Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, where oxidative stress and neuronal apoptosis are key pathogenic events. In this study, we identified a downregulated TRIM2 in the substantia nigra pars compacta (SNc) of PD rats based on label-free proteomics. However, the impact of TRIM2 on PD is unknown.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder caused by excessive fat accumulation in hepatocytes. PNPLA3 is one of the most important genes involved in hepatic lipid metabolism, and its dysregulation contributes to triglyceride accumulation and the development and progression of Non-alcoholic fatty liver disease (NAFLD). Therefore, this study aimed to investigate the effects of eight weeks of interval aerobic training and Echium officinalis on PNPLA3 gene expression and liver function in male Wistar rats with Non-alcoholic fatty liver disease (NAFLD).

The increasing prevalence of antibiotic-resistant pathogens such as Enterococcus faecalis in persistent endodontic infections, coupled with therapeutic challenges in managing oral malignancies, necessitates exploration of novel bioactive compounds. Bacteriocins-ribosomally synthesized antimicrobial peptides-represent promising alternatives with multiple mechanisms of action. This study investigates the dual functionality of bacteriocin Basin, purified from Bacillus halophilus, against E. faecalis virulence determinants and KB (HeLa‑derived) cells ).

CPPU treatment increased the supply of carbohydrates in the fruiting branches, and the upregulation of genes related to lignin synthesis improved the tensile strength of the AZ, thereby inhibiting fruitlet abscission in A. catechu. Forchlorfenuron (CPPU) is a synthetic plant growth regulator with cytokinin activity that effectively promotes cell division and expansion, thereby enhancing fruit set rate and improving fruit quality. In this study, CPPU has been verified to effectively suppress fruitlet abscission in A. catechu. The CPPU treatment resulted in a notable increase in the levels of total sugar, starch, sucrose, glucose, and lignin in the abscission zones (AZs) of A. catechu fruitlets. Concurrently, the levels of ACC (1-aminocyclopropane-1-carboxylic acid) and ABA (abscisic acid) significantly decreased, while the levels of ZR (zeatin riboside) and GA3 (gibberellic acid) significantly increased. Furthermore, totally 1,503 differentially expressed genes (DEGs) between the AZs treated by CPPU and control have been identified through RNA-Seq, including 778 upregulated and 725 downregulated genes. Within the phytohormone signaling pathways, two genes involved in GA3 signaling transduction, AcCXE and AcGAST, were significantly upregulated, while AcABI, a gene related to ABA signaling, was significantly downregulated. Additionally, genes involved in sucrose and starch metabolism pathways, such as AcSUS4 and AcFRK, and genes associated with lignin biosynthesis, including AcPAL, AcC4H, AcOMT, and AcF5H, were significantly upregulated. These results suggest that CPPU may accelerate the transport of carbohydrates in the leaves and increasing the carbohydrate supply in fruit-bearing branches, and the elevated lignin content improves the tensile strength of the AZ, thereby suppressing fruitlet abscission. These results not only provide preliminary insights into the regulatory mechanisms underlying the suppression of CPPU on fruitlet abscission, but also offer a practical strategy for improving the management of A. catechu industrial.

We established a non-sterile root transformation system in peach seedlings. Using this system, we demonstrated that BA treatment inhibits plant growth and lateral root emergence by SA-mediated disruption of auxin distribution. Allelopathic autotoxins, particularly benzoic acid (BA), are recognized as primary contributors to peach (Prunus persica) replant disease; however, the molecular mechanisms by which BA disrupts root development remain poorly understood. BA treatment significantly reduced stem and root length and inhibited lateral root emergence without affecting lateral root initiation. To investigate the underlying mechanism at cellular resolution, we established a non-sterile Agrobacterium rhizogenes-based root transformation system achieving 27.11% transformation efficiency. Auxin biosynthesis (PpYUC10), influx transport (PpAUX1), and response (PpARF19) genes were markedly downregulated following BA treatment. Transgenic roots expressing the DR5::GUS auxin reporter exhibited reduced DR5 activity in root tips and suppressed expression in tissues surrounding lateral root primordia, indicating impaired auxin signaling at both developmental sites. Hormone profiling revealed a non-significant trend toward reduced auxin metabolites alongside significant accumulation of salicylic acid (SA), an auxin-antagonistic hormone, and its storage conjugate SA 2-O-β-glucoside. Supporting a causal role for SA, exogenous SA phenocopied BA-induced root growth inhibition, whereas co-treatment with IAA or the SA-biosynthesis inhibitor aminoindan-1-phosphonic acid (AIP) significantly rescued lateral root number and root fresh weight. Multi-treatment RNA-seq identified "response to auxin" and "response to salicylic acid" as the most enriched GO terms in BA-treated roots, and AIP treatment restored the expression of key auxin-related genes while reversing BA-induced SA-pathway changes. Together, these findings suggest that BA-induced SA accumulation suppresses auxin biosynthesis, transport, and signaling, thereby inhibiting peach root growth and lateral root emergence. This study elucidates the molecular basis of BA autotoxicity and establishes a transformation platform for functional genomic studies in Prunus.

This study aims to explore the underlying mechanism by which theabrownin extracted from Fu brick tea (FBTB) alleviates obesity induced by a high-fat diet (HFD) in mice. Results showed that FBTB intervention ameliorated metabolic disorders, suppressed jejunal lipid accumulation, and enhanced fecal lipid excretion. 16S rRNA gene sequencing demonstrated that FBTB reversed gut microbiota dysbiosis and increased the abundance of potentially beneficial genera such as Dubosiella and Lactobacillus. Metabolomics revealed that FBTB altered tryptophan metabolism and significantly increased cecal levels of indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA). Furthermore, these metabolites activated jejunal aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) signaling, subsequently downregulating lipid transporters FATP4 and CD36 to reduce jejunal lipid accumulation. Notably, antibiotic treatment significantly blunted the suppressive effect of FBTB on jejunal lipid accumulation. Overall, FBTB prevents obesity may be through modulating the gut microbiota-tryptophan-IL-22 axis to reduce intestinal lipid accumulation.

In this study, we used Mendelian randomization analysis to explore the causal relationships between drug targets and cutaneous melanoma (CM) and subsequently screened for new drug targets for CM. In addition, we verified whether targeted drugs could inhibit the development of CM in CM cells by suppressing the expression of target genes.

Metformin is a biguanide and first line drug for type 2 diabetes (T2D) mellitus that is being recognized as a geroprotective agent capable of influencing important hallmarks of aging. Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level. It acts by activating the AMPK, which leads to a cascade of downstream events such as the inhibition of mTOR, increased mitochondrial biogenesis, and autophagy, as well as epigenetic modifications. Current findings also showed its capacity to alter the gut microbiota by increasing short-chain fatty acid producing bacteria, indicating the involvement of other systemic pathways that aid in lowering inflammation, increasing metabolic fitness, and keeping epigenetic stability. The Targeting Ageing with Metformin (TAME), a landmark trial which seeks to evaluate metformin's ability to slow down several age-associated diseases, could lead to a paradigm shift in the clinical approach to aging. This article looks at metformin's various effects on aging and longevity by consolidating findings from cellular, molecular, and organismal levels. It also calls for more studies and trials on metformin and aging.

Blueberry (Vaccinium spp.) has gained worldwide popularity as a fruit crop of exceptional flavor and high nutritional value. Fruit acidity, a critical determinant of consumer preference in rabbiteye blueberry, is primarily governed by vacuolar malic acid accumulation; however, the underlying regulatory mechanism remains unclear. In the current study, VaALMT9, encoding an aluminum-activated malate transporter, was identified from rabbiteye blueberry transcriptome data. The full-length coding sequence encodes a 574 amino acid protein harboring the characteristic WEP fingerprint motif of the ALMT family. Subcellular localization analysis suggested that VaALMT9 localizes to the endomembrane system, most likely the tonoplast (vacuolar membrane). Expression analysis revealed that VaALMT9 transcript levels paralleled malate accumulation during fruit development, with both peaking at the purple stage and declining at the late ripening stage. Virus-induced gene silencing of VaALMT9 in blueberry fruits significantly reduced its transcript levels (by 96.74%) and malate contents of the two independent silenced lines were remarkably decreased by 0.62 mg/g and 0.50 mg/g, which were reduced by 19.37% and 15.78% in comparison with those of the control. Conversely, VaALMT9-overexpressing tomato markedly increased malate accumulation by 13.79-44.37%. Moreover, yeast one-hybrid and dual-luciferase reporter assays revealed that VaMYB1R1 and VaWRKY21 bind to the VaALMT9 promoter and repress its transcriptional activity. In conclusion, VaALMT9 was identified as a key gene promoting malate accumulation, and is transcriptionally inhibited by VaMYB1R1 and VaWRKY21. The findings provide new insights into the molecular regulation underlying fruit acid accumulation and offer valuable gene targets for genetic improvement of fruit quality in this fruit crop.

Acquired temozolomide (TMZ) resistance remains a major challenge in glioblastoma and may involve the emergence or enrichment of cancer stem cell (CSC)-like characteristics. However, whether stem-like characteristics differ across increasing levels of acquired TMZ resistance remains unclear. This study compared stem-like characteristics among parental TMZ-sensitive glioblastoma cells and two sequentially generated TMZ-adapted populations with different levels of acquired TMZ resistance.

This study uncovers a novel concentration-dependent signaling network through which abscisic acid (ABA) modulates acid metabolism in grape berries. Treatment with 800 μM ABA significantly decreased malate and citrate synthesis and transport while enhancing glucose and fructose accumulation, optimizing the sugar-acid ratio. Multi-omics analysis revealed differential changes in 96 organic acids and identified a key malate transporter, VvALMT9. Through yeast two-hybrid screening, the VvPP2C-VvALMT9-VvSnRK2.3-VvCDPK interaction network was characterized in a dual regulatory mode. Under low-ABA conditions, VvSnRK2.3 and VvPP2C are synergistically upregulated to impair VvALMT9 function via direct binding and transcriptional repression, respectively, while reduced VvCDPK expression leads to insufficient VvSnRK2.3 phosphorylation, establishing a "low ABA-high VvALMT9" state with high acid accumulation; when low temperature is coupled with low ABA, the inactivation of the temperature-sensing domain of VvPP2C further relieves this repression, delaying acid degradation. Conversely, a high-ABA environment suppresses the basal expression of VvPP2C/VvSnRK2.3 and activates the VvCDPK-VvSnRK2.3 cascade to efficiently inhibit ALMT9 phosphorylation, blocking malate accumulation and reducing acidity. Transgenic validation demonstrated that VvALMT9 overexpression promotes acid accumulation under ambient temperature, whereas high temperature induces VvPP2C to inhibit VvALMT9, an effect reversed by ABA. Overall, this study elucidates the mechanism of ABA-temperature synergistic regulation of VvALMT9-mediated acid metabolism homeostasis, providing a theoretical basis for targeted fruit quality improvement.

Berberine (BBR), a natural alkaloid, exhibits potent anti-tumor activity in colorectal cancer (CRC), but its mechanisms are not fully elucidated. Analysis of GEO datasets (GSE216908 and GSE184414) identified WDR54 as a key target of BBR treatment. In vitro, BBR treatment of CRC cell lines (HT-29 and SW480) markedly inhibited cell proliferation, DNA synthesis, and colony formation. Notably, BBR triggered G1-phase cell cycle arrest and promoted apoptosis, as validated by flow cytometry and molecular marker analysis. WDR54 overexpression partially rescued these anti-tumor effects, confirming its functional importance. Mechanistically, cellular thermal shift assays (CETSA) and mRNA stability assays revealed that BBR suppresses WDR54 expression via indirect transcriptional inhibition rather than direct protein binding or altered mRNA stability. Dual-luciferase reporter assays further confirmed that BBR dose-dependently inhibits WDR54 promoter activity. In vivo, an AOM/DSS-induced CRC mouse model showed that BBR reduced tumor number and size, alleviated pathological progression, and suppressed the WDR54/β-catenin axis. These findings suggest that BBR exerts significant anti-tumor effects in CRC by downregulating WDR54 and inhibiting Wnt/β-catenin signaling, highlighting WDR54 as a potential therapeutic target and BBR as a promising treatment for CRC.

Induction of programmed cancer cell death by selective aryl hydrocarbon receptor (AHR) ligands represents a promising strategy for developing novel anticancer therapeutics. In this study, we characterized the anticancer activity and underlying mechanism of the selective AHR ligand CGS-15943 in lung cancer cells. CGS-15943 potently inhibited the growth of lung cancer cell lines expressing high levels of AHR, whereas CRISPR-mediated knockout of AHR in H460 and H69AR cells markedly rescued cells from CGS-15943-induced cell death, demonstrating an essential role for AHR. To identify additional mediators of this response, we performed a genome-wide CRISPR knockout screen, which revealed eight enzymes involved in the heme biosynthesis pathway, three heme-containing enzymes, as well as AHR and its transcriptional partner ARNT, as critical determinants of CGS-15943-induced cell death. Transcriptomic analyses further showed that CGS-15943 induced AHR-dependent transcriptional programs enriched for oxidative stress and oxidized phospholipid response pathways. Together, these findings identify key components of the AHR signaling network that regulate a programmed heme-dependent cell death pathway and establish CGS-15943 as a promising lead compound for targeting AHR-positive lung cancers.

We investigated the potential of miR-640 to downregulate CDK4/6 inhibitor resistance-associated genes and evaluated its apoptotic, anti-metastatic and anti-proliferative effects, both alone and in combination with abemaciclib in breast cancer cells. miR-640 was identified via GSE126125 dataset analysis. Targets were predicted using miRDB, TargetScan and TargetMiner, filtering for resistance-associated genes. MTT assays determined IC50 values for abemaciclib and combinations. Functional effects were evaluated in MCF7 and MDA-MB-231 cells through Annexin V, cell cycle and wound healing assays. Target gene expression was quantified by RT-qPCR. Successful transfection significantly upregulated miR-640 (~50-fold). The miR-640/abemaciclib combination strongly inhibited migration, induced apoptosis and triggered cell line-specific phase arrests (S and G2/M in MCF7; G0/G1 in MDA-MB-231). Gene expression analysis showed significant downregulation of a comprehensive resistance network (including CDK4/6, CDKN2B, WNT7B, MAP3K1 and AURKA) in MCF7 cells. In MDA-MB-231 cells, PDK1, CDK6, CDKN2B, SMAD2, ZFP91, MAP3K1 and AURKA were significantly suppressed. This study identifies miR-640 as a potent tumour suppressor that resensitises breast cancer cells to CDK4/6 inhibition. By post-transcriptionally downregulating key resistance genes, miR-640-alone or additively with abemaciclib-suppresses proliferation and migration while inducing apoptosis, emerging as a promising combinatorial therapeutic strategy.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment.

Alzheimer's disease is a progressive neurodegenerative condition characterized by cognitive deterioration, memory loss, and persistent neuroinflammation. Notwithstanding considerable scientific advancements, current therapy strategies predominantly address symptoms and are ineffective in arresting illness progression. Recent studies have demonstrated the crucial role of epigenetic changes, especially histone modifications, in the pathophysiology of Alzheimer's disease. Removal of the acetyl group from histones and non-histone proteins by histone deacetylases (HDACs) plays a pivotal role in the regulation of gene expression, synaptic plasticity, and neuronal survival. Such changes lead to dysregulated HDAC activity, which is further associated with significant clinical characteristics of Alzheimer's disease, including amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. In Alzheimer's disease and other neurodegenerative diseases, the histone acetylation equilibrium is markedly disrupted, resulting in a shift towards hypoacetylation, which further inhibits the production of neuroprotective genes. Pharmacological inhibition of HDACs can reinstate hyperacetylation, therefore facilitating neuroprotective effects. This chapter explores the therapeutic potential of HDAC inhibitors in relation to Alzheimer's disease. This chapter also focuses on various HDAC isoforms associated with disease progression and explores the detailed mechanism by which HDAC inhibitors affect the epigenetic regulation and neuronal function. Preclinical investigations focusing on the role of HDAC inhibitors in mitigating neuroinflammation and Alzheimer's diseases, with a special focus on HDAC inhibitors in clinical trials, present intriguing opportunities for therapeutic advancement. The chapter further explores various challenges such as off-target effects, restricted isoform specificity, and inadequate blood-brain barrier permeability. To address these constraints, various strategies such as isoform-selective inhibitors, targeted delivery methods, and combination treatments are also explored. Thus, the chapter provides in-depth information on the role of HDAC inhibitors, which hold significant potential as disease-modifying agents in the treatment of Alzheimer's disease.

Drug resistance limits the long-term survival of patients with multiple myeloma. The role of tRNA-derived fragments (tsRNAs) in bortezomib resistance in myeloma remains unknown. In this study, the most significantly upregulated tsRNA in relapsed/refractory myeloma was screened. RNA interference was used to explore the function of this tsRNA. The mechanism of the tsRNA-mediated resistance was explored by Ago-RIP-sequencing, dual-luciferase reporter assay, and transmission electron microscopy. tRF-17-8SPOL52 was identified as the most highly expressed tsRNA in relapsed/refractory myeloma. tRF-17-8SPOL52 promoted bortezomib resistance in vitro and in vivo. Ago-RIP-sequencing and dual-luciferase reporter assay showed that tRF-17-8SPOL52 negatively regulated RUBCN. Data from Ago-silenced myeloma cells suggested that the regulation of RUBCN by tRF-17-8SPOL52 was Ago-dependent. Further research showed increased autophagy induced by tRF-17-8SPOL52. In constructed RUBCN overexpressed or inhibited myeloma cells, tRF-17-8SPOL52 promoted cell autophagy by inhibiting RUBCN. Rescue experiments with chloroquine and rapamycin showed that tRF-17-8SPOL52 mediated bortezomib resistance by promoting autophagy. We concluded that tRF-17-8SPOL52 activates autophagy by inhibiting RUBCN in an Ago-dependent manner, which in turn leads to bortezomib resistance in myeloma.

Abscisic acid (ABA) acts as a key signalling molecule that mediates plant responses to environmental cues as well as plant growth and development. Stress-induced and developmental changes in ABA content trigger a myriad of post-transcriptional and transcriptional events. Yet, ABA-dependent transcriptional responses are context dependent, and their temporal dynamics in roots under non-stress conditions remain poorly resolved. In this study, we characterised the hallmarks of ABA signalling and responses in the poplar root transcriptome (Populus nigra L.). We disturbed ABA homeostasis by exogenous ABA treatments, and we combined time-resolved transcriptomics with unsupervised gene network analysis to identify ABA-activated and ABA-inactivated gene co-expression modules. Considering the temporal dynamics of transcriptional events, we predicted the primary targets of the ABA signal, characterised early responding ABA-dependent processes, identified hub genes and revealed their putative functional links. We demonstrated that the properties of a master ABA-activated module induced by exogenous treatments were preserved in the transcriptome response to osmotic stress, revealing a core gene set of ABA-dependent stress responses. Our work sheds light on ABA repression of gene expression, the reprogramming of metabolism and the leaf-senescence pathway. Based on current functional knowledge and phylogenetic information, including poplar-specific features, we proposed a working model of ABA action on root transcriptome in poplar that integrates master genes, key responsive processes, and their putative regulatory architecture.

The rapid emergence of antibiotic resistance represents a critical global health challenge, particularly in biofilm-associated infections caused by Pseudomonas aeruginosa (P. aeruginosa). Quorum sensing plays a pivotal role in regulating bacterial virulence and biofilm formation. Consequently, targeting quorum sensing-regulated virulence factors represents a promising anti-virulence strategy to combat antibiotic resistance. In this study, the FDA-approved drugs vardenafil, valsartan, and olmesartan did not significantly affect the growth of ten clinical P. aeruginosa isolates. At sub-inhibitory concentrations, these drugs significantly reduced the production of key virulence factors, including hemolysin, proteases, pyocyanin, lipases, as well as impairing swarming motility, and biofilm formation. Gene expression analysis confirmed marked downregulation of quorum sensing-associated genes in five selected isolates. In vivo experiments revealed a substantial reduction in bacterial pathogenicity following treatment. Molecular docking analyses further supported these findings, revealing favorable interactions of the tested drugs with key quorum sensing regulatory proteins. Collectively, these results highlight the anti-quorum sensing, anti-virulence, and antibiofilm potential of these repurposed drugs and suggest their possible application in topical formulations as adjunctive therapies to conventional antibiotics for managing severe pseudomonal infections.

mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.