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The bioinspired black phosphorus was constructed to deliver the histone deacetylase inhibitor (HDACi) and termed as MBS. MBS showed excellent surface properties and acted as a multifunctional platform based on the cell membrane coating structure, which showed great potential in the delivery of a broad spectrum of HDACi and exhibited synergistic therapy by photothermal effect and chemotherapy. [Display omitted] Lung cancer remains one of the most fatal cancers worldwide, with a high incidence of metastasis and a low 5-year survival rate. Histone deacetylase inhibitors (HDACis) have shown significant potential in lung cancer treatment, but their clinical use is often hindered by poor water solubility, rapid clearance, and systemic toxicity. In this study, we developed a novel therapeutic strategy by camouflaging black phosphorus (BP) with M1 macrophage membranes (MB) and loaded HDACi suberoylanilide hydroxamic acid (SAHA) onto the camouflaged black phosphorus (MB) for targeted lung cancer therapy. The M1 membrane coating enhanced the specificity of the SAHA-loaded black phosphorus toward lung cancer cells. Black phosphorus not only served as a carrier for HDACis but also facilitated photothermal therapy (PTT) through its photothermal conversion capabilities, establishing a highly efficient therapeutic platform. MBS demonstrated strong antitumor activity with minimal systemic toxicity. This multifunctional platform, inspired by biological systems, shows great promise for delivering a wide range of HDACis and offers synergistic therapeutic potential through the combination of photothermal therapy and chemotherapy. [ABSTRACT FROM AUTHOR]

This study aims to design and synthesize novel benzimidazole histone deacetylase (HDAC) inhibitors to explore their potential applications in the treatment of cancer and other related diseases. By comparing the structures of our reported benzimidazole HDAC inhibitors, we designed a series of compounds accordingly. We then used experimentally verified their inhibitory activity against HDAC enzymes. The results showed that several of the newly synthesized compounds showed good HDAC inhibition and anti-proliferative activity. Therefore, we conclude that these novel HDAC inhibitors have potential as drug candidates for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Protein lactylation is a new form of post-translational modification that has recently been proposed. Lactoyl groups, derived mainly from the glycolytic product lactate, have been linked to protein lactylation in brain tissue, which has been shown to correlate with increased neuronal excitability. Ischemic stroke may promote neuronal glycolysis, leading to lactate accumulation in brain tissue. This accumulation of lactate accumulation may heighten neuronal excitability by upregulating protein lactylation levels, potentially triggering post-stroke epilepsy. Although current clinical treatments for seizures have advanced significantly, approximately 30% of patients with epilepsy remain unresponsive to medication, and the prevalence of epilepsy continues to rise. This study explores the mechanisms of epilepsy-associated neuronal death mediated by lactate metabolism and protein lactylation. This study also examines the potential for histone deacetylase inhibitors to alleviate seizures by modifying lactylation levels, thereby offering fresh perspectives for future research into the pathogenesis and clinical treatment of epilepsy. [ABSTRACT FROM AUTHOR]

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler. [ABSTRACT FROM AUTHOR]

Muscle repair and regeneration are complex processes. In Duchenne muscular dystrophy (DMD), these processes are disrupted by the loss of functional dystrophin, a key part of the transmembrane dystrophin-associated glycoprotein complex that stabilizes myofibers, indirectly leading to progressive muscle wasting, subsequent loss of ambulation, respiratory and cardiac insufficiency, and premature death. As part of the DMD pathology, histone deacetylase (HDAC) activity is constitutively increased, leading to epigenetic changes and inhibition of muscle regeneration factors, chronic inflammation, fibrosis, and adipogenesis. HDAC inhibition has consequently been investigated as a therapeutic approach for muscular dystrophies that, significantly, works independently from specific genetic mutations, making it potentially suitable for all patients with DMD. This review discusses how HDAC inhibition addresses DMD pathophysiology in a multi-targeted mode of action and summarizes the recent evidence on the rationale for HDAC inhibition with givinostat, which is now approved by the United States Food and Drug Administration for the treatment of DMD in patients aged 6 years and older. [ABSTRACT FROM AUTHOR]

Simple Summary: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, often linked to a poor prognosis for the majority of patients. Platinum–etoposide-based chemotherapy, combined with immunotherapy, constitutes the standard treatment for patients with small-cell lung cancer (SCLC). Nonetheless, SCLC often recurs and develops resistance to treatment. The development of targeted treatment options for patients with SCLC has presented challenges; however, several emerging therapies demonstrate potential efficacy. Recent progress in SCLC research has uncovered essential insights into the biological traits of the disease, which could facilitate the discovery of biomarkers. Additionally, evaluating novel therapies will be crucial for enhancing treatment outcomes for patients with SCLC. Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum–etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), calmodulin-dependent protein kinase (CaMK), NF-κB, mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), and molecules that contain an immunoreceptor tyrosine-based activation motif (ITAM) has been reported. However, the precise molecular steps that regulate RANKL signaling remain largely unknown. Here, we revealed the indispensable role of a class III histone deacetylase (SIRT5) in the processes of RANKL-induced osteoclast differentiation and activation. SIRT5 expression in osteoclasts was increased during osteoclastogenesis upon stimulation with RANKL. The RANKL-induced signaling activation was suppressed in SIRT5-deficient osteoclasts but enhanced by SIRT5 overexpression. Mice with global or conditional monocytic lineage knockout of SIRT5 had increased bone mass and reduced osteoclast numbers. In the cytoplasm, SIRT5 interacted with the scaffold protein JNK-interacting protein 4 (JIP4) to finely regulate MAPK signaling, which was critical for osteoclast differentiation and activation. Pharmacological inhibition of the catalytic activity of SIRT5 effectively reversed bone loss in ovariectomized mice. Taken together, the results of this study reveal that the SIRT5-JIP4 axis is a novel positive regulator that finely regulates RANKL-induced osteoclast differentiation and suggest that targeting this axis is a therapeutic strategy for preventing osteoporotic bone loss. [ABSTRACT FROM AUTHOR]

Post-translational modifications of histone H3 on lysine 9, specifically acetylation (H3K9ac) and tri-methylation (H3K9me3), play a critical role in regulating chromatin accessibility. However, the role of these modifications in lineage segregation in the mammalian blastocyst remains poorly understood. We demonstrate that di- and tri-methylation marks, H3K9me2 and H3K9me3, decrease during cavitation and expansion of the rabbit blastocyst. Notably, H3K9me3 levels are particularly low in inner cell mass cells at the onset of blastocyst formation but increase again just before gastrulation. Conversely, H3K9ac is abundant in early blastocyst stages but decreases during the transition from the inner cell mass to the epiblast. These distinct distribution patterns correlate with high expression levels of methyltransferases (EHMT1, EHMT2, SETDB1) and deacetylases (HDAC1, HDAC2, HDAC5) in expanding blastocysts. Functionally, inhibiting H3K9me2/3 through an EHMT1/2 inhibitor disrupts primitive endoderm segregation, whereas enhancing histone acetylation (including H3K9ac) using a class I HDAC inhibitor promotes epiblast expansion at the expense of the primitive endoderm. These modifications impact the expression of genes associated with pluripotency and lineage determination, underscoring the importance of H3K9 modifications in embryonic cell fate decisions. [ABSTRACT FROM AUTHOR]

Background: Astrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear. Methods: We investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice. Results: Here, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice. Conclusions: Our findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context. It reveals their multifaceted impact on hallmark cancer processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, resisting cell death, inducing angiogenesis, and enabling replicative immortality. SIRT1, for example, fosters chemoresistance and castration-resistant prostate cancer through metabolic reprogramming, immune modulation, androgen receptor signaling, and enhanced DNA repair. SIRT3 and SIRT4 suppress oncogenic pathways by regulating cancer metabolism, while SIRT2 and SIRT6 influence tumor aggressiveness and androgen receptor sensitivity, with SIRT6 promoting metastatic potential. Notably, SIRT5 oscillates between oncogenic and tumor-suppressive roles by regulating key metabolic enzymes; whereas, SIRT7 drives PCa proliferation and metabolic stress adaptation through its chromatin and nucleolar regulatory functions. Furthermore, we provide a comprehensive summary of the roles of individual sirtuins, highlighting their potential as biomarkers in PCa and exploring their therapeutic implications. By examining each of these specific mechanisms through which sirtuins impact PCa, this review underscores the potential of sirtuin modulation to address gaps in managing advanced PCa. Understanding sirtuins' regulatory effects could redefine therapeutic approaches, promoting precision strategies that enhance treatment efficacy and improve outcomes for patients with aggressive disease. [ABSTRACT FROM AUTHOR]

The histone acetylation modification is a conservative post-translational epigenetic regulation in fungi. It includes acetylation and deacetylation at the lysine residues of histone, which are catalyzed by histone acetyltransferase (HAT) and deacetylase (HDAC), respectively. The histone acetylation modification plays crucial roles in fungal growth and development, environmental stress response, secondary metabolite (SM) biosynthesis, and pathogenicity. One of the most important roles is to regulate the gene expression that is responsible for SM biosynthesis in fungi. This mini-review summarized the regulation of histone acetylation modification by HATs and HDACs on the biosynthesis of SMs in fungi. In most cases, histone acetylation by HATs positively regulated the biosynthesis of fungal SMs, while HDACs had their negative regulations. Some HATs and HDACs were revealed to regulate fungal SM biosynthesis. Hda1 was found to be the most efficient regulator to affect the biosynthesis of SMs in fungi. The regulated fungal species were mainly from the genera of Aspergillus, Calcarisporium, Cladosporium, Fusarium, Monascus, Penicillium, and Pestalotiopsis. With the strategy of histone acetylation modification, the biosynthesis of some harmful SMs will be inhibited, while the production of useful bioactive SMs will be promoted in fungi. The subsequent research should focus on the study of regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: To elucidate the regulatory role of Histone Deacetylase Complex 1 (HDC1) in the primary root growth of Arabidopsis thaliana under potassium (K+) deficiency, we examined primary root growth changes in the hdc1-2 mutant under K+ deficiency stress. The hdc1-2 mutant exhibited significantly inhibited primary root growth compared to the wild-type (WT) plants under low-potassium (LK) conditions, indicating that HDC1 positively regulates root growth under LK conditions. We measured various root zones and found that the inhibition of root growth in hdc1-2 was attributed to reduced apical meristem cell proliferation. The root growth of hdc1-2 showed reduced sensitivity compared to WT after auxin treatment under LK conditions. Moreover, HDC1 negatively regulated the expression of the CBL-CIPK module genes. These findings suggest that HDC1 connects histone deacetylation, auxin signaling, and the CBLs-CIPKs pathway in response to K+ deficiency. Plants frequently encounter relatively low and fluctuating potassium (K+) concentrations in soil, with roots serving as primary responders to this stress. Histone modifications, such as de-/acetylation, can function as epigenetic markers of stress-inducible genes. However, the signaling network between histone modifications and low-K+ (LK) response pathways remains unclear. This study investigated the regulatory role of Histone Deacetylase Complex 1 (HDC1) in primary root growth of Arabidopsis thaliana under K+ deficiency stress. Using a hdc1-2 mutant line, we observed that HDC1 positively regulated root growth under LK conditions. Compared to wild-type (WT) plants, the hdc1-2 mutant exhibited significantly inhibited primary root growth under LK conditions, whereas HDC1-overexpression lines displayed opposite phenotypes. No significant differences were observed under HK conditions. Further analysis revealed that the inhibition of hdc1-2 on root growth was due to reduced apical meristem cell proliferation rather than cell elongation. Notably, the root growth of hdc1-2 showed reduced sensitivity compared to WT after auxin treatment under LK conditions. HDC1 may regulate root growth by affecting auxin polar transport and subsequent auxin signaling, as evidenced by the altered expression of auxin transport genes. Moreover, the organ-specific RT-qPCR analyses unraveled that HDC1 negatively regulates the expression of CBL-CIPK-K+ channel-related genes such as CBL1, CBL2, CBL3, AKT1, and TPK1, thereby establishing a molecular link between histone deacetylation, auxin signaling, and CBLs-CIPKs pathway in response to K+ deficiency. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) remains a pandemic threat. Particularly, the evolution and increased interspecies and intercontinental transmission of avian IAV H5N1 subtype highlight the importance of continuously studying the IAV and identifying the determinants of its pathogenesis. Host innate antiviral response is the first line of defense against IAV infection, and the transcription factor, the signal transducer and activator of transcription 3 (STAT3), has emerged as a critical component of this response. Also, histone deacetylase 1 (HDAC1) and HDAC2 have been identified as important components of IAV-induced host innate antiviral response. Upon IAV infection, STAT3 is activated and translocated to the nucleus to initiate the transcription of innate response genes. Also, the HDAC1 and HDAC2 are localized to the nucleus. In this study, we sought to investigate the role of HDAC1 and HDAC2 in IAV-induced STAT3 nuclear translocation. We employed a quantitative confocal microscopy approach and analyzed the nuclear translocation of plasmid-expressed STAT3-GFP in IAV-infected cells depleted with the expression of HDAC1 or HDAC2. We found that the depletion of both HDAC1 and HDAC2 expression inhibits the IAV-induced nuclear translocation of STAT3-GFP. These findings will help elucidate the significance of the emerging role of acetylation in IAV infection and disease severity. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC)-6 has overwhelming implications in multiple cancers and neurodegenerative disorders. Unusual HDAC6 expression modulates various signalling mechanisms which in turn forms the aetiology of the above-mentioned disorders. Thus, restoring the typical activity of HDAC6 through small molecules may prove as a promising approach to beat these disorders. Herein, we employed an integrated approach for exploring the high binding affinity manifesting molecules against HDAC6. We screened the entire PubChem database using Tubastatin A as the reference (query) molecule following which we carried out 110 molecular docking (XP-mode) and 110 MM-GBSA experiments. Thirty-three molecules demonstrated raised binding affinity than query in the HDAC6 active site. Further, the top 3 binders selected on logical grounds were subjected to interaction study, two hit molecules and tubastatin-A were subjected to convoluted molecular dynamics and three-dimensional e-Pharmacophores mapping was done to delineate the rationale behind the high binding tendency of hit molecules over control molecule. This work provides a solid foundation for additional research towards the development of lead molecules from the said hits for therapeutic intervention against HDAC6 overexpression-driven disorders. [ABSTRACT FROM AUTHOR]

Epigenetic processes are the critical events in carcinogenesis. Histone modification plays a crucial role in gene expression regulation, where histone deacetylases (HDACs) are key players in epigenetic processes. Inhibiting HDACs has shown promise in modern cancer therapy. However, the non-selective nature and drug resistance of most HDAC inhibitors (HDACIs) limits their clinical use. This limitation prompts a search for isoform-selective and more effective inhibitors. Histone deacetylase 1 (HDAC1) is a member of the class I HDAC family and has emerged as a promising target in various diseases, including cancer and neurodegeneration. Drug repurposing has gained significant interest in identifying treatments for new targets, which involves finding new uses for existing drugs beyond their original medical indications. Here, we employed virtual screening of repurposed drugs from the DrugBank database to identify potential HDAC1 inhibitors. We conducted a series of analyses, including molecular docking, drug profiling, PASS evaluation, and interaction analysis. Molecular dynamics (MD) simulations and MM-PBSA analysis were also performed for 300 ns. Through these analyses, we pinpointed Alectinib, which exhibits a promising drug profile in PASS analysis and higher affinity and efficiency for HDAC1 than the reference inhibitor. MD simulations revealed that Alectinib stabilizes HDAC1 with minimal structural perturbations. The findings suggest that Alectinib holds promise as a therapeutic lead for HDAC1-associated carcinogenesis after required validation. [ABSTRACT FROM AUTHOR]

Inflammation serves as the foundation for numerous physiological and pathological processes, driving the onset and progression of various diseases. Histone deacetylase 3 (HDAC3), an essential chromatin‐modifying protein within the histone deacetylase superfamily, exerts its transcriptional inhibitory role through enzymatic histone modification to uphold normal physiological function, growth, and development of the body. With both enzymatic and non‐enzymatic activities, HDAC3 plays a pivotal role in regulating diverse transcription factors associated with inflammatory responses and related diseases. This review examines the involvement of HDAC3 in inflammatory responses while exploring its therapeutic potential as a target for treating inflammatory diseases, thereby offering valuable insights for clinical applications. [ABSTRACT FROM AUTHOR]

Aim: Duchenne muscular dystrophy is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene. Despite progress in dystrophin‐targeted gene therapies, it is still a fatal disease requiring novel therapeutics that can be used synergistically or alternatively to emerging gene therapy. Defective autophagy and disorganized microtubule networks contribute to dystrophic pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. The present study was designed to uncover possible mechanisms underpinning the role of microtubules in regulating autophagy in dystrophic mice. Methods: Mdx mice were also supplemented with Tubastatin A, a pharmacological inhibitor of histone deacetylase 6, and pathophysiology was assessed. Mdx mice with a genetic deletion of the Nox‐2 scaffolding subunit p47phox were used to assess redox dependence on tubulin acetylation. Results: Our data show decreased acetylation of α‐tubulin with enhanced histone deacetylase 6 expression. Tubastatin A increases tubulin acetylation and Q‐SNARE complex formation but does not alter microtubule organization or density, indicating improved autophagosome–lysosome fusion. Tubastatin A increases the acetylation of peroxiredoxin and protects it from hyper‐oxidation, hence modulating intracellular redox status in mdx mice. Tubastatin A reduces muscle damage and enhances force production. Genetic down regulation of Nox2 activity in the mdx mice promotes autophagosome maturation but not autolysosome formation. Conclusion: Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By improving autophagy through promoting tubulin acetylation, Tubastatin A decreases the dystrophic phenotype and improves muscle function, suggesting a great potential for clinical translation and treating dystrophic patients. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a major cause of death in bacterial sepsis due to endothelial inflammation and endothelial permeability defects. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of sepsis-induced ALI. Sirtuin 3 (SIRT3) is a histone protein deacetylase involved in preservation of mitochondrial function, which has been demonstrated in our previous study. Here, we investigated the effects of SIRT3 deficiency on impaired mitophagy to promote lung endothelial cells (ECs) pyroptosis during sepsis-induced ALI. We found that 3-TYP aggravated sepsis-induced ALI with increased lung ECs pyroptosis and enhanced NLRP3 activation. Mitochondrial reactive oxygen species (mtROS) and extracellular mitochondrial DNA (mtDNA) released from damaged mitochondria could be exacerbated in SIRT3 deficiency, which further elicit NLRP3 inflammasome activation in lung ECs during sepsis-induced ALI. Furthermore, Knockdown of SIRT3 contributed to impaired mitophagy via downregulating Parkin, which resulted in mitochondrial dysfunction. Moreover, pharmacological inhibition NLRP3 or restoration of SIRT3 attenuates sepsis-induced ALI and sepsis severity in vivo. Taken together, our results demonstrated SIRT3 deficiency facilitated mtROS production and cytosolic release of mtDNA by impaired Parkin-dependent mitophagy, promoting to lung ECs pyroptosis through the NLRP3 inflammasome activation, which providing potential therapeutic targets for sepsis-induced ALI. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Methods Results Conclusions The goal of this study was to determine the role of histone deacetylase 9 (HDAC9) in the development of diet‐induced metabolic dysfunction‐associated steatohepatitis (MASH) and white adipose tissue (WAT) dysfunctions.We fed male and female mice with global Hdac9 knockout (KO) and their wild‐type (WT) littermates an obesogenic high‐fat/high‐sucrose/high‐cholesterol (35%/34%/2%, w/w) diet for 20 weeks.Hdac9 deletion markedly inhibited body weight gain and liver steatosis with lower liver weight and triglyceride content than WT in male mice but not females. Consistently, hepatic expression of genes crucial for de novo lipogenesis was markedly suppressed only in male, but not female, Hdac9 KO mice. However, Hdac9 deletion had a minimal effect on hepatic inflammation and fibrosis. In WAT, Hdac9 KO showed less adipocyte hypertrophy, inflammation, and fibrosis in male mice compared with WT. In addition, indirect calorimetry demonstrated that male Hdac9 KO mice had significantly higher metabolic rates, respiratory exchange ratios, and energy expenditure without altering physical activities than WT, which was not observed in female mice.Our findings indicate that global deletion of Hdac9 prevented the development of obesity, hepatic steatosis, and WAT inflammation and fibrosis in male mice with diet‐induced obesity and MASH, suggesting that a sex‐dependent role of HDAC9 may exist in the pathways mentioned above. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is highly heterogeneous and poses a significant medical challenge due to limited treatment options and poor outcomes. Peroxisome proliferator‐activated receptors (PPARs) play a crucial role in regulating metabolism and cell fate. While the association between PPAR signal and human cancers has been a topic of concern, its specific relationship with TNBC remains unclear. Integrated analysis of large published datasets from clinical cohorts and cell lines through databases has proven to be a powerful and essential approach for understanding cancer and uncovering new molecular targets. Here, we conducted a comprehensive study investigating the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC, using data from The Cancer Genome Atlas (TCGA) for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) for TNBC cell lines, along with drug perturbation information from Connectivity Map (CMap). In the TCGA‐TNBC cohort, higher PPAR signaling activity was not associated with clinical stage, prognosis, tumor mutational burden, microsatellite instability, homologous recombination deficiency, stemness, or proliferation status. However, it was linked to older age; an elevated rate of piccolo presynaptic cytomatrix protein (PCLO) mutations; and oncogenic signal transduction involving MAPK, Ras, and PI3K‐Akt pathways. Additionally, it influenced biological pathways including fatty acid metabolism, AMPK signaling, and ferroptosis. Strikingly, higher PPAR activity appeared to promote the formation of an antitumor immune and microbial microenvironment. In the GDSC‐TNBC cells, nevertheless, it seemed to incur chemoresistance. Furthermore, we identified a batch of potential compounds that can regulate the PPAR signaling pathway. Lastly, our experimental validation demonstrated the ability of the histone deacetylase (HDAC) inhibitor chidamide to activate the PPAR signal in TNBC cells. In conclusion, the PPAR signaling pathway likely has pleiotropic biological effects in TNBC. These preliminary but interesting findings enhance our understanding of the role played by PPAR signal and provide new insights into the heterogeneity driven by it in TNBC. [ABSTRACT FROM AUTHOR]

Background/Objectives: Acute myocardial infarction (AMI) is a critical medical condition that requires immediate attention to minimise heart damage and improve survival rates. Early identification and prompt treatment are essential to save the patient's life. Currently, the treatment strategy focuses on restoring blood flow to the myocardium as quickly as possible. However, reperfusion activates several cellular cascades that contribute to organ dysfunction, resulting in the ischaemia/reperfusion (I/R) injury. The search for treatments against AMI and I/R injury is urgent due to the shortage of effective treatments at present. In this regard, histone deacetylase (HDAC) inhibitors emerge as a promising treatment against myocardial infarction. The objective of this systematic review is to analyse the effects of HDAC inhibitors on ventricular function, cardiac remodelling and infarct size, among other parameters, focusing on the signalling pathways that may mediate these cardiovascular effects and protect against AMI. Methods: Original experimental studies examining the effects of HDAC inhibitors on AMI were included in the review using the PubMed and Scopus databases. Non-experimental papers were excluded. The SYRCLE RoB tool was used to assess risk of bias and the results were summarised in a table and presented in sections according to the type of HDAC inhibitor used. Results: A total of 18 studies were included, 10 of them using trichostatin A (TSA) as an HDAC inhibitor and concluding that the treatment improved ventricular function, reduced infarct size, and inhibited myocardial hypertrophy and remodelling after AMI. Other HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), mocetinostat, givinostat, entinostat, apicidin, and RGFP966, were also analysed, showing antioxidant and anti-inflammatory effects, an improvement in cardiac function and remodelling, and a decrease in apoptosis, among other effects. Conclusions: HDAC inhibitors constitute a significant promise for the treatment of AMI due to their diverse cardioprotective effects. However, high risk of selection, performance, and detection bias in the in vivo studies means that their application in the clinical setting is still a long way off and more research is needed to better understand their benefits and possible side effects. [ABSTRACT FROM AUTHOR]

Indole‐3‐carboxaldehyde (ICA), a microbiota‐derived tryptophan metabolite, has been reported to protect against atherosclerosis. However, the molecular mechanisms for its atheroprotective effect remain largely unknown. This study aimed to explore the influence of ICA on lipid accumulation and inflammatory response in THP‐1 macrophage‐derived foam cells. Our results showed that administration of ICA upregulated the expression of miR‐1271‐5p, ATP binding cassette transporter A1 (ABCA1) and ABCG1, downregulated histone deacetylase 9 (HDAC9) expression and inhibited macrophage lipid accumulation. ICA treatment also facilitated macrophage polarisation to the M2 phenotype and alleviated inflammatory response, as evidenced by decreased IL‐6 levels and increased IL‐10 levels. HDAC9 was identified as a direct target of miR‐1271‐5p. HDAC9 overexpression or miR‐1271‐5p knockdown decreased the effect of ICA on ABCA1 and ABCG1 expression as well as inflammatory response. Taken together, these results suggest that ICA can suppress lipid accumulation and mitigate inflammatory response in macrophages by activating the miR‐1271‐5p/HDAC9 signalling cascade, thereby providing new explanations for how ICA reduces atherosclerosis. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulator's histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/β-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair. [ABSTRACT FROM AUTHOR]

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) characterized by its T-follicular helper (TFH) phenotype. Relapsed and refractory disease is common in AITL and often associated with a poor prognosis. The presence of epigenetic abnormalities, immune dysregulation, hyperinflammation and active angiogenesis in AITL offers potential targets for histone deacetylase (HDAC) inhibitors and immunomodulatory drugs (IMiDs). Herein, we present a case of AITL with multiple relapses over a decade. Following intensive chemotherapy and autologous stem cell transplantation (ASCT), the patient relapsed with extensive nodal and extranodal involvement, particularly pulmonary lesions, and subsequently pursued chemo-free treatments. Initially, the patient exhibited a remarkable response to single-agent chidamide, the first oral HDAC inhibitor. Soon after developing resistance to chidamide, continuous treatment with lenalidomide led to an impressive sustained complete remission lasting 64 months, followed by a diminished response for an additional 11 months. Genetic profiling of the patient revealed mutations in KMT2D and ARID1A, along with chromosomal aberrations such as del(5q). Notably, genes commonly mutated in AITL, including RHOA, TET2, DNMT3A, and IDH2, were absent in this case. A review of the literature highlights the heterogeneous genomic landscape of AITL and the diversity of treatment options available, underscoring the importance of tailored approaches to overcome resistance and improve outcomes in this distinct lymphoma subtype. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) enzymes 1–3 exist in several corepressor complexes and are viable drug targets. To date, proteolysis targeting chimeras (PROTACs) designed to target HDAC1–3 typically exhibit the selective degradation of HDAC3. Herein, we report cereblon-recruiting PROTACs that degrade HDAC1 with selectivity over HDAC3. [ABSTRACT FROM AUTHOR]

Summary Lignin, a major wood component, is the key limiting factor for wood conversion efficiency. Its biosynthesis is controlled by transcriptional regulatory networks involving transcription factor (TF)–DNA interactions. However, the epigenetic mechanisms underlying these interactions in lignin biosynthesis remain largely unknown. Here, using yeast one‐hybrid, chromatin immunoprecipitation, and electrophoretic mobility shift assays, we identified that PtrbZIP44‐A1, a key wood‐forming TF, directly interacts with the promoters of PtrCCoAOMT2 and PtrCCR2, genes involved in the monolignol biosynthetic pathway. We used yeast two‐hybrid, bimolecular fluorescence complementation, biochemical analyses, transient and CRISPR‐mediated transgenesis in Populus trichocarpa to demonstrate that PtrHDA15, a histone deacetylase, acts as an epigenetic inhibitor and is recruited by PtrbZIP44‐A1 for chromatin histone modifications to repress PtrCCoAOMT2 and PtrCCR2, leading to reduced lignin deposition. In transgenic lines overexpressing PtrbZIP44‐A1 or PtrHDA15, histone acetylation at the promoters of PtrCCoAOMT2 and PtrCCR2 decreased, reducing their expression and lignin content. Conversely, in loss‐of‐function ptrbzip44‐a1 and ptrhda15 mutants, histone acetylation levels at PtrCCoAOMT2 and PtrCCR2 promoters increased, enhancing target gene expression and lignin content. Our study uncovered an epigenetic mechanism that suppresses lignin biosynthesis. This finding may help fill a knowledge gap between epigenetic regulation and lignin biosynthesis during wood formation in Populus. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the effects of intrabursal administration of cabergoline and N‐acetylcysteine on ovarian hyperstimulation syndrome (OHSS) in an immature rat model. The study assessed body, ovarian, and uterine weights, as well as the concentrations of vascular endothelial growth factor A (VEGF‐A). Moreover, levels of MDA, 4‐HDA, and nitrites were assessed in ovarian homogenates, and vascular permeability was quantified in the peritoneal cavity. Ovarian morphology was characterized using histology and hematoxylin–eosin staining, determining the count of ovarian follicles and corpus luteum. Our results demonstrated a significant increase in lipoperoxidation, nitrite levels, and VEGF‐A concentrations in the OHSS group compared to the control group. These biochemical alterations corroborate the successful induction of OHSS in the experimental model. Direct injection into the ovarian bursa resulted in reduced vascular permeability and VEGF‐A levels, suggesting that the effects of cabergoline are predominantly ovarian. Particularly, cabergoline did not significantly alter other parameters such as ovarian weight, lipoperoxidation, nitrite levels, or morphology. Conversely, low concentrations of N‐acetylcysteine (25–50 µg/kg) significantly reduced ovarian and uterine weights, VEGF‐A levels, and vascular permeability. Interestingly, this dose–response relationship was not observed at higher NAC concentrations (100–200 μg/kg), suggesting a potential threshold beyond which NAC loses efficacy in these specific parameters. Our results suggest that the localized administration of N‐acetylcysteine shows promise as a therapeutic strategy for OHSS by modulating key parameters associated with the syndrome. These promising results warrant further investigation into its mechanisms and efficacy, potentially expanding therapeutic options for OHSS management. [ABSTRACT FROM AUTHOR]

Chromosome movement speeds during anaphase are regulated by depolymerization of microtubules. Several models describe chromosome movement during cell division but none of them consider post-translational modifications of tubulin, even though such modifications help specify microtubules for unique cellular activities. Among these modifications, acetylation of Lysine 40 is one of the common post-translational modifications. Acetylation of microtubules greatly improves their stability, especially when subjected to cooling or drug treatment. Since kinetochore microtubules are acetylated in a variety of eukaryote cells, we wondered whether deacetylation of kinetochore microtubules was necessary in order for microtubules to be able to depolymerize during anaphase. HDAC6 (Histone Deacetylase 6) deacetylates acetylated tubulin. To study whether tubulin must be deacetylated during anaphase, we added to living cells two different HDAC6 inhibitors (Tubacin and Trichostatin A), separately, as chromosomes moved poleward in anaphase. Both HDAC6 inhibitors altered chromosome movement: chromosomes either completely stopped moving, or moved more slowly, or sometimes continued movement without speed changes. The effects of the inhibitors on chromosome movement are reversible: half-bivalents either restarted anaphase movement by themselves before washing out the inhibitor or resumed their poleward movement after the inhibitor was washed out. We suggest that kinetochore microtubules need to be deacetylated in order for normal anaphase movements to occur. [ABSTRACT FROM AUTHOR]

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers. [ABSTRACT FROM AUTHOR]

Acer tegmentosum Maxim (AT) is a medicinal plant used to treat hepatic, neurological diseases, and cancer. However, the beneficial effects of AT on endothelial dysfunction have not been reported yet. In this study, we evaluated the effects of AT and the main compounds against TNF-α-mediated inflammatory responses and their possible mechanism of action. The anti-inflammatory effect and its molecular mechanism were analyzed by adhesion assay, immunoblotting, promoter-luciferase assay, ELISA, RT-PCR, immunocytochemistry, immunoprecipitation, siRNA gene knockdown, docking, and molecular dynamics simulation. AT and its compounds salidroside and tyrosol reduced TNF-α-induced adhesion between monocytes and endothelial cells. Fermentation of AT with Bacillus subtilis converted salidroside to tyrosol, which is salidroside's aglycone. The fermented AT product (ATF) potently inhibited TNF-α-mediated monocyte adhesion with higher potency than AT. AT or ATF abrogated TNF-α-induced expression of adhesion molecules (VCAM-1 and ICAM-1) and production of MCP-1 with the inhibition of phosphorylated MAP kinases. TNF-α-mediated NF-κB transactivation and RelA/p65 acetylation were suppressed by AT and ATF through the interaction of NF-κB with sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase. Sirt1 gene knockdown diminished the protective effects of AT and ATF against TNF-α-mediated signaling and inflammatory response. Interestingly, SIRT1 protein expression was significantly increased by ATF and tyrosol rather than by AT and salidroside, respectively. Molecular docking showed that the tyrosol moiety is critical for the interaction with Glu230 of SIRT1 (PDB ID: 4ZZH and 4ZZJ) for the deacetylase activity. Molecular dynamics revealed that tyrosol can induce the movement of the N-terminal domain toward the catalytic domain of SIRT1. This study demonstrates the potential of AT and ATF to prevent endothelial inflammation and vascular dysfunction of the retina by the MAPK/NF-κB/SIRT1 signaling pathways and targeting of the tyrosol moiety to Glu230 in SIRT1. [ABSTRACT FROM AUTHOR]

Background and Aims: Ulcerative colitis is an inflammatory bowel disease that affects many people worldwide and has extrain-testinal effects. Dextran sulphate sodium (DSS) is a synthetic polysaccharide widely used to model ulcerative colitis in experimental animals. Histone deacetylase (HDAC) inhibitors are molecules that cause changes in gene expression and play a role in many biological events such as inflammatory response formation, cell growth, and differentiation. The aim of this study was to reveal the effects of HDAC inhibitors such as sodium phenylbutyrate (PBA) and suramin on liver morphology, inflammatory mediators, oxidative stress, and antioxidant system in DSS-induced liver injury. Methods: In this study, 48 male C57BL/6 mice were divided into six groups: control mice; mice administered PBA (150 mg/kg/d, intraperitoneally) or suramin (25 mg/kg/d, intraperitoneally) for 7 days; mice administered 3% DSS orally for 5 days; animals treated with PBA and DSS; and mice treated with suramin and DSS. The effects of PBA and suramin on liver histology were examined microscopically; their impacts on antioxidant parameters and oxidative stress were assessed spectrophotometrically; and their influence on COX-2 and TNF-α expressions was analysed by Western blotting in liver tissues of mice administered DSS. Results: DSS application resulted in extensive necrosis, increased lipid peroxidation levels, and myeloperoxidase activity, as well as decreased GSH levels and SOD activities in liver tissues. It also increased COX-2 and TNF-α expressions in DSS-induced liver toxicity. PBA or suramin treatment prevented liver injury by mitigating the effects of DSS. Conclusion: This study showed that PBA and suramin have cytoprotective, anti-inflammatory, and antioxidant effects on DSS-induced hepatotoxicity. Consequently, HDAC inhibitors such as PBA and suramin may be considered effective prophylactic and therapeutic agents against DSS-induced liver injury. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancers are the seventh-most common cancers worldwide, with reported incidence of ~800,000 cases per year worldwide. Radiotherapy remains an important treatment for the disease, although cancer resistance remains a common problem. We performed a drug screen to identify those that can enhance the sensitivity of head and neck cancer models to radiotherapy. We identified that specific drugs (mocetinostat, CUDC-101, and pracinostat) can cause more effective cell killing of head and neck cancer cells grown in both 2D and 3D, and hold promise as more effective treatments for patients in the clinic. Background/Objectives: The incidence of head and neck squamous cell carcinoma (HNSCC), currently ~800,000 cases per year worldwide, is rising. Radiotherapy remains a mainstay for the treatment of HNSCC, although inherent radioresistance, particularly in human papillomavirus (HPV)-negative disease subtypes, remains a significant barrier to effective treatment. Therefore, combinatorial strategies using drugs or inhibitors against specific cellular targets are necessary to enhance HNSCC radiosensitivity to lead to an improvement in patient outcomes. Given that radiotherapy acts through targeting and damaging DNA, a common strategy is to focus on enzymes within DNA-dependent cellular pathways, such as DNA damage repair. Methods: Here, we have employed a 3D spheroid model of HNSCC (FaDu) in combination with a targeted drug screen to identify novel radiosensitisers that suppress tumour growth. Results: We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC–epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. Conclusions: We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes. [ABSTRACT FROM AUTHOR]

Background: Hericium erinaceus mycelium and its constituents, erinacines A and S, have shown neuroprotective effects in APP/PS1 transgenic mice; however, the precise mechanisms by which they modulate microglial phenotypes remain unclear. Our study is the first to explore the effect of erinacines on microglia morphology and the underlying mechanisms using a novel primary mixed glia cell model and advanced bioinformatic tools. Furthermore, we emphasize the clinical relevance by evaluating erinacines in a metabolically stressed APP/PS1 mouse model, which more accurately reflects the complexities of human Alzheimer's disease (AD), where metabolic syndrome is a common comorbidity. Methods: Rat primary mixed glial cultures were used to simulate the spectrum of microglial phenotypes, particularly the transition from immature to mature states. Microarray sequencing, along with Connectivity Map, ConsensusPathDB, and Gene Set Enrichment Analysis, identified pathways influenced by erinacines. The therapeutic efficacy was further evaluated in metabolically stressed APP/PS1 mice. Results: Erinacines significantly promoted the development of a ramified, neuroprotective microglial phenotype. Bioinformatics revealed potential modulation of microglia via histone deacetylase inhibition, actin filament dynamics, and synaptic structure modification—pathways not previously linked to erinacines in AD. Importantly, erinacines significantly lower fasting blood glucose and insulin levels while reducing amyloid‐beta plaque burden, suppressing hyperactivated glial responses, and enhancing neurogenesis in the metabolically stressed APP/PS1 mice. Conclusion: Our findings demonstrate the dual action of erinacines in modulating microglia morphology and phenotype while providing neuroprotection in a model that closely mimic the complexities of human Alzheimer's disease. Additionally, this study provides the foundation for understanding the potential mechanisms of action of erinacines, highlighting their promise as a novel treatment approach for Alzheimer's, particularly in cases complicated by metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are enzymes that play an essential role in the onset and progression of cancer. As a consequence, a variety of HDAC inhibitors (HDACis) have been developed as potent anticancer agents, several of which have been approved by the FDA for cancer treatment. However, recent accumulated research results have suggested that HDACs are also involved in several other pathophysiological conditions, such as fibrotic, inflammatory, neurodegenerative, and autoimmune diseases. Very recently, the HDAC inhibitor givinostat has been approved by the FDA for an indication beyond cancer: the treatment of Duchenne muscular dystrophy. In recent years, more and more HDACis have been developed as tools to understand the role that HDACs play in various disorders and as a novel therapeutic approach to fight various diseases other than cancer. In the present perspective article, we discuss the development and study of HDACis as anti-fibrotic and anti-inflammatory agents, covering the period from 2020–2024. We envision that the discovery of selective inhibitors targeting specific HDAC isozymes will allow the elucidation of the role of HDACs in various pathological processes and will lead to the development of promising treatments for such diseases. [ABSTRACT FROM AUTHOR]

Patients carrying APOL1 risk alleles (G1 and G2) have a higher risk of developing Focal Segmental Glomerulosclerosis (FSGS); we hypothesized that escalated levels of miR193a contribute to kidney injury by activating renin–angiotensin system (RAS) in the APOL1 milieus. Differentiated podocytes (DPDs) stably expressing vector (V/DPD), G0 (G0/DPDs), G1 (G1/DPDs), and G2 (G2/DPDs) were evaluated for renin, Vitamin D receptor (VDR), and podocyte molecular markers (PDMMs, including WT1, Podocalyxin, Nephrin, and Cluster of Differentiation [CD]2 associated protein [AP]). G0/DPDs displayed attenuated renin but an enhanced expression of VDR and Wilms Tumor [WT]1, including other PDMMs; in contrast, G1/DPDs and G2/DPDs exhibited enhanced expression of renin but decreased expression of VDR and WT1, as well as other PDMMs (at both the protein and mRNA levels). G1/DPDs and G2/DPDs also showed increased mRNA expression for Angiotensinogen and Angiotensin II Type 1 (AT1R) and 2 (AT2R) receptors. Protein concentrations of Brain Acid-Soluble Protein [BASP]1, Enhancer of Zeste Homolog [EZH]2, Histone Deacetylase [HDAC]1, and Histone 3 Lysine27 trimethylated [H3K27me3] in WT1-IP (immunoprecipitated proteins with WT1 antibody) fractions were significantly higher in G0/DPDs vs. G1/DPD and G2/DPDs. Moreover, DPD-silenced BASP1 displayed an increased expression of renin. Notably, VDR agonist-treated DPDs showed escalated levels of VDR and a higher expression of PDMMs, but an attenuated expression of renin. Human Embryonic Kidney (HEK) cells transfected with increasing APOL1(G0) plasmid concentrations showed a corresponding reduction in renin mRNA expression. Bioinformatics studies predicted the miR193a target sites in the VDR 3′UTR (untranslated region), and the luciferase assay confirmed the predicted sites. As expected, podocytes transfected with miR193a plasmid displayed a reduced VDR and an enhanced expression of renin. Renal cortical section immunolabeling in miR193a transgenic (Tr) mice showed renin-expressing podocytes. Kidney tissue extracts from miR193aTr mice also showed reduced expression of VDR and PDMMs, but enhanced expression of Renin. Blood Ang II levels were higher in miR193aTr, APOLG1, and APOL1G1/G2 mice when compared to control mice. Based on these findings, miR193a regulates the activation of RAS and podocyte molecular markers through modulation of VDR and WT1 in the APOL1 milieu. [ABSTRACT FROM AUTHOR]

Intervertebral discs (IVDs) are rhythmic tissues that experience daily low‐load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia‐induced disordered metabolism. Meanwhile, Rev‐erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev‐erbα expression levels and IVD degeneration. Rev‐erbα deficiency accelerated needle puncture or aging‐induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev‐erbα knockdown in NP cells aggravated rhIL1β‐induced NOD‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev‐erbα deficiency and needle puncture‐induced IVD degeneration. Particularly, Rev‐erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme‐binding of nuclear receptor co‐repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev‐erbα in NP cells following short‐term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev‐erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev‐erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases. [ABSTRACT FROM AUTHOR]

Background: Histone deacetylase 4 (HDAC4) is a member of the class II histone deacetylase family, whose members play a crucial role in various biological processes. An in-depth investigation of the transcriptional characteristics of chicken HDAC4 can provide fundamental insights into its function. Methods: We examined HDAC4 expression in chicken embryonic stem cells (ESC) and spermatogonial stem cells (SSC) and cloned a 444 bp fragment from upstream of the chicken HDAC4 transcription start site. Subsequently, we constructed pEGFP-HDAC4 and a series of 5′-deletion luciferase reporter constructs, which we transfected into DF-1 cells to measure their transcriptional activity. The regulatory mechanisms of chicken HDAC4 expression were investigated by performing trichostatin A (TSA) treatment, deleting putative transcription factor binding sites, and altering transcription factor expression levels. Results: HDAC4 exhibited higher expression in SSC than in ESC. We confirmed that the upstream region from −295 bp to 0 bp is the core transcriptional region of HDAC4. TSA effectively inhibited HDAC4 transcription, and bioinformatics analysis indicated that the chicken core HDAC4 promoter sequence exhibits high homology with those of other avian species. The myelocytomatosis viral oncogene homolog (MYC) and hypoxia-inducible factor 1 α (HIF1A) transcription factors were predicted to bind to this core region. Treatment with TSA for 24 h resulted in the upregulation of MYC and HIF1A, which repressed HDAC4 transcription. Conclusions: Our results provide a basis for subsequent investigations into the regulation of HDAC4 expression and biological function. [ABSTRACT FROM AUTHOR]