Search Results (8,390)

Hypopharyngeal carcinoma (HPC) represents the most prognostically unfavorable subtype among head and neck malignancies. Platinum-based neoadjuvant chemotherapy serves as a critical therapeutic approach for improving outcomes in hypopharyngeal carcinoma; however, its efficacy remains suboptimal due to the high incidence of chemoresistance. Current research on chemoresistance has primarily focused on head and neck squamous cell carcinoma (HNSCC), yet significant heterogeneity exists between hypopharyngeal carcinoma and other head and neck tumors, limiting the direct applicability of broader HNSCC research findings to hypopharyngeal carcinoma. This review systematically summarizes recent advances in understanding the mechanisms underlying chemoresistance in hypopharyngeal carcinoma, with emphasis on the comprehensive elucidation of key mechanisms, including apoptosis evasion, enhanced DNA damage repair, augmented autophagy, and increased drug efflux. Moreover, three noteworthy special scenarios involving cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), and cancer-associated fibroblasts (CAFs) are discussed. These entities not only intrinsically participate in multiple chemoresistance mechanisms but also interact synergistically, thereby further exacerbating chemoresistance in hypopharyngeal carcinoma. Full article

G-quadruplexes have been identified as a promising anti-cancer target because of their ability to modulate the stability of mRNAs encoding oncogenes, tumor suppressor genes, and other potential therapeutic targets. Deregulation of DNA damage and Unfolded Protein Response pathways in cancer cells may create vulnerabilities that can be exploited therapeutically. Previous studies have shown variations in the relative expression of DDR and UPR components in canine lymphoma and leukemia cell lines CLBL-1, CLB70, and GL-1. In the present study, we report the presence of G-quadruplex structures in these canine cell lines. Downregulation of the expression of DDR and UPR components at the mRNA level was observed in the CLBL-1 and CLB70 cell lines after stabilization of G4 structures using the ligand PhenDC3. In contrast, in GL-1 cells, important components of the DDR pathway, such as PARP1, GADD45A, and PIK3CB were upregulated in response to PhenDC3 treatment. Downregulation of DDIT4 mRNA expression, which encodes an important UPR component, was detected in the CLBL-1 and GL-1 cell lines after PhenDC3 exposure. These results suggest that G4 structures can be used to manipulate the expression of potential targets to treat lymphoma in dogs. A substantial enrichment of DNA replication and pyrimidine metabolism pathways was found in the GL-1 cell line after G4 stabilization. This finding suggests that PhenDC3 may induce DNA replication stress in this cell line. Collectively, these results support the feasibility of employing canine cancer cells as a model system to investigate the role of G-quadruplex structures in cancer. Full article

Objectives: This review examines the role of oxidative stress in the survival, apoptosis, and therapy resistance of head and neck squamous cell carcinoma (HNSCC) cells, with a focus on how redox imbalance influences tumour progression and treatment outcomes. Methods: A literature search was conducted in Scopus using the keywords head and neck squamous cell carcinoma, oxidative stress, reactive oxygen species (ROS), and antioxidant systems. Articles published in English were included, without restrictions on publication year. Reviews, clinical studies, and experimental research addressing oxidative stress mechanisms in HNSCC were considered, while non-English papers and studies unrelated to HNSCC were excluded. Key Findings: ROS exhibit dual effects in HNSCC, promoting tumour growth and DNA damage while also inducing apoptosis through molecular interactions. Elevated ROS contribute to drug resistance by inhibiting apoptosis, altering autophagy, and enhancing proliferation. Cancer cells counteract this via adaptive antioxidant responses involving transcriptional regulation and upregulation of enzymatic defences. Major risk factors for HNSCC—alcohol, tobacco, and high-risk HPV infection—disrupt redox homeostasis, underscoring the central role of oxidative stress in both carcinogenesis and therapy response. Conclusions: Oxidative stress plays a context-dependent role in HNSCC progression and treatment resistance. Targeting redox-regulatory pathways may provide therapeutic benefit. This review synthesizes recent insights on ROS-mediated mechanisms, highlighting potential strategies for improving HNSCC management beyond existing literature. Full article

Background/Objectives: Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach and causes various gastrointestinal diseases. Although antibiotic therapy is the most effective method for its eradication, the increasing prevalence of antibiotic resistance has made treatment increasingly challenging in recent years. In this study, the antimicrobial activity, synergistic effects with antibiotics, and mechanisms of action of Bicarinalin, an antimicrobial peptide (AMP) derived from the venom of Tetramorium bicarinatum, were investigated against H. pylori. Methods: To determine the antibacterial activity of Bicarinalin, a well diffusion assay was performed, yielding an inhibition zone of 18.3 mm at a concentration of 32 µg/mL for ATCC strain. MIC₉₉ values were determined by microdilution tests as 4.8 μg/mL for the reference strain. The enhancement of the antimicrobial potential of levofloxacin and clarithromycin when administered together with Bicarinalin has been demonstrated using the well diffusion method. Results: Inhibition zones increased from 14.2 mm to 20 mm for levofloxacin and from 7.3 mm to 16 mm for clarithromycin. This study is the first to identify DNA and protein leakage caused by Bicarinalin in H. pylori. Intracellular protein and DNA leakage were measured, with protein and DNA levels released into the extracellular environment determined as 33.25% and 55.10%, respectively, following Bicarinalin treatment. Furthermore, to investigate its effect on membrane damage, scanning electron microscopy (SEM) was performed, revealing disrupted cell membrane structures, penetration between cells, and severe deterioration of morphological integrity. Conclusions: This study has demonstrated for the first time that, when administered concomitantly, Bicarinalin enhances the antimicrobial activities of levofloxacin and clarithromycin. This highlights its potential as an adjunctive treatment for H. pylori alongside existing drugs. Full article

Background: Interleukin-6 (IL-6) is a multifunctional cytokine implicated in various inflammatory and immune-mediated processes. Its involvement in systemic lupus erythematosus (SLE) has been increasingly investigated, particularly related to disease activity and tissue damage. This study aimed to quantify serum IL-6 levels in patients with SLE and assess their associations with clinical manifestations and laboratory parameters. Methods: A total of 88 patients diagnosed with SLE and 87 matched healthy controls were included. Serum IL-6 concentrations were measured by ELISA. Clinical data, SLEDAI scores, organ involvement, inflammatory markers, and autoantibody profiles were recorded. The statistical analysis involved non-parametric testing, correlation analysis, and linear regression. Results: IL-6 concentrations were higher in SLE patients than in controls (7.46 ± 6.73 vs. 5.30 ± 10.89 pg/mL). Significantly increased IL-6 levels were observed in patients with active disease (SLEDAI ≥ 6; p = 0.025) and renal (p = 0.001) involvement. Positive correlations were identified between IL-6 and ESR, creatinine, ANA, and specific autoantibodies (anti-dsDNA, SSA, and SSB). IL-6 also correlated with IL-10 (p = 0.010) but showed no significant association with IL-17A, TNF-α, CRP, or complement levels. Conclusions: Elevated IL-6 levels are associated with greater disease activity and specific organ involvement in SLE. These findings highlight IL-6 as a measurable indicator of immunological and clinical disease expression, supporting its relevance in disease monitoring. Full article

Stem cell (SC)-based therapy exploits the ability of cells to migrate to damaged tissues and repair them. In this context, there is a strong interest in the use of mesenchymal stem cells (MSCs), multipotent SCs that are easy to obtain and are able to differentiate into various cell lineages. However, MSCs undergo cellular senescence during in vitro expansion, and may also become senescent in vivo, influenced by multiple molecular, cellular, and environmental interactions. Therefore, the development of in vitro cell models is crucial to study the mechanisms underlying senescence in MSCs. This study aimed to investigate the effects of tert-butyl hydroperoxide (t-BHP) as a senescence inducer in human dermal MSCs (hDMSCs), a promising tool for tissue repair. t-BHP induced a pro-senescent effect on hDMSCs greater than hydrogen peroxide (H₂O₂), as evidenced by ROS production, DNA damage, cell cycle arrest, inhibition of cell proliferation, changes in cellular and nuclear morphology, and cytoskeletal reorganization, as well as the increase in other senescence markers, including senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and senescence-associated secretory phenotype (SASP). These results indicate that t-BHP could be a promising compound for inducing stress-induced premature senescence (SIPS) in hDMSCs, providing a valuable tool to investigate this process and evaluate the efficacy of senolytic compounds. Full article

In Bhutan, information on rickettsiae is limited to a few epidemiological studies. There is no information on ticks and tick-associated rickettsiae. Ticks were collected opportunistically from domestic animals residing in eight districts where a seroprevalence study had been carried out previously. Morphological identification of the ticks was performed in the United States National Tick Collection and testing for rickettsiae was carried out in the Australian Rickettsial Reference Laboratory. Samples positive for rickettsiae by qPCR were subjected to conventional PCR followed by DNA sequencing and phylogenetic analysis. A total of 200 ticks were sampled from 155 domestic animals including cattle, dogs, goats, horses, yaks, sheep and cats. The ticks belonged to twelve different species, the commonest being Rhipicephalus microplus, followed by Rhipicephalus haemaphysaloides, Haemaphysalis sp. near ramachandrai, Haemaphysalis tibetensis, Haemaphysalis bispinosa, Haemaphysalis sp., Haemaphysalis sp. near davisi, Rhipicephalus sanguineus, Haemaphysalis shimoga, Haemaphysalis hystricis, Ixodes ovatus, and Amblyomma testudinarium. Rickettsial DNA sequence analysis showed that the rickettsiae infesting ticks in Bhutanese domestic animals aligned with R. gravesii, R. canadensis, R. honei, R. africae, R. felis, R. akari, R. australis, R. japonica, R. africae, R. heilongjiangensis, R. conorii, R. peacockii, R. honei, R. massiliae and R. rhipicephali. However, these may not be conclusive due to low bootstrap values in the phylogenetic tree. Bhutan will benefit from larger studies on ticks and tick-borne infections, burden and damage assessment to livestock and human health, public health interventions and clinical guidelines to reduce morbidity and mortality in human and animal health. Full article

The fruiting stage of soybean (Glycine max L.) is critical for determining both its yield and quality, thereby influencing global production. While some studies have provided partial explanations for the occurrence of Fusarium species on soybean seeds and pods, the fungal diversity affecting soybean pods in Sichuan Province, a major soybean cultivation region in Southwestern China, remains inadequately understood. In this study, 182 infected pods were collected from a maize–soybean relay strip intercropping system. A total of 10 distinct pod-infecting fungal genera (132 isolates) were identified, and their pathogenic potential on soybean seeds and pods was evaluated. Using morphological characteristics and DNA barcode markers, we identified 43 Fusarium isolates belonging to 8 species, including F. verticillioides, F. incarnatum, F. equiseti, F. proliferatum, F. fujikuroi, F. oxysporum, F. chlamydosporum, and F. acutatum through the analysis of the translation elongation factor gene (EF1-α) and RNA polymerases II second largest subunit (RPB2) gene. Multi-locus phylogenetic analysis, incorporating the Internal Transcribed Spacer (rDNA ITS), β-tubulin (β-tubulin), Glyceraldehyde 3-phosphate dehydrogenase (GADPH), Chitin Synthase 1 (CHS-1), Actin (ACT), Beta-tubulin II (TUB2), and Calmodulin (CAL) genes distinguished 37 isolates as 6 Colletotrichum species, including C. truncatum, C. karstii, C. cliviicola, C. plurivorum, C. boninense, and C. fructicola. Among these, F. proliferatum and C. fructicola were the most dominant species, representing 20.93% and 21.62% of the isolation frequency, respectively. Pathogenicity assays revealed significant damage from both Fusarium and Colletotrichum isolates on soybean pods and seeds, with varying isolation frequencies. Of these, F. proliferatum, F. acutatum, and F. verticillioides caused the most severe symptoms. Similarly, within Colletotrichum genus, C. fructicola was the most pathogenic, followed by C. truncatum, C. karstii, C. cliviicola, C. plurivorum, and C. boninense. Notably, F. acutatum, C. cliviicola, C. boninense, and C. fructicola were identified for the first time as pathogens of soybean pods under the maize–soybean strip intercropping system in Southwestern China. These findings highlight emerging virulent pathogens responsible for soybean pod decay and provide a valuable foundation for understanding the pathogen population during the later growth stages of soybean. Full article

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function (“OXPHOS-high” cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy. Full article

Post-translational modifications (PTMs) of proteins in eukaryotic cells are essential for regulating proteome function and maintaining cellular homeostasis. Among these, the methylation modification of arginine has received much attention in recent years. The enzymatic process of arginine methylation is catalyzed by a family of approximately nine known protein arginine methyltransferases (PRMTs) in humans, which utilize S-adenosylmethionine (SAM) as the methyl group donor. PRMTs are involved in biological processes such as gene transcription, signal transduction, and DNA damage repair. Their role in normal cellular functions and pathological disease states is becoming increasingly clear with the advancement of research. This paper provides a review of the numerous roles of members of the PRMT family in normal cellular function and disease pathophysiology, with a focus on their association with the tumor immune microenvironment (TIME), and discusses their broad impact on various physiological processes and pathological conditions. Full article

Autism spectrum disorder (ASD) is a complex group of severe neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social abilities as well as repetitive and compulsive stereotypic behaviors. We aim to evaluate the genetic predisposition to oxidative response and its relationship with altered oxidative stress markers in ASD patients. Genomic DNA was isolated from peripheral blood lymphocytes of 106 (83 M, 23 F; 7.9 ± 3.2 years) ASD patients and 90 healthy subjects (63 M, 27 F; 21.2 ± 1.8 years). Genotyping was performed by real-time PCR-based allelic discrimination, PCR and electrophoresis of GST deletion variants. Reactive oxygen metabolites (dROMs), the Biological Antioxidant Potential (BAP), and the advanced oxidation protein products (AOPP) were also measured. Furthermore, we assessed oxidative DNA damage by Single Cell Gel Electrophoresis. The evaluation of oxidative stress markers indicated a mild oxidative stress status and a higher level of DNA damage in nuclei of ASD patients’ lymphocytes. We found significant associations between ASD and several polymorphisms of genes involved in the detoxification and the response to oxidative stress. Genetic and environmental factors contribute to the onset of autism spectrum disorder, and ASD patients’ treatment requires a multimodal approach, including behavioral, educational, and pharmacological approaches. Full article

Background and aims: The senescent phenotype transition of vascular smooth muscle cells (VSMCs) is a crucial risk factor for the occurrence and development of vascular diseases. Intermedin (IMD) has various protective effects on cardiovascular diseases. In this study, we aimed to explore the role and the related mechanism of IMD in the senescent phenotype transition of VSMCs of aorta in mice. Methods: The senescent phenotype transition of VSMCs was induced by angiotensin II (Ang II) administered by mini-osmotic pumps in Adm2^fl/fl and Adm2^fl/flTagCre mice. Mouse VSMCs from aorta were used in in vitro experiments. Results: The aortic mRNA level of IMD, namely Adm2, was significantly decreased in Ang II-treated mice. Senescence-associated β-galactosidase activity and protein expressions of p16 and p21 were increased in the aortas of Adm2^fl/flTagCre mice, which were further elevated in Ang II-treated Adm2^fl/flTagCre mice. In addition, Adm2 deficiency in VSMCs further increased the protein expressions of DNA damage markers including 53BP1 and γH2AX in aortas of Adm2^fl/flTagCre mice, and Ang II treatment increased their levels in aortas of Adm2^fl/flTagCre mice or in VSMCs. However, Ang II-induced increases in senescence-associated proteins and DNA damage markers could be mitigated by the administration of IMD in vitro. Mechanistically, IMD increased intracellular NAD⁺ by activating nicotinamide phosphoribosyl transferase (NAMPT), followed by enhancing poly (ADP-ribose) polymerase-1 (PARP1) activity. Inhibitors of PARP1 or NAMPT effectively blocked the beneficial role of IMD in the DNA damage of VSMCs. Conclusions: IMD alleviates DNA damage partially by activating NAMPT/PARP1, thereby inhibiting the senescent phenotype transition of VSMCs of aorta, which might shed new light on the prevention of vascular aging. Full article

Introduction: Fusobacterium nucleatum, a common oral microbe associated with periodontal disease, has emerged as a significant prognostic indicator in colorectal cancer (CRC). This organism is notably enriched in CRC tissues and is associated with reduced survival times and relapse. Fusobacterium is implicated in encouraging the development of chemoresistance through diverse tumor-promoting pathways that are increasingly being elucidated across molecular domains. Methods: This work uses a combined analysis of public data examining the role of F. nucleatum in CRC by investigating multiple transcriptomic datasets derived from co-culture infections in vitro. Results: In tandem with previously identified mechanisms known to be influenced by F. nucleatum, this analysis revealed that the bacterium activates multiple chemoresistance-associated pathways, including those driving inflammation, immune evasion, DNA damage, and metastasis. Notably, this study uncovered a novel induction of type I and type II interferon signaling, suggesting activation of a pseudo-antiviral state. Furthermore, pathway analysis (IPA) predicted altered regulation of several therapeutic agents, suggesting that F. nucleatum may compromise drug efficacy through transcriptional reprogramming. Conclusions: These findings reinforce the role of F. nucleatum in modulating host cellular pathways and support the hypothesis that bacterial association potentiates chemoresistance. Full article

Obesity contributes to the development of metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained low-grade inflammation and mitochondrial dysfunction. In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates β-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function—including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy—may retard disease progression. Full article

High non-esterified fatty acids (NEFAs) during negative energy balance in dairy cattle can impair reproduction. While their effects on oocyte maturation and preimplantation embryo development are known, their impact during fertilisation is largely unexplored. This study examined the effects of high NEFA exposure exclusively during in vitro fertilisation (IVF). Bovine oocytes were matured in vitro and fertilised under physiological or high NEFA concentrations. High NEFA concentrations decreased fertilisation, cleavage, and blastocyst rates. Reactive oxygen species production in zygotes was not affected, but blastocysts derived from the High-NEFA group had fewer cells. Spermatozoa exposed to high NEFA concentrations exhibited increased plasma membrane and acrosome damage, higher DNA fragmentation, and reduced mitochondrial membrane potential. The expression of H3K27me3, a repressive histone mark normally erased from fertilisation to embryonic genome activation, was higher in 2-cell than in 4-cell embryos on day 2 after IVF, but only in the High-NEFA group. This delayed H3K27me3 loss, along with increased DNA damage, could partially explain the reduced blastocyst formation observed. In conclusion, high NEFA concentrations can impair pre-implantation embryo development during zygote formation, potentially via effects on both the oocyte and spermatozoon. The latter warrants further investigation using an intracytoplasmic sperm injection model. Full article