Search Results (34)

Pyridoxine-dependent epilepsy due to ALDH7A1 deficiency (PDE-ALDH7A1) is a rare but treatable epileptic encephalopathy caused by disruption of lysine catabolism and secondary depletion of pyridoxal-5′-phosphate (PLP). Although seizures are often controlled with pyridoxine supplementation, many patients continue to experience neurodevelopmental impairment, underscoring the importance of early diagnosis and improved therapeutic strategies. Central to both diagnosis and pathophysiology is the accumulation of lysine-derived metabolites, most notably α-aminoadipate semialdehyde (α-AASA), its cyclic Schiff base Δ¹-piperideine-6-carboxylate (P6C), and pipecolic acid. These metabolites have become the biochemical hallmarks of PDE-ALDH7A1, linking ALDH7A1 pathogenic variants to PLP inactivation and neuronal dysfunction. However, their chemical instability and analytical requirements pose challenges for universal diagnostics and newborn screening. This review summarizes current understanding of lysine catabolism in health and disease, critically evaluates the diagnostic utility and limitations of classical biomarkers, and discusses emerging insights into their pathophysiological roles. We further highlight recent discoveries of novel, chemically stable biomarkers, including 6-oxopiperidine-2-carboxylic acid (6-oxo-PIP), 2-oxopropylpiperidine-2-carboxylic acid (2-OPP), and 6-hydroxy-2-aminocaproic acid (HACA), identified through advanced metabolomics approaches. These metabolites show promise for newborn screening and provide new mechanistic links between metabolic stress, seizure susceptibility, and ongoing neurological morbidity despite pyridoxine treatment. Collectively, advances in biomarker discovery are reshaping diagnostic strategies for PDE-ALDH7A1 and offering new perspectives on disease mechanisms, paving the way for earlier detection and the development of more effective, mechanism-based therapies. Full article

Pseudouridine (Ψ), the most abundant RNA modification, plays essential roles in shaping RNA structure, stability, and translational output. Beyond cancer, Ψ is dynamically regulated across numerous physiological and pathological contexts—including immune activation, metabolic disorders, stress responses, and pregnancy-related conditions such as preeclampsia—where elevated Ψ levels reflect intensified RNA turnover and modification activity. These broad functional roles highlight pseudouridylation as a central regulator of cellular homeostasis. Emerging evidence demonstrates that Ψ dysregulation contributes directly to the development and progression of several women’s cancers, including breast, ovarian, endometrial, and cervical malignancies. Elevated Ψ levels in tissues, blood, and urine correlate with tumor burden, metastatic potential, and therapeutic responsiveness. Aberrant activity of Ψ synthases such as PUS1, PUS7, and the H/ACA ribonucleoprotein component dyskerin alters pseudouridylation patterns across multiple RNA substrates, including rRNA, tRNA, mRNA, lncRNAs, snoRNAs, and ncRNAs. These widespread modifications reshape ribosome function, modify transcript stability and translational efficiency, reprogram RNA–protein interactions, and activate oncogenic signaling programs. Advances in high-resolution, site-specific Ψ mapping technologies have further revealed mechanistic links between pseudouridylation and malignant transformation, highlighting how modification of distinct RNA classes contributes to altered cellular identity and tumor progression. Collectively, Ψ and its modifying enzymes represent promising biomarkers and therapeutic targets across women’s cancers, while also serving as sensitive indicators of diverse non-cancer physiological and disease states. Full article

Homogeneous Kolbe-Schmitt carboxylation of phenoxides offers a mild and effective alternative to the classical high-temperature solid-phase Kolbe-Schmitt reaction. To develop this into a practical synthetic approach, we investigated several fundamental dependencies, particularly the impact of cations (Na, K, Li, Cs, and Rb), phenoxide concentration, and solvents (DMSO or DMF) on the yield and regioisomeric ratio of hydroxyaromatic carboxylic acids (HACAs). We identified optimal conditions for the effective carboxylation of different phenoxides, including a chiral Ellman’s sulfinamide derived from ortho-vanillin. Both solvents and cations were found to be crucial in the carboxylation of phenoxides. Due to solvation effects, DMSO directs CO₂ attack to the para-position of phenoxide, while DMF, although less selective, generally affords higher HACA yields. The addition of equiv. amounts of mesitolate salt to phenoxide in either DMSO or DMF solution often drives the reaction to completion, resulting in yields of up to 98%. Phenoxides containing several EWG groups, such as halogens or alkyl groups, adjacent to the reaction center show considerably lower reactivity in carboxylation; however, by carefully adjusting parameters, acceptable conversions (>70%) can be achieved. Using the gasometry, we assessed the stability of phenoxide and mesitolate carbonate complexes in DMSO. These experiments revealed distinct stages for the onset of decomposition and carboxylation at atmospheric pressure, indicating a lower energy barrier in the homogeneous process. Further insight into carbonate complex behavior was obtained through DOSY and ¹³C NMR experiments, which support increased molecular association in solution and correlate with enhanced reactivity. Full article

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with notable sex-specific differences in its incidence, diagnosis, and outcomes. Our previous work identified casein kinase 2 alpha (CK2α) as being capable of impairing DNA mismatch repair (MMR) via phosphorylation of MLH1, thereby increasing the tumor mutational burden. This study aimed to investigate sex-specific differences in CK2α protein expression in CRC. Methods: Immunohistochemical (IHC) analysis was performed on 161 CRC tumors and adjacent normal tissues to quantify the CK2α protein levels. A multi-cohort meta-analysis of proteomic and clinical data was conducted to validate our findings and assess the correlations with age, sex, and relevant signaling pathways. Results: Female CRC patients exhibited significantly higher CK2α expression than male patients, which was confirmed in two independent cohorts. Additionally, CK2α expression was positively correlated with age in female but not male patients. Cross-cohort correlation analyses linked CK2α levels with key proteins involved in estrogen receptor signaling and aging, including DEAD-box helicase 5 (DDX5), histone deacetylase 1 (HDAC1), proliferating cell nuclear antigen (PCNA), prohibitin-2 (PHB2), H/ACA ribonucleoprotein complex subunit 2 (NHP2), and dual-specificity mitogen-activated protein kinase kinase 3 (MAP2K3). Conclusions: CK2α is significantly overexpressed in the tumor tissue of female CRC patients and shows a strong age-related correlation. These findings suggest a sex- and age-specific regulatory mechanism potentially influenced by estrogen signaling or menopause. Such dimorphisms underscore the need for sex-specific strategies in CRC biomarker development and therapy. Full article

Fungal HacA/Hac1 transcription factors play a crucial role in regulating the unfolded protein response (UPR). The UPR helps cells to maintain endoplasmic reticulum (ER) protein homeostasis, which is critical for growth, development, and virulence. The Aspergillus flavus hacA gene encodes a domain rich in basic and acidic amino acids (Bsc) and a basic leucine zipper (bZip) domain, and features a non-conventional intron (Nt20). In this study, CRISPR/Cas9 was utilized to dissect the Bsc-coding, bZip-coding, and Nt20 sequences to elucidate the relationship between genotype and phenotype. In the Bsc and bZip experimental sets, all observed mutations in both coding sequences were in frame, suggesting that out-of-frame mutations are lethal. The survival rate of transformants in the Nt20 experiment set was low, at approximately 7%. Mutations in the intron primarily consisted of out-of-frame insertions and deletions. In addition to the wild-type-like conidial morphology, the mutants exhibited varied colony morphologies, including sclerotial, mixed (conidial and sclerotial), and mycelial morphologies. An ER stress test using dithiothreitol revealed that the sclerotial and mycelial mutants were much more sensitive than the conidial mutants. Additionally, the mycelial mutants were unable to produce aflatoxin but still produced aspergillic acid and kojic acid. RNAi experiments targeting the region encompassing Bsc and bZip indicated that transformant survival rates generally decreased, with a small number of transformants displaying phenotypic changes. Defects in the hacA gene at the DNA and transcript levels affected the survival, growth, and development of A. flavus. Thus, this gene may serve as a promising target for future host-induced gene-silencing strategies aimed at controlling infection and reducing aflatoxin contamination in crops. Full article

Conversion of CO₂ into organic chemicals offers a promising route for advancing the circularity of carbon capture, utilisation, and storage in line with the international 2050 Net Zero agenda. The widely known commercialised chemical fixation of CO₂ into organic chemicals is the century-old Kolbe–Schmitt reaction, which carboxylates phenol (via sodium phenoxide) into salicylic acid. The carboxylation reaction is normally carried out between the gas–solid phases in a batch reactor. The mass and heat transfer limitations of such systems require rather long reaction times and a high pressure of CO₂ and are often characterised by the low formation of undesirable side products. To address these drawbacks, a novel suspension-based carboxylation method has been designed and carried out in this present study, where sodium phenoxide is dispersed in toluene to react with CO₂. Importantly, the addition of phenol played a critical role in promoting the stoichiometric conversion of phenoxide to salicylic acid. Under the optimal conditions of a phenol/phenoxide molar ratio of 2:1 in toluene, a reaction temperature of 225 °C, a CO₂ pressure of 30 bar, a reaction time of 2 h, and stirring at 1000 rpm, an impressive salicylic acid molar yield of 92.68% has been achieved. The reaction mechanism behind this has been discussed. This development provides us with the potential to achieve a carboxylation reaction of phenoxide with CO₂ more effectively in a continuous reactor. It can also facilitate the large-scale fixing of CO₂ into hydroxy aromatic carboxylic acids, which can be used as green organic chemical feedstocks for making various products, including long-lived polymeric materials. Full article

Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, is marked by impaired skin barrier function and persistent pruritus. It significantly deteriorates patients’ quality of life, making it one of the most burdensome non-lethal skin disorders. Filaggrin plays a crucial role in the pathophysiology of barrier disruption in AD, interacting with inflammatory mediators. It is an integral part of the extracellular matrix architecture, serving to protect the skin barrier and attenuate the inflammatory cascade. In this study, we engineered a novel recombinant human filaggrin (rhFLA-10) expression vector, which was subsequently synthesized and purified. In vitro and ex vivo efficacy experiments were conducted for AD. rhFLA-10, at low concentrations (5 to 20 μg/mL), was non-toxic to HACaT cells, significantly inhibited the degranulation of P815 mast cells, and was readily absorbed by cells, thereby exerting a soothing therapeutic effect. Furthermore, rhFLA-10 demonstrated anti-inflammatory properties (p < 0.05). In vivo, efficacy experiments further substantiated that rhFLA-10 could effectively ameliorate AD in mice and facilitate the repair of damaged skin (p < 0.001). These findings underscore the considerable potential of rhFLA-10 in the treatment of AD. Full article

Psoriasis, a chronic inflammatory skin disease induced by various factors, including genetic factors, immune factors, environmental factors, and psychological factors, is characterized by thickening of the epidermis, excessive proliferation of keratinocytes, abnormal differentiation, and an excessive inflammatory response. Traditional treatments for psoriasis still face challenges because of limited curative effects, notable side effects, and a tendency for recurrence. In contrast, topical therapy provides a favorable option for psoriasis treatment because of its noninvasive and self-administered method. In this study, gentiopicrin (Gen) is encapsulated in the liposomes to form a nanodrug, and then chitosan is covered on the nanodrug to assemble the nanodrug delivery system (CS@Gen), which is used as a topical agent for treating psoriasis. Then M5 (a mixture of five pro-inflammatory cytokines, i.e., IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α)-induced HacaT cells and imiquimod-induced psoriasis mouse models are established, whose results show that CS@Gen induces apoptosis and inhibits the proliferation and cell migration of psoriasis keratinocytes. Additionally, the application of CS@Gen cream can significantly reduce epidermal thickness, diminish skin scaling, and improve other related mechanisms in mice affected by psoriasis. Meanwhile, the prepared CS@Gen can significantly reduce the expression levels of IL-17a, Cxcl2, S100a, Mki67, and other related inflammatory factors, resulting in indirectly inhibiting the inflammation of keratinocytes. In summary, the present study provides an ideal loading for an anti-inflammatory and immunomodulatory drug delivery system for the treatment of psoriasis. Full article

Small nucleolar RNAs (snoRNAs) constitute a class of intron-derived non-coding RNAs ranging from 60 to 300 nucleotides. Canonically localized in the nucleolus, snoRNAs play a pivotal role in RNA modifications and pre-ribosomal RNA processing. Based on the types of modifications they involve, such as methylation and pseudouridylation, they are classified into two main families—box C/D and H/ACA snoRNAs. Recent investigations have revealed the unconventional synthesis and biogenesis strategies of snoRNAs, indicating their more profound roles in pathogenesis than previously envisioned. This review consolidates recent discoveries surrounding snoRNAs and provides insights into their mechanistic roles in cancer. It explores the intricate interactions of snoRNAs within signaling pathways and speculates on potential therapeutic solutions emerging from snoRNA research. In addition, it presents recent findings on the long non-coding small nucleolar RNA host gene (lncSNHG), a subset of long non-coding RNAs (lncRNAs), which are the transcripts of parental SNHGs that generate snoRNA. The nucleolus, the functional epicenter of snoRNAs, is also discussed. Through a deconstruction of the pathways driving snoRNA-induced oncogenesis, this review aims to serve as a roadmap to guide future research in the nuanced field of snoRNA–cancer interactions and inspire potential snoRNA-related cancer therapies. Full article

The conserved MYST proteins form the largest family of histone acetyltransferases (HATs) that acetylate lysines within the N-terminal tails of histone, enabling active gene transcription. Here, we have investigated the biological and regulatory functions of the MYST family HAT SasC in the opportunistic human pathogenic fungus Aspergillus fumigatus using a series of genetic, biochemical, pathogenic, and transcriptomic analyses. The deletion (Δ) of sasC results in a drastically reduced colony growth, asexual development, spore germination, response to stresses, and the fungal virulence. Genome-wide expression analyses have revealed that the ΔsasC mutant showed 2402 significant differentially expressed genes: 1147 upregulated and 1255 downregulated. The representative upregulated gene resulting from ΔsasC is hacA, predicted to encode a bZIP transcription factor, whereas the UV-endonuclease UVE-1 was significantly downregulated by ΔsasC. Furthermore, our Western blot analyses suggest that SasC likely catalyzes the acetylation of H3K9, K3K14, and H3K29 in A. fumigatus. In conclusion, SasC is associated with diverse biological processes and can be a potential target for controlling pathogenic fungi. Full article

The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl–prolyl cis–trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal–Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs. Full article

The family Thymelaeaceae, which includes huge evergreen trees that are sparsely distributed in tropical rainforests, includes the genus Aquilaria. Numerous medical conditions, including inflammation, cancer, and oxidative stress have been traditionally treated using Aquilaria agallocha and Aquilaria malaccensis. In this study, we evaluated in silico and biological activity with A. agallocha and A. malaccensis sample for more conformation. Raw 264.7 macrophage cells and HacaT cells were used, together with the MTT, ROS, NO, and wound healing assays, to investigate the possible cytotoxicity in A549 lung cancer. Thus, A. agallocha and A. malaccensis showed significant cytotoxicity against A549 cancer cells at 1000 µg/mL. Furthermore, we observed an elevated ROS level in cancer cells. The wound healing assay showed cancer cell inhibition activity. While BCL-2 decreased in the intrinsic route, p53, Bax, Caspase 3, and Caspase 9 were elevated by A.A and A.M. Additionally, we have also conducted an in silico evaluation followed by molecular dynamics (MD) simulations, along with ADMET and biological activity prediction to further validate the experimental results. In normal cells, both samples showed less toxicity at 1000 µg/mL and suppressed the LPS-treated NO and ROS levels against the inflammation. Additionally, A.A and A.M suppressed the pro-inflammatory gene expression of COX-2, iNOS, TNF-α, IL-6, and IL-8 in RAW 264.7 cells. On the other hand, A.A and A.M extract effectively suppressed oxidative stress by increasing the antioxidative gene expression in H₂O₂-induced HaCat cells at 50 μg/mL. This study revealed that the plant extracts from A. agallocha and A. malaccensis could exert a cytotoxic effect on lung adenocarcinoma cells through the activation of an intrinsic signaling pathway. Moreover, it could be a potential source of anti-inflammatory, antioxidant, and anti-cancer agents after consideration of in vivo and clinical studies. Full article

Radioactive elements, such as tritium, have been released into the ocean in large quantities as a result of the reactor leakage accident. In this study, an MTT assay demonstrated that the viability of HacaT cells decreased after tritiated water treatment. Bioinformatics analysis was used to analyze gene changes in the HacaT cells. The sequencing results showed 267 significantly differentially expressed genes (DEGs), and GO enrichment analysis showed that the DEGs were mainly divided into three parts. The KEGG pathway analysis showed that the up-regulated DEGs were involved in Wnt and other pathways, while the down-regulated DEGs were involved in Jak–STAT and others. A Western blot assay was used to verify the parts of the sequencing results. This study was the first to explore the mechanism of tritiated water on HacaT cells using Transcriptome analysis. The results will provide a theoretical basis for the study of tritiated water hazard mechanisms. Full article

Health- and oral health-compromising behaviours (HOHCBs) impact the health readiness of military personnel, resulting in decreased fitness performance, thus affecting combat readiness. This study aimed to identify the clustering patterns and number of HOHCBs in army personnel in Central Peninsular Malaysia. Thus, a cross-sectional study using a multistage sampling technique and a validated 42-item online questionnaire was conducted to assess ten health (medical screening, physical activity, sedentary lifestyle, smoking status, alcohol consumption, substance abuse, aggressive behaviours, sleep, and road safety habits) and five oral health behaviour domains (tooth brushing, fluoridated toothpaste use, flossing, dental visits, and bruxism). Each HOHCB was dichotomised into healthy and health-compromising behaviour and analysed using hierarchical agglomerative cluster analysis (HACA). With the majority being males (92.5%), of other ranks (96.8%), and healthy (83.9%), 2435 army members of a mean age of 30.3 years (SD = 5.9) participated, with a response rate of 100%. HACA identified two clustering patterns: (i) ‘high-risk behaviours’ (30 HOHCBs) and (ii) ‘most common risk behaviours’ (12 HOHCBs) with a mean clustering number of 14.1 (SD = 4.1). In conclusion, army personnel in Central Peninsular Malaysia displayed 2 broad HOHCB clustering patterns, ‘high-risk’ and ‘most common risk’, with an average of 14 HOHCB clusters per person. Full article

Groundwater contamination by heavy metals (HMs) released by weathering and mineral dissolution of granite, gneisses, ultramafic, and basaltic rock composition causes human health concerns worldwide. This paper evaluated the heavy metals (HMs) concentrations and physicochemical variables of groundwater around enriched chromite mines of Malakand, Pakistan, with particular emphasis on water quality, hydro-geochemistry, spatial distribution, geochemical speciation, and human health impacts. To better understand the groundwater hydrogeochemical profile and HMs enrichment, groundwater samples were collected from the mining region (n = 35), non-mining region (n = 20), and chromite mines water (n = 5) and then analyzed using ICPMS (Agilent 7500 ICPMS). The ranges of concentrations in the mining, non-mining, and chromite mines water were 0.02–4.5, 0.02–2.3, and 5.8–6.0 mg/L for CR, 0.4–3.8, 0.05–3.6, and 3.2–5.8 mg/L for Ni, and 0.05–0.8, 0.05–0.8, and 0.6–1.2 mg/L for Mn. Geochemical speciation of groundwater variables such as OH⁻, H⁺, Cr⁺², Cr⁺³, Cr⁺⁶, Ni⁺², Mn⁺², and Mn⁺³ was assessed by atomic fluorescence spectrometry (AFS). Geochemical speciation determined the mobilization, reactivity, and toxicity of HMs in complex groundwater systems. Groundwater facies showed 45% CaHCO₃, 30% NaHCO₃, 23.4% NaCl, and 1.6% Ca-Mg-Cl water types. The noncarcinogenic and carcinogenic risk of HMs outlined via hazard quotient (HQ) and total hazard indices (THI) showed the following order: Ni > Cr > Mn. Thus, the HHRA model suggested that children are more vulnerable to HMs toxicity than adults. Hierarchical agglomerative cluster analysis (HACA) showed three distinct clusters, namely the least, moderately, and severely polluted clusters, which determined the severity of HMs contamination to be 66.67% overall. The PCAMLR and PMF receptor model suggested geogenic (minerals prospects), anthropogenic (industrial waste and chromite mining practices), and mixed (geogenic and anthropogenic) sources for groundwater contamination. The mineral phases of groundwater suggested saturation and undersaturation. Nemerow’s pollution index (NPI) values determined the unsuitability of groundwater for domestic purposes. The EC, turbidity, PO₄⁻³, Na⁺, Mg⁺², Ca⁺², Cr, Ni, and Mn exceeded the guidelines suggested by the World Health Organization (WHO). The HMs contamination and carcinogenic and non-carcinogenic health impacts of HMs showed that the groundwater is extremely unfit for drinking, agriculture, and domestic demands. Therefore, groundwater wells around the mining region need remedial measures. Thus, to overcome the enrichment of HMs in groundwater sources, sustainable management plans are needed to reduce health risks and ensure health safety. Full article