH, and ARG levels markedly increasing in the hepatopancreas. Transcriptome analysis revealed that after 24 h of exposure, differentially expressed genes (DEGs) were enriched in apoptosis and inflammation-related pathways (MAPK, NF-kB, NOD-like receptor signaling). By 96 h, DEGs in the gills were associated with nitrogen metabolism and transport, while those in the hepatopancreas were linked to oxidative phosphorylation and amino acid metabolism. Key ammonia transport and excretion genes, including V-type H⁺-ATPase, Ammonium transporter Rh, and Na⁺/K⁺-ATPase, were significantly upregulated in the gills, while glutamine synthetase and glutamate dehydrogenase were upregulated in the hepatopancreas (p < 0.05). These findings suggest that ammonia stress disrupts antioxidant defense, triggers inflammation and apoptosis, and enhances ammonia tolerance through excretion, glutamine conversion, and urea synthesis. This study provides insights into the molecular mechanisms underlying ammonia tolerance in bivalves. Full article

Background: Bai Hu Tang (BHT) is a classic antipyretic in traditional Chinese medicine, however, there is little scientific evidence on the mechanism and material basis of its antipyretic effect. Methods: In LPS-induced febrile rats, after administration of BHT at 42 g/kg for half an hour, body temperature was measured at hourly intervals for 9 consecutive hours. Then, serum levels of TNF-α, IL-1β, and IL-6, and serum and cerebrospinal fluid (CSF) levels of AVP, cAMP, PGE2, Ca and CRH, and the remaining sera were used for metabolomics. These were then combined with network pharmacology methodology to further analyse the antipyretic effect of BHT and then dock key targets with differential components. Results: Administration of BHT to LPS-induced febrile rats significantly reduced elevated body temperature, TNF-α, IL-1β and IL-6 levels, but serum and CSF levels of AVP, cAMP, PGE2, Ca²⁺ and CRH were significantly elevated compared to the control group. Network pharmacological analyses indicated that the putative functional targets of BHT were regulation of immune responses, associated protein binding and inflammatory responses, and fine-tuning of phosphatase binding and activation of signalling pathways such as MAPK, PI3K, AKT, NF-kB, cAMP and inflammatory pathways. Metabolomic analysis showed that the antipyretic effect of BHT and its mechanism are likely to be involved in fatty acid metabolism, bile acid metabolism and amino acid metabolism in the organism, with L-arginine, glycyrrhetinic acid and N-acetylpentraxine as the main differential metabolites that play a significant role in heat recovery. The results also showed better docking of glycyrrhetinic acid with TNF-α, IL-6R, PTGS2. Conclusions: BHT provides a valuable adjunct to traditional clinical antipyretics by improving body temperature and metabolism and reducing inflammation. Full article

The retinal pigment epithelium (RPE) serves as a critical guardian of subretinal homeostasis, with its dysfunction implicated in major retinal pathologies, including age-related macular degeneration (AMD) and retinitis pigmentosa. While cellular senescence has emerged as a key driver of RPE degeneration, the molecular mechanisms underlying this process remain incompletely defined. Emerging evidence implicates dual-specificity phosphatase 4 (DUSP4) in cellular stress responses through its antioxidant and anti-inflammatory capacities, yet its role in RPE pathophysiology remains unexplored. Our study reveals a compensatory increase in DUSP4 expression during AMD-associated RPE senescence. To functionally characterize this observation, we knocked down DUSP4 in the RPE of mice via subretinal injection of AAV-shDUSP4. In a sodium iodate-induced dry AMD model, mice with DUSP4 knockdown presented more severe visual impairment than control mice did. To further investigate the molecular mechanism, stable DUSP4-knockout cell lines were constructed via CRISPR/Cas9 technology. The high expression of senescence markers in the DUSP4-knockout cell lines was reversed by DUSP4 overexpression. Furthermore, DUSP4 coordinates the modulation of cell cycle, stress response, and pro-inflammatory signaling by inhibiting the p53, p38, and NF-kB pathways. These findings establish DUSP4 as a multi-functional regulator of RPE senescence. Our work not only elucidates a novel DUSP4-dependent mechanism in AMD pathogenesis but also highlights its therapeutic potential for preserving RPE function in AMD. Full article

Endometrial cancer is one of the most common malignancies seen in women in developed countries. While patients in the early stages of this cancer show better responses to surgery, adjuvant hormonal therapy, and chemotherapy, patients with recurrence show treatment resistance. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer in general but also specifically in endometrial cancer. CSCs have been investigated because of their resistance to conventional therapies, such as chemo- and radiotherapy, and their ability to induce the progression and recurrence of malignancy. The activation of alternative pathways, such as WNT, PI3K, NF-kB, or NOTCH, could be the basis of the acquisition of these abilities of CSCs. Their specific markers and signaling pathways could be treatment targets for CSCs. In this article, we discuss the importance of obtaining a better understanding of the molecular basis and pathways of CSCs in endometrial cancer and the role of CSCs, aiming to discover more specific therapeutic approaches. Full article

Background/Objectives: The kidney plays a crucial role in regulating normal blood pressure and is one of the major organs affected by hypertension. The present study aimed to investigate the hypotensive and renoprotective effects of four specific green tea peptides extracted from green tea dregs on spontaneously hypertensive rats (SHRs) and to investigate the underlying mechanisms. Methods: Four specific green tea peptides (40 mg/kg) were gavaged to SHRs for 4 weeks, and blood pressure, renal function, renal pathological changes, renal tissue fibrosis indexes, and inflammation indexes were examined in SHRs to analyze the role of the four green tea peptides in alleviating hypertension and its renal injury. Results: The results showed that the four TPs significantly reduced systolic and diastolic blood pressure (20–24% and 18–28%) in SHR compared to the model group. Meanwhile, gene levels and protein expression of renal fibrosis-related targets such as phospho-Smad2/3 (p-Smad2/3) (26–47%), Sma- and Mad-related proteins 2/3 (Smad2/3) (19–38%), transforming growth factor-β1 (TGF-β1) (36–63%), and alpha-smooth muscle actin (alpha-SMA) (58–86%) were also significantly reduced. In addition, the reduced expression levels of medullary differentiation factor 88 (MyD88) (14–36%), inducible nitric oxide synthase (iNOS) (58–73%), and nuclear factor-κB p65 (NF-kB p65) (35–78%) in kidneys also confirmed that TPs attenuated renal inflammation in SHR. Therefore, green tea peptides could attenuate the fibrosis and inflammatory responses occurring in hypertensive kidneys by inhibiting the Ang II/TGF-β1/SMAD signaling pathway and MyD88/NF-κB p65/iNOS signaling pathway. Conclusions: The results showed that green tea peptides may be effective candidates for lowering blood pressure and attenuating kidney injury. Full article

Inflammation contributes to the onset and development of many diseases, including neurodegenerative diseases, caused by the activation of microglia, leading to neurological deterioration. Nuclear factor-κB (NF-κB) is one of the most relevant pathways for identifying anti-inflammatory molecules. In this study, polygodial and isotadeonal, two drimane sesquiterpene dialdehydes, were isolated from Drimys winteri, a medicinal tree of the Mapuche people in Chile. Isotadeonal, or epi-polygodial, was obtained from polygodial by epimerization in basic media (60% yield, Na₂CO₃, r/t, 24 h). Both sesquiterpenoids were evaluated on the NF-κB pathway, with the result that isotadeonal inhibited the phosphorylation of IκB-α at 10 μM with higher potency by Western blotting. The final inhibition of the pathway was evaluated using a SEAP reporter (secreted alkaline phosphatase) on THP-1 cells. Isotadeonal inhibited SEAP with higher potency than polygodial, quercetin, and CAPE (phenethyl ester of caffeic acid). In silico analysis suggests that the α-aldehyde of isotadeonal adopts a more stable conformation in the active pocket of IκB-α than polygodial. Full article

This study aimed to evaluate the intrinsic in vitro performance of naïve porcine prepubertal Sertoli cells (SCs) and SCs loaded with blank poly(lactic acid) microparticles (MP) or amphotericin B poly(lactic acid) microparticles (AmB-MP) against Candida tropicalis, a prevalent pathogenic non-albicans species. The objective was to assess their impact on biofilm formation and the cellular response mechanisms involved, building on previous findings that highlight SCs’ potential as anti-infective agents and drug carriers. Our results demonstrated that SCs successfully internalized Candida tropicalis while maintaining viability and exhibited a strong anti-infective effect, inhibiting biofilm formation by 70%. This inhibition increased to 80–90% when SCs were combined with AmB-MP. The interaction between SCs (both naïve and MP-loaded) and Candida tropicalis triggered the activation of MAPK, AKT, and NF-kB signaling pathways, leading to the upregulated expression of innate immune factors such as MHC-II, TLR-4, TGF-β, IDO, and β-defensin 123. These findings reinforce the role of SCs in infection control and drug delivery. Furthermore, their anti-infective and scavenging activity is linked to a tolerogenic phenotype, suggesting a potential dual therapeutic role at the host–pathogen interface. Full article

The widespread use of food additives, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tert-butylhydroquinone (TBHQ), has raised concerns about their potential toxicity, especially their hepatotoxicity, nephrotoxicity, and neurotoxicity. This study explores the targets and mechanisms of food additive-induced toxicity using network toxicology. Toxicity predictions of BHA, BHT, and TBHQ were performed using the ProTox-3.0, ADMETlab 3.0, and Xundrug databases, and potential targets were identified using the SwissTargetPrediction, Batman-TCM, SuperPred, and SEA databases. These were integrated with GeneCards—The Human Gene Database (GeneCards) and the Online Mendelian Inheritance in Man (OMIM) database to extract toxicity-related targets for subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Core-acting genes were further screened through protein–protein interactions (PPIs), and molecular docking was performed to verify the binding free energy between BHA, BHT, and TBHQ and their core targets. Additionally, the mRNA-miRNA-lnRNA interaction regulatory networks of the core targets and potential carcinogenic mechanisms were analyzed. The targets of BHA, BHT, and TBHQ were as follows: ACE, HIF1A, NR1H4, NFKB1, TNF, IL6, IFNG, IL1B, and ESR1 for hepatotoxicity; APP, NFKB1, ACE, FOS, IL10, IL1B, IL6, TNF, and ALB for nephrotoxicity; and GRIN2B, IL1B, and TNF for neurotoxicity. These interactions primarily involved pathways such as interleukin-17 (IL-17) and Janus kinase-signal transducer and activator of transcription (JAK-STAT), as well as various pathways related to non-alcoholic fatty liver disease (NAFLD). This study highlights the potential toxicity of BHA, BHT, and TBHQ to the liver, kidneys, and nerves, providing insights for better safety evaluations. Full article

The persistence of latent HIV-1 proviruses in CD4⁺ T cells is a major obstacle to curing HIV. The “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4⁺ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir. Full article

Background: Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of the BCR-ABL1 fusion gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signaling pathways, which drive the regeneration of LSCs. Despite nilotinib’s action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drive relapse and progression in CML patients. Methods: Our study investigated the gene expression profiling (GEP) of BM CD34+/lin− cells from 79 CP-CML patients at diagnosis, compared to the BM CD34+/lin− cells from the same patients after 12 months of nilotinib treatment and to the normal counterpart cells from 10 donors (CTRLs). Results: GEP analyses identified 3012 significantly differentially expressed genes across these comparisons. Among these, we focused on certain key genes associated with eight crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. Within these pathways, we observed the up-regulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs. Conclusions: We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML. Full article

Background: Hodgkin lymphoma (HL) is a B-cell-derived malignancy and one of the most frequent types of lymphoma. The tumour cells typically exhibit multiple genomic alterations together with aberrantly activated signalling pathways, driven by paracrine and/or autocrine modes. SPP1 (alias osteopontin) is a cytokine acting as a signalling activator and has been connected with relapse in HL patients. To understand its pathogenic role, here, we investigated the mechanisms and function of deregulated SPP1 in HL. Methods: We screened public patient datasets and cell lines for aberrant SPP1 expression. HL cell lines were stimulated with SPP1 and subjected to siRNA-mediated knockdown. Gene and protein activities were analyzed by RQ-PCR, ELISA, Western blot, and immuno-cytology. Results: SPP1 expression was detected in 8.3% of classic HL patients and in HL cell line SUP-HD1, chosen to serve as an experimental model. The gene encoding SPP1 is located at chromosomal position 4q22 and is genomically amplified in SUP-HD1. Transcription factor binding site analysis revealed TALE and HOX factors as potential regulators. Consistent with this finding, we showed that aberrantly expressed PBX1 and HOXB9 mediate the transcriptional activation of SPP1. RNA-seq data and knockdown experiments indicated that SPP1 signals via integrin ITGB1 in SUP-HD1. Accordingly, SPP1 activated NFkB in addition to MAPK/ERK which in turn mediated the nuclear import of ETS2, activating oncogenic JUNB expression. Conclusions: SPP1 is aberrantly activated in HL cell line SUP-HD1 via genomic copy number gain and by homeodomain transcription factors PBX1 and HOXB9. SPP1-activated NFkB and MAPK merit further investigation as potential therapeutic targets in affected HL patients. Full article