Search Results (57)

Background: Cancer stem cells (CSCs) are a subpopulation of cancer cells known for their self-renewal capacity, tumorigenicity, and resistance to treatment. Toll-like receptor 3 (TLR3) plays a complex role in cancer, exhibiting both pro-apoptotic and pro-tumorigenic effects. This study investigates the pro-tumorigenic role of TLR3, specifically its impact on CSCs in head and neck cancer. Methods: We have investigated Detroit 562, FaDu and SQ20B cell lines, the latter being stably transfected with a plasmid containing inducible shRNA for TLR3, by cultivating them to form tumor spheres in order to study CSCs. Results: Our findings demonstrate that TLR3 activation promotes stemness in head and neck cancer cell lines. This is evidenced by increased tumor sphere formation, promotion of epithelial-to-mesenchymal transition (EMT), upregulated stemness gene expression, and elevated aldehyde dehydrogenase (ALDH) activity. Conditional TLR3 knockdown abolished tumor sphere formation, confirming its important role. Furthermore, TLR3 activation triggers the secretion of damage-associated molecular patterns (DAMPs) into the tumor microenvironment, leading to increased cancer cell migration. This was inhibited by DAMP inhibitors. In patient tissue samples, we observed co-localization of TLR3 with stemness markers CD133 and ALDH1, as well as with heat shock protein 70 (HSP70) and receptor for advanced glycation end products (RAGE). We then explored potential CSC-targeted therapies, initially combining the apoptosis inducer poly (I:C) with DAMP inhibitors and γ-irradiation. While this combination proved effective in adherent cells, it failed to eliminate tumor spheres. Nevertheless, we discovered that proton radiotherapy, particularly when combined with aspirin (HMGB1 inhibitor) and poly (I:C), effectively eliminates CSCs. Conclusions: This novel combination holds promise for the development of new therapeutic strategies for head and neck cancers, particularly given the promising results of proton therapy in treating this disease. Full article

Background/Objectives: Abiotic stresses severely constrain the yield of Brassica juncea, and aldehyde dehydrogenases (ALDHs) play a pivotal role in plant stress resistance. This study aims to systematically identify the ALDH gene family members in B. juncea and elucidate their expression patterns under salt and drought stress. Methods: Using the Arabidopsis thaliana AtALDH proteins as seed sequences, BLASTp alignment was performed against the B. juncea whole-protein sequence database, combined with the conserved domain PF00171 of the ALDH proteins. A total of 39 BjALDH gene family members were identified, and their physicochemical properties, structures, phylogenetic relationships, interspecies collinearity, and intraspecies collinearity were analyzed. The qRT-PCR method was employed to quantify the relative expression levels of the BjALDH genes potentially associated with stress resistance under various treatments, and their effects on drought and salt stress tolerance were evaluated. Results: The results demonstrated that BjALDH were universally significantly upregulated under salt stress, while exhibiting predominantly upregulated trends under drought stress. These findings suggest that BjALDH may enhance plant resistance to both salt and drought stress by modulating the aldehyde metabolic pathways. Conclusions: This study provides a theoretical basis for elucidating the functional roles and molecular genetic mechanisms of the BjALDH gene family in B. juncea under salt and drought stress. Full article

The Aldehyde Dehydrogenase (ALDH) superfamily comprises a group of NAD⁺ or NADP⁺-dependent enzymes that play essential roles in responding to abiotic stresses in plants. In Brassica napus L., however, the increasing frequency of extremely low temperatures during winter in recent years has significantly affected both yield and quality. This study conducted a genome-wide screening of ALDH superfamily genes, analyzing their gene structures, evolutionary relationships, protein physicochemical properties, and expression patterns under low-temperature stress to explore the function of the ALDH superfamily gene in cold tolerance in Brassica napus L. A total of six BnALDH genes with significant differences in expression levels were verified utilizing quantitative real-time polymerase chain reaction (qRT-PCR), revealing that BnALDH11A2, BnALDH7B2, BnALDH3F5, BnALDH12A3, BnALDH2B6, and BnALDH7B3 all exhibited higher expression in cold-tolerant material 24W233 compared with cold-sensitive material 24W259. Additionally, a single nucleotide polymorphism (SNP) in the BnALDH11A2 promoter region shows differences between the cold-tolerant (24W233) and the cold-sensitive (24W259) Brassica napus varieties, and it may be associated with the cold tolerance of these two varieties. This comprehensive analysis offers valuable insights into the role of ALDH family genes in low-temperature stress adaptation in Brassica napus and offers genetic resources for the development of novel cold-tolerant cultivars. Full article

Aldehyde dehydrogenases (ALDHs) are a gene family that relies on NAD +/NADP + proteins to oxidize toxic aldehydes to non-toxic carboxylic acids, and they play a crucial role in the growth and development of plants, as well as in their ability to withstand stress. This study identified 26 ALDH genes from six Glycyrrhiza uralensis gene families distributed on six chromosomes. By analyzing the phylogeny, gene structure, conserved motifs, cis-regulatory elements, collinearity of homologs, evolutionary patterns, differentiation patterns, and expression variations under drought stress, we found that the ALDH gene is involved in phytohormones and exhibits responsiveness to various environmental stressors by modulating multiple cis-regulatory elements. In addition, GuALDH3H1, GuALDH6B1, GuALDH12A2, and GuALDH12A1 have been identified as playing a crucial role in the response to drought stress. By analyzing the expression patterns of different tissues under drought stress, we discovered that GuALDH3I2 and GuALDH2B2 exhibited the most pronounced impact in relation to the drought stress response, which indicates that they play a positive role in the response to abiotic stress. These findings provide a comprehensive theoretical basis for the ALDH gene family in Glycyrrhiza uralensis and enhance our understanding of the molecular mechanisms underlying ALDH genes in licorice growth, development, and adaptation to drought stress. Full article

Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial–mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk. Full article

This study investigated the protective effect of Dai Bai Jie (DBJ) extract against acute alcoholic liver injury (AALI) and elucidated its potential mechanism. The total saponin level in the DBJ extracts was measured using vanillin–chloroform acid colorimetry. To observe the preventive and protective effects of DBJ on AML-12 cells in an ethanol environment, the effective components of DBJ were identified. An alcohol-induced AALI mouse model was used to evaluate the efficacy of DBJ against AALI. For this purpose, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) levels were assessed, liver function indices and oxidative and inflammatory markers were determined, and histopathological examinations were performed. Mechanistic investigations were conducted using RT-qPCR assays and immunohistochemical analysis to determine the protective effects of DBJ. The samples (DBJ-1, DBJ-2, and DBJ-3) were obtained by extracting DBJ with water, 50% ethanol, and 95% ethanol, yielding total saponin contents of 5.35%, 6.64%, and 11.83%, respectively. DBJ-3 was isolated and purified, and its components were identified by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). DBJ-3 had the greatest effect on cell viability in an ethanol environment. Moreover, DBJ-3 reduced inflammatory infiltration, liver cell degeneration, and hemorrhage, while increasing ADH and ALDH levels in liver tissues. Additionally, DBJ-3 considerably decreased the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG) levels. DBJ-3 reduced malondialdehyde (MDA), reactive oxygen species (ROS), and inflammatory factors, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), while increasing superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. Furthermore, DBJ-3 significantly increased alcohol dehydrogenase 1b (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) expression at the gene and protein levels within alcohol metabolism pathways and reduced the nuclear factor kappa-B (NF-κB) gene and protein levels. These findings suggest that DBJ-3 can prevent AALI by enhancing alcohol metabolism via the regulation of ADH1B and ALDH2 and the modulation of the NF-κB pathway to improve antioxidant and anti-inflammatory effects. Full article

Diets containing higher-amylose-content starches were proved to have some beneficial effects on monogastric animals, such as promoting the proliferation of intestinal probiotics. However, current research on the effects of diets with different starch sources on animals at the extraintestinal level is still very limited. We hypothesized that diets with different starch sources may affect lipid-related gene expression and metabolism in the liver of pigs. This study aimed to use adult pig models to evaluate the effects of diets with different starch sources (tapioca starch, TS; pea starch, PS) on the liver gene expressions and metabolism. In total, 48 growing pigs were randomly assigned to the TS and PS diets with 8 replicate pens/group and 3 pigs per pen. On day 44 of the experiment, liver samples were collected for metabolome and transcriptome analysis. Metabolome data suggested that different starch sources affected (p < 0.05) the metabolic patterns of liver. Compared with the TS diet, the PS diet increased (p < 0.05) some unsaturated fatty acids and several amino acids or peptide levels in the liver of pigs. Moreover, transcriptome data indicated the PS diets elevated (p < 0.05) fatty acid β-oxidation-related gene expression in the liver of pigs, and reduced (p < 0.05) unsaturated fatty acid metabolism-related gene expression. The results of quantitative real-time PCR confirmed that the PS diet upregulated (p < 0.05) the expression of acyl-CoA dehydrogenase very long chain (ACADVL), carnitine palmitoyl transferase (CPT) 1A, and malonyl-CoA decarboxylase (MLYCD), and downregulated (p < 0.05) the expression level of cytochrome P450 2U1 (CYP2U1) and aldehyde dehydrogenase 1B1 (ALDH1B1) in the liver. In addition, the results of a Mantel test indicated the muscle fatty acids were significantly closely correlated (p < 0.05) with liver gene expressions and metabolites. In summary, these findings suggest that diets containing higher amylose starches improved the lipid degradation and the unsaturated fatty acid levels in pig livers, and thus can generate some potential beneficial effects (such as anti-inflammatory and antioxidant) on pig health. Full article

Aldehyde dehydrogenases (ALDHs) constitute a diverse superfamily of NAD(P)⁺-dependent enzymes pivotal in oxidizing endogenous and exogenous aldehydes to carboxylic acids. Beyond metabolic roles, ALDHs participate in essential biological processes, including differentiation, embryogenesis and the DNA damage response, while also serving as markers for cancer stem cells (CSCs). Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme involved in the detoxification of lipid peroxidation by-products and metabolism of various aldehyde substrates. This study examines the potential role of ALDH1B1 in human lung adenocarcinoma and its association with the CSC phenotype. To this end, we utilized the lung adenocarcinoma cell line A549, engineered to stably express the human ALDH1B1 protein tagged with green fluorescent protein (GFP). Overexpression of ALDH1B1 led to notable changes in cell morphology, proliferation rate and clonogenic efficiency. Furthermore, ALDH1B1-overexpressing A549 cells exhibited enhanced resistance to the chemotherapeutic agents etoposide and cisplatin. Additionally, ALDH1B1 overexpression correlated with increased migratory potential and epithelial–mesenchymal transition (EMT), mediated by the upregulation of transcription factors such as SNAI2, ZEB2 and TWIST1, alongside the downregulation of E-cadherin. Moreover, Spearman’s rank correlation coefficient analysis using data from 507 publicly available lung adenocarcinoma clinical samples revealed a significant correlation between ALDH1B1 and various molecules implicated in CSC-related signaling pathways, including Wnt, Notch, hypoxia, Hedgehog, retinoic acid, Hippo, NF-κΒ, TGF-β, PI3K/PTEN-AKT and glycolysis/gluconeogenesis. These findings provide insights into the role of ALDH1B1 in lung tumor progression and its relation to the lung CSC phenotype, thereby offering potential therapeutic targets in the clinical management of lung adenocarcinoma. Full article

This open-labeled and comparative study aimed to test the efficacy and safety of a fermented rice extract-based substance containing yeast-fermented powder having aldehyde dehydrogenase (KisLip^®, Pico Entech, Republic of Korea) in healthy male individuals. Healthy male subjects (n = 20) consumed 90 g of alcohol at their first visit. At the second visit, participants consumed 90 g of alcohol or alcohol with a low dose of KISLip^® (2000 mg, KL-L) and then 90 g of alcohol or alcohol with a high dose of KISLip^® (3000 mg, KL-H) at the third visit. The efficacy of KISLip^® depends on the mutational status of important genes related to alcohol metabolism, including alcohol dehydrogenase (ADH1B), cytochrome P4502E1 (CYP2E1 (5B) and CYP2E1 (6)), and aldehyde dehydrogenase (ALDH2). KISLip^® significantly reduced the highest level (Cmax) of alcohol and overall levels of acetaldehyde compared to the alcohol-only group in a dose-dependent manner. These significant effects of KISLip^® on alcohol metabolism were observed independent of mutations in the four genes. In addition, hangover symptoms were significantly decreased in the KISLip^® treated groups. During the study, the participants did not show any adverse events after KISLip^® intake. This clinical study suggested that supplementation of KISLip^® had beneficial effects on alcohol metabolism and might ameliorate the severity of hangovers without any adverse events. Full article

(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy. Full article

Despite advances in therapeutic approaches, the five-year survival rate for head and neck squamous cell carcinoma (HNSCC) patients is still less than fifty percent. Research has indicated that the consumption of Allium vegetables or processed garlic containing diallyl trisulfide (DATS) can lower the risk of multiple types of cancer. Nevertheless, the effectiveness and underlying mechanisms of DATS against HNSCC have not been thoroughly explored until the current study. In this research, it was found that DATS notably curtailed the growth and viability of HNSCC cells. Additionally, DATS triggered a significant G2/M cell cycle arrest in these cells, accumulating cyclin B1, Cip1/p21, and Ser-10 phospho-histone H3—this was indicative of mitotic arrest attenuated by NAC pretreatment, suggesting the role of reactive oxygen species (ROS) induction. The production of ROS induced by DATS led to DNA damage and apoptosis, a process associated with elevated levels of cleaved caspase-3 and cleaved PARP, along with reduced XIAP. When HNSCC cells were exposed to pharmacological concentrations of DATS, it resulted in the suppression of cancer stem cell (CSC) populations, as indicated by a decrease in the CD133^high/CD44^high cell fraction, reduced aldehyde dehydrogenase 1 (ALDH1) activity, inhibited spheroid formation and downregulated SOX2 and Oct4 expression. Furthermore, the administration of DATS to tumor xenografts demonstrated its in vivo capacity to hinder CSCs. Further, DATS treatment inhibited the growth of UMSCC-22B head and neck cancer tumor xenograft in immunocompromised mice. Overall, DATS inhibited cell proliferation; induced cell cycle mitotic arrest and apoptosis involving DNA damage through ROS generation; reduced the CSC fraction and spheroid formation; and downregulated SOX2 and Oct4 expression. More importantly, DATS inhibited HNSCC tumor growth and CSC fraction in vivo. Thus, DATS could be a potential anticancer agent that can be used against head and neck cancer. Full article

Background: Gamma-hydroxybutyric acid (GHB) at low dosages has anxiolytic effects and promotes REM sleep and low-wave deep sleep. In the U.S., the legal form of GHB is prescribed to adults suffering from narcolepsy-associated cataplexy; the sodium salt of GHB is reserved for alcohol-addiction treatment. GHB is also a molecule of abuse and recreational use, it is a controlled substance in several countries, so gamma-valerolactone (GVL) has frequently been used as a legal substitute for it. GHB’s abuse profile is most likely attributable to its anxiolytic, hypnotic, and euphoric properties, as well as its widespread availability and inexpensive/low cost on the illicit market. Methods: Our study is focused on evaluating the potential effects on the mouse brain after repeated/prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg/kg) through behavioral study and immunohistochemical analysis using the markers tetraspanin 17 (TSPAN17), aldehyde dehydrogenase 5 (ALDH5A1), Gamma-aminobutyric acid type A receptor (GABA-A), and Gamma-aminobutyric acid type B receptor (GABA-B). Results: Our findings revealed that prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg/kg) can have effects on a component of the mouse brain, the intensity of which can be assessed using immunohistochemistry. The findings revealed that long-term GHB administration causes a significant plastic alteration of the GHB signaling system, with downregulation of the putative binding site (TSPAN17) and overexpression of ALDH5A1, especially in hippocampal neurons. Our findings further revealed that GABA-A and GABA-B receptors are downregulated in these brain locations, resulting in a greater decrease in GABA-B expression. Conclusions: The goal of this study, from the point of view of forensic pathology, is to provide a new methodological strategy for better understanding the properties of this controversial substance, which could help us better grasp the unknown mechanism underlying its abuse profile. Full article

Soybeans are the main source of oils and protein for humans and animals; however, cold stress jeopardizes their growth and limits the soybean planting area. Aldehyde dehydrogenases (ALDH) are conserved enzymes that catalyze aldehyde oxidation for detoxification in response to stress. Additionally, transgenic breeding is an efficient method for producing stress-resistant germplasms. In this study, the peanut ALDH gene AhALDH2B6 was heterologously expressed in soybean, and its function was tested. We performed RNA-seq using transgenic and wild-type soybeans with and without cold treatment to investigate the potential mechanism. Transgenic soybeans developed stronger cold tolerance, with longer roots and taller stems than P3 soybeans. Biochemically, the transgenic soybeans exhibited a decrease in malondialdehyde activity and an increase in peroxidase and catalase content, both of which are indicative of stress alleviation. They also possessed higher levels of ALDH enzyme activity. Two phenylpropanoid-related pathways were specifically enriched in up-regulated differentially expressed genes (DEGs), including the phenylpropanoid metabolic process and phenylpropanoid biosynthetic process. Our findings suggest that AhALDH2B6 specifically up-regulates genes involved in oxidoreductase-related functions such as peroxidase, oxidoreductase, monooxygenase, and antioxidant activity, which is partially consistent with our biochemical data. These findings established the function of AhALDH2B6, especially its role in cold stress processes, and provided a foundation for molecular plant breeding, especially plant-stress-resistance breeding. Full article

Background and Objectives: Parkinson’s disease (PD) is a clinically heterogeneous disorder with poorly understood pathological contributing factors. Depression presents one of the most frequent non-motor PD manifestations, and several genetic polymorphisms have been suggested that could affect the depression risk in PD. Therefore, in this review we have collected recent studies addressing the role of genetic factors in the development of depression in PD, aiming to gain insights into its molecular pathobiology and enable the future development of targeted and effective treatment strategies. Materials and Methods: we have searched PubMed and Scopus databases for peer-reviewed research articles published in English (pre-clinical and clinical studies as well as relevant reviews and meta-analyses) investigating the genetic architecture and pathophysiology of PD depression. Results: in particular, polymorphisms in genes related to the serotoninergic pathway (sodium-dependent serotonin transporter gene, SLC6A4, tryptophan hydrolase-2 gene, TPH2), dopamine metabolism and neurotransmission (dopamine receptor D3 gene, DRD3, aldehyde dehydrogenase 2 gene, ALDH2), neurotrophic factors (brain-derived neurotrophic factor gene, BDNF), endocannabinoid system (cannabinoid receptor gene, CNR1), circadian rhythm (thyrotroph embryonic factor gene, TEF), the sodium-dependent neutral amino acid transporter B(0)AT2 gene, SLC6A15), and PARK16 genetic locus were detected as altering susceptibility to depression among PD patients. However, polymorphisms in the dopamine transporter gene (SLC6A3), monoamine oxidase A (MAOA) and B (MAOB) genes, catechol-O-methyltransferase gene (COMT), CRY1, and CRY2 have not been related to PD depression. Conclusions: the specific mechanisms underlying the potential role of genetic diversity in PD depression are still under investigation, however, there is evidence that they may involve neurotransmitter imbalance, mitochondrial impairment, oxidative stress, and neuroinflammation, as well as the dysregulation of neurotrophic factors and their downstream signaling pathways. Full article

Cucurbitacins are secondary metabolites that are commonly found in the Cucurbitacae family. Many biological properties have been reported for cucurbitacins, including anti-inflammatory, antioxidant, antiviral, anti-malaria, and anticancer properties. While studies for the anticancer property of cucurbitacins focus mostly on the cell-cycle progression and apoptosis, no study has considered the effect of cucurbitacin on other cancer behaviors. Here, we report cell-proliferation-based drug testing on random herbal extracts leading to the identification of cucurbitacin B as an anticancer compound. Interestingly, cucurbitacin B had no effect on the proliferation of rat embryonic myoblast cells. We also found that cucurbitacin B significantly reduced the invasiveness of at least two highly metastatic breast cancer and melanoma cells. Using known cancer stem-cell markers, we observed a significant reduction of the melanoma stem cells. Molecularly, cucurbitacin B caused reduction of the metastasis-promoting gene Snail in melanoma and one of the cancer stem cell markers, ALDH1A1 (aldehyde dehydrogenase 1 A1), in breast cancer. Finally, we report the potential toxicity of cucurbitacin B in developing skin tissue and the olfactory organ using zebrafish embryo. In summary, our study suggests the potential use of cucurbitacin B for cancer metastasis and relapse treatment. Full article