Search Results (93)

Androgenetic alopecia (AGA) is a common progressive hair loss disorder driven by elevated dihydrotestosterone (DHT) levels, leading to follicular miniaturization. This study investigated sulforaphane-rich broccoli sprout extract (BSE) as a potential oral therapy for AGA. BSE exhibited dose-dependent proliferative and migratory effects on keratinocytes, dermal fibroblasts, and dermal papilla cells, showing greater in vitro activity than sulforaphane (SFN) and minoxidil under the tested conditions, while maintaining low cytotoxicity. In a testosterone-induced AGA mouse model, oral BSE significantly accelerated hair regrowth, with 20 mg/kg achieving 99% recovery by day 15, alongside increased follicle length, density, and hair weight. Mechanistically, BSE upregulated hepatic and dermal DHT-metabolizing enzymes (Akr1c21, Dhrs9) and activated Wnt/β-catenin signaling in the skin, suggesting dual actions via androgen metabolism modulation and follicular regeneration. Pharmacokinetic analysis revealed prolonged SFN plasma exposure following BSE administration, and in silico docking showed strong binding affinities of key BSE constituents to Akr1c2 and β-catenin. No systemic toxicity was observed in liver histology. These findings indicate that BSE may serve as a safe, effective, and multitargeted natural therapy for AGA. Further clinical studies are needed to validate its efficacy in human populations. Full article

Multiple sclerosis (MS) is a long-term disease that causes inflammation and damage to the nervous system. This study evaluated steroidomic alterations related to MS in 57 female MS patients during the follicular phase and 17 during the luteal phase, as well as in age- and phase-matched controls. The data showed that (1) unconjugated and conjugated steroids were strongly linked between the blood and CSF. (2) MS patients have lower levels of unconjugated steroids compared to controls. However, unchanged levels of conjugated steroids suggest a possible increase in steroid sulfotransferase functioning. (3) MS patients show altered levels of steroids linked to 11β-hydroxylase (CYP11B1) function. While direct enzyme activity was not measured, disrupted cortisol biosynthesis—potentially linked to reduced functioning of both CYP11B1 and 17α-hydroxylase/17,20-lyase—is associated with more severe cases of MS. (4) Reduced levels of 5α/β-steroids and protective GABAergic 3α-hydroxy-5α/β-steroids in MS patients might be linked to the pathophysiology of MS. (5) A potential increase in AKR1C3 function in MS could contribute to inflammation, as this enzyme catalyzes the synthesis of both steroids and prostaglandins. However, direct measurements of enzyme activity are needed to confirm this hypothesis. (6) Lower pregnenolone levels in MS patients might weaken neuroprotection, while higher pregnenolone sulfate levels could support cognitive function. (7) Lower levels of protective pregnenolone, DHEA, and androstenediol were associated with worse MS, suggesting these steroids may help shield against the disease. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma is a lethal malignancy, necessitating an understanding of its molecular mechanisms for the development of new therapeutic strategies. The tight junction protein claudin-1, known to influence cellular functions in various cancers and is considered a therapeutic target, remains unclear in pancreatic cancer. Methods: This study assessed claudin-1 expression in resected pancreatic cancer samples, public databases, and pancreatic cancer cell lines. Claudin-1 knockout with CRISPR/Cas9 on poorly differentiated pancreatic cancer cell lines and a proteome analysis were performed to investigate the intracellular mechanisms of claudin-1. Results: Claudin-1 was markedly overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia compared to normal ducts, and high claudin-1 levels were an independent predictor of poor prognosis. Claudin-1 knockout diminished cell proliferation, migration, invasion, and chemoresistance in pancreatic ductal adenocarcinoma. Proteome analysis revealed the significant downregulation of aldo-keto reductase family proteins (AKR1C2, AKR1C3, and AKR1B1) in claudin-1 knockout cells, which are linked to metabolic pathways. Aldo-keto reductase knockdown reduced chemoresistance, proliferation, and invasion in these cell lines. Conclusions: These findings indicate that the abnormal expression of claudin-1 promotes tumor progression and drug resistance through its interaction with aldo-keto reductase proteins, highlighting claudin-1 and aldo-keto reductase family proteins as potential biomarkers and therapeutic targets for pancreatic cancer. Full article

Lignocellulosic biomass is widely recognized as a renewable resource for bioconversion. However, the presence of inhibitors such as furfural, 5-HMF, and acetic acid can inhibit cell growth, thereby affecting the overall efficiency of the bioconversion process. The studies on the degradation of lignocellulosic hydrolysate inhibitors by Saccharomyces cerevisiae have been limited. In this research, a yeast strain Kodamaea ohmeri can degrade inhibitors furfural, 5-HMF, and acetic acid, and the genome sequence of the strain was analyzed. Furthermore, the molecular detoxification mechanism of K. ohmeri SSK against lignocellulosic hydrolysate inhibitors was predicted using whole genome sequencing. Annotation based on the COG/KEGG databases identified 57 key detoxification genes, including the alcohol dehydrogenase (ADH) gene, aldo-keto/aldehyde reductase (AKR/ARI) gene, and aldehyde dehydrogenase (ALDH) gene. Stress tolerance experiments revealed that the maximum tolerance concentration for the strain was 5.2 g/L of furfural, 2.5 g/L of 5-HMF, and 5.9 g/L of acetic acid, respectively. A NAD(P)⁺-dependent bifunctional enzyme with possible ADH and ARI activities was found by conserved domain analysis. Phylogenetic analysis indicated that this enzyme shared 99% homology with the detoxification enzyme from S. cerevisiae S288C (GenBank: Q04894.1). This study represents the first comprehensive analysis of the inhibitor detoxification network in K. ohmeri SSK from a genome perspective, providing theoretical targets and design strategies for developing highly efficient biorefinery strains. Full article

Protein S-acyl transferases (PATs) are a family of enzymes that catalyze protein S-acylation, a post-translational lipid modification involved in protein membrane targeting, trafficking, stability, and protein–protein interaction. S-acylation plays important roles in plant growth, development, and stress responses. Here, we report the genome-wide analysis of the PAT family genes in the woodland strawberry (Fragaria vesca), a model plant for studying the economically important Rosaceae family. In total, 21 ‘Asp-His-His-Cys’ Cys Rich Domain (DHHC-CRD)-containing sequences were identified, named here as FvPAT1-21. Expression profiling by reverse transcription quantitative PCR (RT-qPCR) showed that all the 21 FvPATs were expressed ubiquitously in seedlings and different tissues from adult plants, with notably high levels present in vegetative tissues and young fruits. Treating seedlings with hormones indole-3-acetic acid (IAA), abscisic acid (ABA), and salicylic acid (SA) rapidly increased the transcription of most FvPATs. A complementation assay in yeast PAT mutant akr1 and auto-S-acylation assay of one FvPAT (FvPAT19) confirmed its enzyme activity where the Cys in the DHHC motif was required. An AlphaFold prediction of the DHHC and the mutated DHHC155S of FvPAT19 provided further proof of the importance of C155 in fatty acid binding. Together, our data clearly demonstrated that S-acylation catalyzed by FvPATs plays important roles in growth, development, and stress signaling in strawberries. These preliminary results could contribute to further research to understand S-acylation in strawberries and plants in general. Full article

Aleurocanthus spiniferus not only damages plant leaves directly but also causes a sooty blotch due to the honeydew secreted by the nymphs and adults. This pest is widespread and seems to be spreading from low latitude to higher latitude areas where winters are typically colder, indicating an increase in its cold tolerance. Changes in temperature help insects to anticipate the arrival of winter, allowing them to take defensive measures in advance. This study examines the impacts of brief warm pulses on the low-temperature tolerance of A. spiniferus, and analyzes the physiological and biochemical mechanisms underlying its cold adaptation, utilizing seasonal differences in cold tolerance. Intermittent training at 25 °C significantly improved the survival rate of overwintering nymphs (third and fourth instar) at −7 °C. Analysis of seasonal differences in the supercooling point (SCP) and freezing point (FP) revealed that overwintering nymph had the highest cold tolerance in November. Seasonal variation in levels of cold-resistant substances were also observed, with moisture decreasing during overwintering, while fat and glycerol levels increased. Conversely, glucose, sorbitol, and trehalose levels rose significantly at the end of the overwintering period. The expression profile of cold-resistant genes indicated that the aldo-keto reductase family 1 member B1 in Aleurocanthus spiniferus (AspiAKR1B1) shows a significant decrease at the end of the overwintering period. Knocking down AspiAKR1B1 led to a marked reduction in the cold tolerance of A. spiniferus. Therefore, brief warm pulses and AspiAKR1B1 are key factors contributing to the enhanced cold tolerance of A. spiniferus. This research provides theoretical support for preventing the further spread of A. spiniferus to higher latitudes, and offers technical guidance for developing effective pest control measures. Full article

We studied the associations between 3′UTR genetic variants in ADME genes, clinical factors, and the risk of breast cancer chemotherapy toxicity. Those variants and factors were tested in relation to seven symptoms belonging to myelotoxicity (anemia, leukopenia, neutropenia), gastrointestinal side effects (vomiting, nausea), nephrotoxicity, and hepatotoxicity, occurring in overall, early, or recurrent settings. The cumulative risk of overall symptoms of anemia was connected with AKR1C3 rs3209896 AG, ERCC1 rs3212986 GT, and >6 cycles of chemotherapy; leukopenia was determined by ABCC1 rs129081 allele G and DPYD rs291593 allele T; neutropenia risk was correlated with accumulation of genetic variants of DPYD rs291583 allele G, ABCB1 rs17064 AT, and positive HER2 status. Risk of nephrotoxicity was determined by homozygote DPYD rs291593, homozygote AKR1C3 rs3209896, postmenopausal age, and negative ER status. Increased risk of hepatotoxicity was connected with NR1/2 rs3732359 allele G, postmenopausal age, and with present metastases. The risk of nausea and vomiting was linked to several genetic factors and premenopausal age. We concluded that chemotherapy tolerance emerges from the simultaneous interaction of many genetic and clinical factors. Full article

Head and Neck Squamous Cell Carcinoma (HNSCC), particularly Oropharyngeal Squamous Cell Carcinoma (OPSCC), is a major global health challenge due to its increasing incidence and high mortality rate. This study investigates the role of aldo-keto reductase 1C2 (AKR1C2) in OPSCC, focusing on its expression, correlation with Human Papillomavirus (HPV) status, oxidative stress status, and clinical outcomes, with an emphasis on sex-specific differences. We analyzed AKR1C2 expression using immunohistochemistry in formalin-fixed, paraffin-embedded tissue samples from 51 OPSCC patients. Additionally, we performed RT-qPCR in cultured HPV16-E6*I and HPV16-E6 overexpressing HEK293 cell lines (p53^WT). Statistical analyses were performed to assess the correlation between AKR1C2 expression and patient data. Our results indicate a significant association between increased AKR1C2 expression and higher AJCC classification (p = 0.009) as well as positive HPV status (p = 0.008). Prognostic implications of AKR1C2 varied by sex, whereby female patients with high AKR1C2 expression had better overall survival, whereas male patients exhibited poorer outcomes. Additionally, AKR1C2 expression was linked to HPV status, suggesting a potential HPV-specific regulatory mechanism. These findings underscore the complex interplay among AKR1C2, HPV, and patient sex, highlighting the need for personalized treatment strategies for OPSCC. Targeted inhibition of AKR1C2, considering sex-specific differences, may enhance therapeutic outcomes. Future research should investigate these mechanisms to enhance treatment efficacy. Full article

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors. Full article

Background: Aggressive mature T-cell lymphoma (TCL) is a disease that carries a poor prognosis. Methods: We analyzed the expression of 22 tumor cell functional proteins in 16 randomly selected patients with TCL. Immunohistochemistry was performed in paraffin-embedded tumor tissue sections to determine the protein expression statuses in tumor cells. Results: Glucose-regulated protein 94 (GRP94), a protein that serves as a pro-survival component under endoplasmic reticulum (ER) stress in the tumor microenvironment, was significantly associated with a shortened survival. Furthermore, significant differences were observed when GRP94 was combined with six other factors. The six factors were (1) programmed cell death-ligand 1 (PD-L1); (2) programmed cell death 1 (PD-1); (3) aldo-keto reductase family 1 member C3 (AKR1C3); (4) P53, a tumor suppressor; (5) glucose-regulated protein 78 (GRP78), an ER stress protein; and (6) thymidine phosphorylase (TP). Based on the combination of GRP94 and the six other factors expressed in the tumors, we propose a new prognostic classification system for TCL (TCL Urayasu classification). Group 1 (relatively good prognosis): GRP94-negative (n = 6; median OS, 88 months; p < 0.01); Group 2 (poor prognosis): GRP94-positive, plus expression of two of the six factors mentioned above (n = 5; median OS, 25 months; p > 0.05); and Group 3 (very poor prognosis): GRP94-positive, plus expression of at least three of the six factors mentioned above (n = 5; median OS, 10 months; p < 0.01). Conclusions: Thus, the TCL Urayasu prognostic classification may be a simple, useful, and innovative classification that also explains the mechanism of resistance to treatment for each functional protein. If validated in a larger number of patients, the TCL Urayasu classification will enable a targeted treatment using selected inhibitors acting on the abnormal protein found in each patient. Full article

Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive E. coli (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na⁺-dependent ¹⁴C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1β treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis. Full article

The objective of this study was to investigate gene regulation of the developing fetal brain from congenic or inbred mice strains that differed in longevity. Gene expression and alternative splice variants were analyzed in a genome-wide manner in the fetal brain of C57BL/6J mice (long-lived) in comparison to B6.Cg-Cav1^tm1Mls/J (congenic, short-lived) and AKR/J (inbred, short-lived) mice on day(d) 12, 15, and 17 of gestation. The analysis showed a contrasting gene expression pattern during fetal brain development in these mice. Genes related to brain development, aging, and the regulation of alternative splicing were significantly differentially regulated in the fetal brain of the short-lived compared to long-lived mice during development from d15 and d17. A significantly reduced number of splice variants was observed on d15 compared to d12 or d17 in a strain-dependent manner. An epigenetic clock analysis of d15 fetal brain identified DNA methylations that were significantly associated with single-nucleotide polymorphic sites between AKR/J and C57BL/6J strains. These methylations were associated with genes that show epigenetic changes in an age-correlated manner in mice. Together, the finding of this study suggest that fetal brain development and longevity are epigenetically linked, supporting the emerging concept of the early-life origin of longevity. Full article

Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure–activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (−11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment. Full article

As one of the most salt-tolerant grasses, characterizing salt-tolerance genes of Zoysia matrella [L.] Merr. not only broaden the theoretical information of salt tolerance, but also provide new salt-resistant genetic resources for crop breeding. The salt-inducible protein disulfide isomerase (ZmPDI) of Zoysia matrella [L.] Merr. was proved to enhance salt tolerance in homologous overexpression transgenic plants. In order to evaluate its potential application in crops, we conducted the salt tolerance evaluation in heterologous overexpression transgenic rice (OX-ZmPDI), Wild-type (WT) rice, and LOC_Os11g09280 (OsPDI, homologous gene of ZmPDI in rice) knock-out rice generated by CRISPR-Cas9 system (CR-OsPDI). Our findings revealed that OX-ZmPDI rice was higher and exhibited longer main root length, more proline (Pro) and malondialdehyde (MDA), and higher peroxidase (POD) activity than WT control after salt treatment, while CR-OsPDI resulted in contrary phenotypes. These results indicated that ZmPDI can significantly enhance the salt tolerance in rice, whereas loss-of-function of OsPDI reduces the salt tolerance. To further investigate these differences at the molecular level, we collected roots from OX-ZmPDI transgenic, CR-OsPDI transgenic, and wild-type (WT) plants at 0 and 24 h after salt treatment for RNA-seq and data-independent acquisition (DIA) proteome sequencing. Combined analysis of the transcriptome and proteome revealed that ZmPDI has the potential to enhance the salt tolerance of rice by modulating the expression of laccase-6, zingipain-2, WIP3, FKBP65, AKR4C10, GBSSII, Pho1, and TRXf1. Those results provided new information for the molecular regulation mechanism by which ZmPDI improves salt tolerance, and prove the potential of ZmPDI for application in crop breeding. Full article

Deoxynivalenol (DON), primarily generated by Fusarium species, often exists in agricultural products. It can be transformed to 3-epi-deoxynivalenol (3-epi-DON), with a relatively low toxicity, via two steps. DDH in Pelagibacterium halotolerans ANSP101 was proved to convert DON to 3-keto-deoxynivalenol (3-keto-DON). In the present research, AKR4, a NADPH-dependent aldo/keto reductase from P. halotolerans ANSP101, was identified to be capable of converting 3-keto-DON into 3-epi-DON. Our results demonstrated that AKR4 is clearly a NADPH-dependent enzyme, for its utilization of NADPH is higher than that of NADH. AKR4 functions at a range of pH 5–10 and temperatures of 20–60 °C. AKR4 is able to degrade 89% of 3-keto-DON in 90 min at pH 7 and 50 °C with NADPH as the cofactor. The discovery of AKR4, serving as an enzyme involved in the final step in DON degradation, might provide an option for the final detoxification of DON in food and feed. Full article