Transcription Factor HSF1 Research Articles

Cytotoxicity of Activator Expression in CRISPR-based Transcriptional Activation Systems.

CRISPR-based transcriptional activation (CRISPRa) has extensive research and clinical potential. Here, we show that commonly used CRISPRa systems can exhibit pronounced cytotoxicity. We demonstrate the toxicity of published and new CRISPRa vectors expressing the activation domains (ADs) of the transcription factors p65 and HSF1, components of the synergistic activation mediator (SAM) CRISPRa system. Based on our findings for the SAM system, we extended our studies to additional ADs and the p300 acetyltransferase core domain. We show that the expression of potent transcriptional activators in lentiviral producer cells leads to low lentiviral titers, while their expression in the transduced target cells leads to cell death. Using inducible lentiviral vectors, we could not identify an activator expression window for effective SAM-based CRISPRa without measurable toxicity. The toxicity of current SAM-based CRISPRa systems hinders their wide adoption in biomedical research and introduces selection bottlenecks that may confound genetic screens. Our results suggest that the further development of CRISPRa technology should consider both the efficiency of gene activation and activator toxicity.

Targeting the host transcription factor HSF1 prevents human cytomegalovirus replication in vitro and in vivo.

Inhibiting of HSF1 as a host-directed antiviral therapy attenuates HCMV replication in vitro and in vivo.

Human coronaviruses activate and hijack the host transcription factor HSF1 to enhance viral replication

Organisms respond to proteotoxic-stress by activating the heat-shock response, a cellular defense mechanism regulated by a family of heat-shock factors (HSFs); among six human HSFs, HSF1 acts as a proteostasis guardian regulating severe stress-driven transcriptional responses. Herein we show that human coronaviruses (HCoV), both low-pathogenic seasonal-HCoVs and highly-pathogenic SARS-CoV-2 variants, are potent inducers of HSF1, promoting HSF1 serine-326 phosphorylation and triggering a powerful and distinct HSF1-driven transcriptional-translational response in infected cells. Despite the coronavirus-mediated shut-down of the host translational machinery, selected HSF1-target gene products, including HSP70, HSPA6 and AIRAP, are highly expressed in HCoV-infected cells. Using silencing experiments and a direct HSF1 small-molecule inhibitor we show that, intriguingly, HCoV-mediated activation of the HSF1-pathway, rather than representing a host defense response to infection, is hijacked by the pathogen and is essential for efficient progeny particles production. The results open new scenarios for the search of innovative antiviral strategies against coronavirus infections.

Allosteric Activation of Protein Phosphatase 5 with Small Molecules.

The activation of PP5 is essential for a variety of cellular processes, as it participates in a variety of biological pathways by dephosphorylating substrates. However, activation of PP5 by small molecules has been a challenge due to its native "self-inhibition" mechanism, which is controlled by the N-terminal TPR domain and the C-terminal αJ helix. Here, we reported the discovery of DDO-3733, a well-identified TPR-independent PP5 allosteric activator, which facilitates the dephosphorylation process of downstream substrates. Considering the negative regulatory effect of PP5 on heat shock transcription factor HSF1, pharmacologic activation of PP5 by DDO-3733 was found to reduce the HSP90 inhibitor-induced heat shock response. These results provide a chemical tool to advance the exploration of PP5 as a potential therapeutic target and highlight the value of pharmacological activation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.

Epigenomic features associated with body temperature stabilize tissues during cold exposure in cold-resistant pigs

Cold stress in low-temperature environments can trigger changes in gene expression, but epigenomics regulation of temperature stability in vital tissues, including the fat and diencephalon, is still unclear. Here, we explore the cold-induced changes in epigenomic features in the diencephalon and fat tissues of two cold-resistant Chinese pig breeds, Min and Enshi black (ES) pigs, utilizing H3K27ac CUT&Tag, RNA-seq, and selective signature analysis. Our results show significant alterations in H3K27ac modifications in the diencephalon of Min pigs and the fat of ES pigs after cold exposure. Dramatic changes in H3K27ac modifications in the diencephalon of Min pig are primarily associated with genes involved in energy metabolism and hormone regulation, whereas those in the fat of ES pig are primarily associated with immunity-related genes. Moreover, transcription factors PRDM1 and HSF1, which show evidence of selection, are enriched in genomic regions presenting cold-responsive alterations in H3K27ac modification in the Min pig diencephalon and ES pig fat, respectively. Our results indicate the diversity of epigenomic response mechanisms to cold exposure between Min and ES pigs, providing unique epigenetic resources for studies of low-temperature adaptation in large mammals.

Antioxidant and Stress Resistance Properties of Flavonoids from Chinese Sea Buckthorn Leaves from the Qinghai-Tibet Plateau.

The unique ecological environment of the Qinghai-Tibetan Plateau has endowed Chinese sea buckthorn leaves with rich bioactivities. In this study, we investigated the bioactivity and stress resistance mechanisms of flavonoids derived from Chinese sea buckthorn leaves (FCL) native to the Qinghai-Tibet Plateau. Our analysis identified a total of 57 flavonoids, mainly flavonol glycosides, from FCL, of which 6 were novel flavonoids. Isorhamnetin glycosides, quercetin glycosides and kaempferol glycosides were the three most dominant classes of compounds in FCL. In particular, isorhamnetin-3-O-glucoside-7-O-rhamnoside emerged as the most abundant compound. Our results showed that FCL possesses potent antioxidant properties, as evidenced by its ability to effectively scavenge DPPH free radicals and demonstrate ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) levels comparable to Trolox, a well-known antioxidant standard. Furthermore, FCL showed remarkable efficacy in reducing reactive oxygen species (ROS) levels and malondialdehyde (MDA) levels while enhancing the activities of key antioxidant enzymes, namely superoxide dismutase (SOD) and catalase (CAT), in Caenorhabditis elegans, a widely used model organism. Mechanistically, we elucidated that FCL exerts its stress resistance effects by modulating of transcription factors DAF-16 and HSF-1 within the insulin/insulin-like growth factor-1 signaling pathway (IIS). Activation of these transcription factors orchestrates the expression of downstream target genes including sod-3, ctl-1, hsp16.2, and hsp12.6, thus enhancing the organism's ability to cope with stressors. Overall, our study highlights the rich reservoir of flavonoids in Chinese sea buckthorn leaves as promising candidates for natural medicines, due to their robust antioxidant properties and ability to enhance stress resistance.

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.

Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Dendrobium Nobile Alcohol Extract Extends the Lifespan of Caenorhabditis elegans via hsf-1 and daf-16.

Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aβ-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway.

Deletion of the transcription factors Hsf1, Msn2 and Msn4 in yeast uncovers transcriptional reprogramming in response to proteotoxic stress.

The response to proteotoxic stresses such as heat shock allows organisms to maintain protein homeostasis under changing environmental conditions. We asked what happens if an organism can no longer react to cytosolic proteotoxic stress. To test this, we deleted or depleted, either individually or in combination, the stress-responsive transcription factors Msn2, Msn4, and Hsf1 in Saccharomyces cerevisiae. Our study reveals a combination of survival strategies, which together protect essential proteins. Msn2 and 4 broadly reprogram transcription, triggering the response to oxidative stress, as well as biosynthesis of the protective sugar trehalose and glycolytic enzymes, while Hsf1 mainly induces the synthesis of molecular chaperones and reverses the transcriptional response upon prolonged mild heat stress (adaptation).

StHsfB5 Promotes Heat Resistance by Directly Regulating the Expression of Hsp Genes in Potato.

With global warming, high temperatures have become a major environmental stress that inhibits plant growth and development. Plants evolve several mechanisms to cope with heat stress accordingly. One of the important mechanisms is the Hsf (heat shock factor)-Hsp (heat shock protein) signaling pathway. Therefore, the plant transcription factor Hsf family plays important roles in response to heat stress. All Hsfs can be divided into three classes (A, B, and C). Usually, class-A Hsfs are transcriptional activators, while class-B Hsfs are transcriptional repressors. In potato, our previous work identified 27 Hsfs in the genome and analyzed HsfA3 and HsfA4C functions that promote potato heat resistance. However, the function of HsfB is still elusive. In this study, the unique B5 member StHsfB5 in potato was obtained, and its characterizations and functions were comprehensively analyzed. A quantitative real-time PCR (qRT-PCR) assay showed that StHsfB5 was highly expressed in root, and its expression was induced by heat treatment and different kinds of phytohormones. The subcellular localization of StHsfB5 was in the nucleus, which is consistent with the characterization of transcription factors. The transgenic lines overexpressing StHsfB5 showed higher heat resistance compared with that of the control nontransgenic lines and inhibitory lines. Experiments on the interaction between protein and DNA indicated that the StHsfB5 protein can directly bind to the promoters of target genes small Hsps (sHsp17.6, sHsp21, and sHsp22.7) and Hsp80, and then induce the expressions of these target genes. All these results showed that StHsfB5 may be a coactivator that promotes potato heat resistance ability by directly inducing the expression of its target genes sHsp17.6, sHsp21, sHsp22.7, and Hsp80.

HSF1 Inhibits Antitumor Immune Activity in Breast Cancer by Suppressing CCL5 to Block CD8+ T-cell Recruitment.

The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.

SIRT1 and HSP90α feed-forward circuit safeguards chromosome segregation integrity in diffuse large B cell lymphomas

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma in adults, exhibiting highly heterogenous clinical behavior and complex molecular background. In addition to the genetic complexity, different DLBCL subsets exhibit phenotypic features independent of the genetic background. For example, a subset of DLBCLs is distinguished by increased oxidative phosphorylation and unique transcriptional features, including overexpression of certain mitochondrial genes and a molecular chaperone, heat shock protein HSP90α (termed “OxPhos” DLBCLs). In this study, we identified a feed-forward pathogenetic circuit linking HSP90α and SIRT1 in OxPhos DLBCLs. The expression of the inducible HSP90α isoform remains under SIRT1-mediated regulation. SIRT1 knockdown or chemical inhibition reduced HSP90α expression in a mechanism involving HSF1 transcription factor, whereas HSP90 inhibition reduced SIRT1 protein stability, indicating that HSP90 chaperones SIRT1. SIRT1-HSP90α interaction in DLBCL cells was confirmed by co-immunoprecipitation and proximity ligation assay (PLA). The number of SIRT1-HSP90α complexes in PLA was significantly higher in OxPhos- dependent than -independent cells. Importantly, SIRT1-HSP90α interactions in OxPhos DLBCLs markedly increased in mitosis, suggesting a specific role of the complex during this cell cycle phase. RNAi-mediated and chemical inhibition of SIRT1 and/or HSP90 significantly increased the number of cells with chromosome segregation errors (multipolar spindle formation, anaphase bridges and lagging chromosomes). Finally, chemical SIRT1 inhibitors induced dose-dependent cytotoxicity in OxPhos-dependent DLBCL cell lines and synergized with the HSP90 inhibitor. Taken together, our findings define a new OxPhos-DLBCL-specific pathogenetic loop involving SIRT1 and HSP90α that regulates chromosome dynamics during mitosis and may be exploited therapeutically.

Comparative chromatin dynamics reveal differential thermal tolerance mechanisms between two congeneric oyster species

Oysters, being globally farmed bivalve of significant economic and ecological value, are increasingly confronted with heat stress induced by global warming, such as the frequent occurrence of mass summer mortality events worldwide. The role of epigenetics in adapting to high-temperature environments has garnered growing attention; however, its application in oysters remains poorly understood. In this study, we conducted a comparative analysis between two closely related oyster species (the relatively thermosensitive Crassostrea gigas and the relatively thermotolerant Crassostrea angulata) using ATAC-Seq and RNA-Seq to reveal the differential thermal tolerance mechanisms at the chromatin dynamics level in response to high-temperature stress. The comparative analysis showed that the inhibitor of apoptosis protein (IAP) family and its associated apoptosis pathways were the major divergent pathway between the two species. The promoter regions of differentially expressed genes in C. gigas under heat stress were found to be enriched with motifs such as Foxp1, Foxk2, Myc, Cebpd, Foxo3, and Hsf1 motifs and expressed genes related to molecular chaperones, including heat shock protein family. And C. angulata activated the genes related to anti-apoptosis, DNA damage repair, and fatty acid synthesis (decreasing fatty acid unsaturation of membrane to regulate membrane fluidity). These findings suggest that C. angulata may have evolved a more centralized and energy-efficient transcriptional regulatory network at the genomic level, thereby facilitating its long-term adaptation to relatively high temperature environments. Furthermore, the key transcription factor Hsf1, involved in heat shock responses, may contribute to the differential heat response patterns in C. gigas and C. angulata through divergent expression levels of its alternatively spliced isoforms (Hsf1a and Hsf1d). Our work will contribute to predicting the adaptive potential of oysters and other marine invertebrates in facing future global warming, and provide a theoretical foundation for genetic improvement of resistance traits and sustainable development of oyster industry.

Isolation, cloning, and tissue distribution and functional analysis of ShP-glycoprotein in the freshwater crab Sinopotamon henanense exposed to Cd and Cd-QDs

P-glycoprotein (Pgp), a member of ATP binding cassette (ABC) transporter family, can extrude toxic substances out of cells by mediating multi-xenobiotic resistance (MXR) in aquatic organisms, however, its regulation and association with MXR are still unclear. In this work, the genetic information of Pgp in freshwater crab Sinopotamon henanense (ShPgp) was revealed for the first time. ShPgp with a total of 4488 bp was cloned and analyzed, which includes 4044 bp open reading frame, 353 bp 3′ untranslated region, and 91 bp 5′ untranslated region. The recombinant ShPGP were expressed in Saccharomyces cerevisiae and taken for SDS-PAGE and western blot analysis. ShPGP was widely expressed in the midgut, hepatopancreas, testis, ovary, gill, hemocytes, accessory gonad and myocardium of the crabs studied. The images of immunohistochemistry indicated that ShPgp was mainly distributed in the cytoplasm and cell membrane. When the crabs were exposed to cadmium or cadmium containing quantum dots (Cd-QDs), not only the relative expression of ShPgp mRNA and the protein produced were enhanced, but also the MXR activity and ATP contents. The relative expression of target genes related to energy metabolism, detoxification and apoptosis was also determined in the carbs exposed to Cd or Cd-QDs. The results showed that bcl-2 was significantly down-regulated, while other genes were up-regulated except PPAR (not affected). However, when the Shpgp in treated crabs was interfering by knockdown technique, their apoptosis and the expression of proteolytic enzyme genes and transcription factors MTF1 and HSF1 were also elevated, while the expression of apoptosis inhibiting and fat metabolism genes were compromised. Based on the observation, we concluded that MTF1 and HSF1 were involved in gene transcription regulation of mt and MXR, respectively, while PPAR had limited regulatory effect on those genes in S. henanense. NF-κB may play a negligible role in the process of apoptosis in testes induced by cadmium or Cd-QDs. However, the detail information regarding Pgp involvement in SOD or MT, and its association with apoptosis during xenobiotics insults remain to be explored.

Heat shock transcriptional factor HSF1 is activated by phosphorylation in response to ginger oleoresin stress in S. cerevisiae

Ginger in traditional Chinese medicine is widely applied to dispel cold due to ginger's thermogenic effects when consumed. Heat shock response is a classical and highly conserved signaling pathway in cells regulating gene expressions in response to heat stress. However, the potential molecular links between ginger and heat shock response are still unexplored. We described that the ginger oleoresin stress and heat stress produced similar yeast phenotypes and shared genes in RNA-seq analyses. In saccharomyces cerevisiae, a high-osmolarity glycerol pathway (HOG) and critical transcription factors, Msn2/4 and Hsf1 are mainly involved in response to heat stress. Compared with heat shock, we found that only transcription factor Hsf1 was phosphorylated and activated in response to ginger oleoresin stress, accumulating in the nucleus and increasing expression of heat shock proteins such as Hsp104, Hsp78, and Hsp82. Three serine or threonine residues of Hsf1, T162, T163, and S168 were phosphorylated in response to ginger oleoresin stress. These results address the link between ginger and heat shock and their potential molecular mechanism.

Oxidized quercetin has stronger anti-amyloid activity and anti-aging effect than native form

Quercetin (QUE) is one of the most widely distributed and used flavonoid. It has many biological activities and pharmacological effect. As a polyhydroxy phenol, QUE is easily oxidized. However, it is unclear how its biology efficacy changes after oxidation. In this study, we prepared QUE oxidation product (QUE-ox) through enzymatic oxidation of QUE. We found the oxidation reduced the antioxidant activity of QUE but increased its anti-amyloid activity in vitro. In C. elegans, oxidation increased the anti-aging effects of QUE. Further experiments showed that both QUE and QUE-ox delayed aging by improving stress resistance, but they have different molecular mechanisms. QUE mainly increased the transcriptional activities of DAF-16 and SKN-1, resulting in the enhancement of expression of oxidative stress resistance genes, and further increased the oxidative resistance in C. elegans. QUE-ox increased the transcriptional activities of DAF-16 and HSF-1 transcription factors to enhance the heat stress resistance. In summary, our study indicated oxidized QUE has stronger anti-amyloid activity and anti-aging effect than native form. This study provides a theoretical basis for the safe and rational application of QUE, especially for its antioxidant, anti-amyloid and anti-aging effects.

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as "the most cytoprotective protein ever been described". HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

Food Toxicity of Mycotoxin Citrinin and Molecular Mechanisms of Its Potential Toxicity Effects through the Implicated Targets Predicted by Computer-Aided Multidimensional Data Analysis.

The mycotoxin citrinin, which can contaminate food, is a major global concern. Citrinin is regarded as an inevitable pollutant in foods and feed since fungi are widely present in the environment. To identify contentious toxicity and lessen its severity by understanding the targets of citrinin in the human body and the impacted biosynthetic pathways, we analyzed the production of citrinin from Aspergillus flavus and Penicillium notatum and used a thorough bioinformatics analysis to characterize the toxicity and predict genes and protein targets for it. The predicted median fatal dosage (LD50) for citrinin was 105 mg/kg weight, and it belonged to toxicity class 3 (toxic if swallowed). Citrinin was found to be well absorbed by human intestinal epithelium and was a Pgp nonsubstrate (permeability glycoprotein), which means that once it is absorbed, it cannot be pumped out, hence leading to bioconcentration or biomagnification in the human body. The main targets of toxicity were casp3, TNF, IL10, IL1B, BAG3, CCNB1, CCNE1, and CDC25A, and the biological pathways implicated were signal transduction involved in DNA damage checkpoints, cellular and chemical responses to oxidative stress, DNA damage response signal transduction by P53, stress-activated protein kinase signaling cascade, netrin-UNC5B signaling, PTEN gene regulation, and immune response. Citrinin was linked to neutrophilia, squamous cell carcinoma, Fanconi anemia, leukemia, hepatoblastoma, and fatty liver diseases. The transcription factors E2F1, HSF1, SIRT1, RELA, NFKB, JUN, and MYC were found to be responsible. When data mining was performed on citrinin targets, the top five functional descriptions were a cell's response to an organic cyclic compound, the netrin-UNC5B signaling pathway, lipids and atherosclerosis, thyroid cancer, and controlling the transcription of the PTEN gene.

Zhuyeqing liquor promotes longevity through enhancing stress resistance via regulation of SKN-1 and HSF-1 transcription factors in Caenorhabditis elegans

Zhuyeqing liquor (ZYQL) is well-known traditional functional liquor in China that contains twelve crude drugs. Studies have shown that ZYQL has many beneficial effects, but its anti-aging effect has not been reported. Here, we found that ZYQL had excellent antioxidant activity in vitro. In C. elegans, ZYQL could significantly extend the lifespan, and decreased aging related phenotype including accumulation of lipofuscin and the decrease of food intake and motility. Further, ZYQL significantly reduced ROS level and enhanced the antioxidant defense in C. elegans. ZYQL increased transcriptional activity of transcription factors HSF-1 and SKN-1, and ZYQL-mediated longevity was dependent on these factors. Taken together, the data suggested that ZYQL enhanced the transcriptional activity of transcription factors HSF-1 and SKN-1, which in turn increased oxidative/heat stress resistance to exert its anti-aging effect in C. elegans. Our results provide new insights into the beneficial effects and underlying mechanisms of ZYQL, which might be useful for further developing ZYQL into health or anti-aging beverages.