Histone Deacetylase Research Articles

Different Short-Chain Fatty Acids Unequally Modulate Intestinal Homeostasis and Reverse Obesity-Related Symptoms in Lead-Exposed High-Fat Diet Mice.

Our previous study showed that heavy metal lead (Pb) exposure exacerbates high-fat-diet (HFD)-induced metabolic damage and significantly depletes the gut microbiota-derived metabolite short-chain fatty acid (SCFA) levels. However, it remains unclear whether SCFA is a key metabolite involved in accelerating adverse consequences after Pb exposure. In this study, we explored the effects of exogenous supplementation of acetate, propionate, and butyrate on a metabolic disorder model in Pb-exposed HFD mice. We found that three SCFA interventions attenuated glycolipid metabolism disorders and liver damage, with butyrate performing the best effects in improving obesity-related symptoms. All three SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion of SCFA production forming a virtuous cycle. Besides, butyrate inhibited Gram-negative bacteria Escherichia-Shigella. All of these events alleviated the intestinal Th17/Treg imbalance and inflammatory response through crosstalk between the G protein-coupled receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide (LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB) pathways and ultimately improved the intestinal barrier function. SCFA further upregulated the monocarboxylate transporter 1 (MCT1) and GPR43/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA, especially butyrate, is an effective modulator to improve metabolic disorders in obese individuals exposed to heavy metals by targeting gut microecology.

Predicting the efficiency of chidamide in patients with angioimmunoblastic T-cell lymphoma using machine learning algorithm.

Chidamide is subtype-selective histone deacetylase (HDAC) inhibitor that showed promising result in clinical trials to improve prognosis of angioimmunoblastic T-cell lymphoma (AITL) patients. However, in real world settings, contradictory reports existed as to whether chidamide improve overall survival (OS). Therefore, we aimed to develop an interpretable machine learning (Machine learning)-based model to predict the 2-year overall survival of AITL patients based on chidamide usage and baseline features. A total of 183 patients with AITL were randomly divided into training set and testing set. We used 5ML algorithms to build predictive models. Recursive feature elimination (RFE) method was used to filter for the most important features. The ML models were interpreted and the relevance of the selected features was determined using the Shapley additive explanations (SHAP) method and the local interpretable model-agnostic explanationalgorithm. A total of 183 patients with newly diagnosed AITL from 2012 to 2022 from 3 centers in China were enrolled in our study. Seventy-one patients were dead within 2years after diagnosis. Five ML algorithms were built based on chidamide usage and 16 baseline features to predict 2-year OS. Catboost model presented to be the best predictive model. After RFE screening, 12 variables demonstrated the best performance (AUC = 0.8651). Using chidamide ranked third among all the variables that correlated with 2-year OS. This study demonstrated that the Catboost model with 12 variables could effectively predict the 2-year OS of AITL patients. Combining chidamide in the treatment therapy was positively correlated with longer OS of AITL patients.

Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer.

How dysregulated liquid-liquid phase separation (LLPS) contributes to the oncogenesis of female triple-negative breast cancer (TNBC) remains unknown. Here we demonstrate that phosphorylated histone deacetylase 6 (phospho-HDAC6) forms LLPS condensates in the nuclei of TNBC cells that are essential for establishing aberrant chromatin architecture. The disordered N-terminal domain and phosphorylated residue of HDAC6 facilitate effective LLPS, whereas nuclear export regions exert a negative dominant effect. Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth. Mechanistically, importin-β interacts with phospho-HDAC6, promoting its translocation to the nucleus, where 14-3-3θ mediates the condensate formation. Disruption of phospho-HDAC6 LLPS re-established chromatin compartments and topologically associating domain boundaries, leading to disturbed chromatin loops. The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression.

Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II, IV, and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine. Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.

Omega-3 polyunsaturated fatty acids alleviate endoplasmic reticulum stress-induced neuroinflammation by protecting against traumatic spinal cord injury through the histone deacetylase 3/ peroxisome proliferator-activated receptor-γ coactivator pathway.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) attenuate inflammatory responses in the central nervous system, leading to neuroprotective effects. Inhibition of histone deacetylase 3 (HDAC3) has neuroprotective effects after spinal cord injury (SCI) through the SIRT1 pathway, but the pathophysiological mechanisms of SCI are complex and the interactions between ω-3 PUFAs and organelles remain largely unknown. This study aimed to investigate the effect of ω-3 PUFAs on endoplasmic reticulum (ER) stress-induced neuroinflammation through the HDAC3/peroxisome proliferator-activated receptor-γ coactivator (PGC)-1ɑ pathway after SCI. To this end, a contusion-induced SCI rat model was established to evaluate the effects of ω-3 PUFAs on ER stress-mediated inflammation in SCI. ER stress was rapidly induced in spinal cord lesions after SCI and was significantly reduced after ω-3 PUFA treatment. Consistent with reduced ER stress, HDAC3 expression levels and inflammatory responses were decreased, and PGC-1ɑ expression levels were increased after SCI. We found that ω-3 PUFA treatment attenuated ER stress through HDAC3 inhibition, thereby reducing SCI-induced inflammation. Taken together, these results suggest a role for ω-3 PUFA in protecting against SCI-induced neuroinflammation and promoting neurological functional recovery by regulating the histone deacetylase 3/ peroxisome proliferator-activated receptor-γ coactivatorpathway.

Novel and recurrent hemizygous variants in BCORL1 cause oligoasthenoteratozoospermia by interfering transcription.

Oligoasthenoteratozoospermia (OAT) is a common cause of male infertility, of which the causes remain largely unknown. Recently, BCORL1 was identified as a contributor to male infertility from non-obstructive azoospermia (NOA) to OAT. To identify novel and hotspot variants in BCORL1 from infertile men with OAT and reveal their outcomes of assisted reproductive treatments (ARTs). Forty-six infertile men characterized by OAT were recruited from 2017 to 2022. Variants in OAT patients were identified by whole-exome sequencing (WES) and verified by Sanger sequencing. Papanicolaou staining was used for sperm morphology analysis. Pathogenicity of BCORL1 variants were analyzed by bioinformatics analysis, and further confirmed in vitro by using recombinant plasmids and cells. Meanwhile, ARTs were performed on these patients to investigate the appropriate clinical treatment strategy. We identified a novel hemizygous missense variant (NM_021946: c.G4171A; p.G1391R) and a recurrent variant (NM_021946: c.T2615G; p.V872G) in BCORL1 from four OAT patients. Notably, routine semen assessment and Papanicolaou staining revealed a special OAT phenotype of patients with BCORL1 variants, whose rare mature sperm characterized by acephalic and abnormal acrosome. Pathogenicity analysis showed the interaction between BCORL1 with histone deacetylases (HDACs) were disrupted after variance, accompanied with epigenetic alterations and finally the orderly transcriptions of spermatogenetic genes were interfering. Besides, clinical record presented the poor outcomes of ARTs in these patients with BCORL1 variants. Our findings further expand the variant spectrum of BCORL1 related to OAT, and provide new evidences that BCORL1 acts as an important transcriptional regulator, participating in epigenetic regulation and directing the expression of key genes throughout spermatogenesis. The outcomes of ARTs will facilitate the genetic counseling and clinical treatment of infertile men with BCORL1 variants in the future.

SAHA potentiates the activity of repurposed drug promethazine loaded PLGA nanoparticles in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is considered the most aggressive form of breast cancer owing to the negative expression of targetable bioreceptors. Epithelial to mesenchymal transition (EMT) associated with metastatic abilities is its critical feature. As an attempt to target TNBC, nanotechnology was utilised to augment the effects of drug repurposing. Concerning that, a combination therapeutic module was structured with one of the aspects being a repurposed antihistamine, promethazine hydrochloride loaded PLGA nanoparticles. The as-synthesized nanoparticles were 217 nm in size and fluoresced at 522 nm, rendering them suitable for theranostic applications too. The second feature of the module was a common histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), used as a form of pre-treatment. Experimental studies demonstrated efficient cellular internalisation and significant innate anti-proliferative potential. The use of SAHA sensitised the cells to the drug loaded nanoparticle treatment. Mechanistic studies showed increase in ROS generation, mitochondrial dysfunction followed by apoptosis. Investigations into protein expression also revealed reduction of mesenchymal proteins like vimentin by 1.90 fold; while increase in epithelial marker like E-Cadherin by 1.42 fold, thus indicating an altered EMT dynamics. Further findings also provided better insight into the benefits of SAHA potentiated targeting of tumor spheroids that mimic solid tumors of TNBC. Thus, this study paves the avenue to a more rational translational validation of combining nanotherapeutics with drug repurposing.

TRIP13 regulates progression of gastric cancer through stabilising the expression of DDX21

GC (Gastric cancer) is one of the most common malignant tumours, with over 95% of gastric cancer patients being adenocarcinoma and most gastric cancer patients having no apparent symptoms in the early stages. Finding biomarkers for early screening of gastric cancer and exploring new targets for gastric cancer treatment are urgent problems to be solved in the treatment of gastric cancer, with significant clinical outcomes for the survival rate of gastric cancer patients. The AAA+ family ATPase thyroid hormone receptor-interacting protein 13 (TRIP13) has been reported to play an essential role in developing various tumours. However, the biological function and molecular mechanism of TRIP13 in gastric cancer remain unclear. This study confirms that TRIP13 is highly expressed in gastric cancer tissue samples and that TRIP13 participates in the proliferation, migration, invasion in vitro, and tumourigenesis and metastasis in vivo of gastric cancer cells. Mechanistically, this study confirms that TRIP13 directly interacts with DDX21 and stabilises its expression by restraining its ubiquitination degradation, thereby promoting gastric cancer progression. Additionally, histone deacetylase 1 (HDAC1) is an upstream factor of TRIP13, which could target the TRIP13 promoter region to promote the proliferation, migration, and invasion of gastric cancer cells. These results indicate that TRIP13 serve is a promising biomarker for the treating of gastric cancer patients, and the HDAC1-TRIP13/DDX21 axis might provide a solid theoretical basis for clinical treatment of gastric cancer patients.

TSA attenuates the progression of c-Myc-driven hepatocarcinogenesis by pAKT-ADH4 pathway

Hepatocellular carcinoma (HCC) is the primary malignant tumor of the liver. c-Myc is one of the most common oncogenes in clinical settings, and amplified levels of c-Myc are frequently found in HCC. Histone deacetylase inhibitors (HDACi), such as Trichostatin A (TSA), hold enormous promise for the treatment of HCC. However, the potential and mechanism of TSA in the treatment of c-Myc-induced HCC are unclear. In this study, we investigated the effects of TSA treatment on a c-Myc-induced HCC model in mice. TSA treatment delayed the development of HCC, and liver function indicators such as ALT, AST, liver weight ratio, and spleen weight ratio demonstrated the effectiveness of TSA treatment. Oil red staining further demonstrated that TSA attenuated lipid accumulation in the HCC tissues of mice. Through mRNA sequencing, we identified that TSA mainly affected cell cycle and fatty acid degradation genes, with alcohol dehydrogenase 4 (ADH4) potentially being the core molecular downstream target. QPCR, immunohistochemistry, and western blot analysis revealed that ADH4 expression was repressed by c-Myc and restored after TSA treatment both in vitro and in vivo. Furthermore, we observed that the levels of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration increased after c-Myc transfection in liver cells but decreased after TSA intervention. The levels of phosphorylated protein kinase B (p-AKT) and p-mTOR were identified as targets regulated by TSA, and they governed the ADH4 expression and the downstream regulation of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration. Overall, our study suggests that TSA has a therapeutic effect on c-Myc-induced HCC through the AKT-mTOR-ADH4 pathway. These findings provide valuable insights into the potential treatment of HCC using TSA and shed light on the underlying molecular mechanisms involved.

Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations.

Breast and ovarian cancers pose significant therapeutic challenges. We explored the synergistic cytotoxicity of histone deacetylase inhibitors (HDACis), poly(ADP-ribose) polymerase inhibitors (PARPis), and decitabine in breast (MDA-MB-231 and MCF-7) and ovarian (HEY-T30 and SKOV-3) cancer cell lines that were exposed to HDACi (panobinostat or vorinostat), PARPi (talazoparib or olaparib), decitabine, or their combinations. HDACi, PARPi, and decitabine combinations had synergistic cytotoxicity (assessed by MTT and clonogenic assays) in all cell lines (combination index < 1). Clonogenic assays confirmed the sensitivity of breast and ovarian cancer cell lines to the three-drug combinations (panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine; vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine). Cell proliferation was inhibited by 48-70%, and Annexin V positivity was 42-59% in all cell lines exposed to the three-drug combinations. Western blot analysis showed protein PARylation inhibition, caspase 3 and PARP1 cleavage, and c-MYC down-regulation. The three-drug combinations induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs, impaired the DNA repair pathways, and altered the epigenetic regulation of gene expression. These results indicate that HDACi, PARPi, and decitabine combinations should be further explored in these tumor types. Further clinical validation is warranted to assess their safety and efficacy.

Stack-HDAC3i: A high-precision identification of HDAC3 inhibitors by exploiting a stacked ensemble-learning framework

Epigenetics involves reversible modifications in gene expression without altering the genetic code itself. Among these modifications, histone deacetylases (HDACs) play a key role by removing acetyl groups from lysine residues on histones. Overexpression of HDACs is linked to the proliferation and survival of tumor cells. To combat this, HDAC inhibitors (HDACi) are commonly used in cancer treatments. However, pan-HDAC inhibition can lead to numerous side effects. Therefore, isoform-selective HDAC inhibitors, such as HDAC3i, could be advantageous for treating various medical conditions while minimizing off-target effects. To date, computational approaches that use only the SMILES notation without any experimental evidence have become increasingly popular and necessary for the initial discovery of novel potential therapeutic drugs. In this study, we develop an innovative and high-precision stacked-ensemble framework, called Stack-HDAC3i, which can directly identify HDAC3i using only the SMILES notation. Using an up-to-date benchmark dataset, we first employed both molecular descriptors and Mol2Vec embeddings to generate feature representations that cover multi-view information embedded in HDAC3i, such as structural and contextual information. Subsequently, these feature representations were used to train baseline models using nine popular ML algorithms. Finally, the probabilistic features derived from the selected baseline models were fused to construct the final stacked model. Both cross-validation and independent tests showed that Stack-HDAC3i is a high-accuracy prediction model with great generalization ability for identifying HDAC3i. Furthermore, in the independent test, Stack-HDAC3i achieved an accuracy of 0.926 and Matthew’s correlation coefficient of 0.850, which are 0.44–6.11% and 0.83–11.90% higher than its constituent baseline models, respectively.

Systematic Analysis of the BrHAT Gene Family and Physiological Characteristics of Brassica rapa L. Treated with Histone Acetylase and Deacetylase Inhibitors under Low Temperature.

Brassica rapa L. is an important overwintering oilseed crop in Northwest China. Histone acetyltransferases (HATs) play an important role in epigenetic regulation, as well as the regulation of plant growth, development, and responses to abiotic stresses. To clarify the role of histone acetylation in the low-temperature response of B. rapa L., we identified 29 HAT genes in B. rapa L. using bioinformatics tools. We also conducted a comprehensive analysis of the physicochemical properties, gene structure, chromosomal localization, conserved structural domains and motifs, cis-acting regulatory elements, and evolutionary relationships of these genes. Using transcriptome data, we analyzed the expression patterns of BrHAT family members and predicted interactions between proteins; the results indicated that BrHATs play an important role in the low-temperature response of B. rapa L. HAT inhibitor (curcumin; CUR) and histone deacetylase inhibitor (Trichostatin A; TSA) were applied to four B. rapa L. varieties varying in cold resistance under the same low-temperature conditions, and changes in the physiological indexes of these four varieties were analyzed. The inhibitor treatment attenuated the effect of low temperature on seed germination, and curcumin treatment was most effective, indicating that the germination period was primarily regulated by histone acetylase. Both inhibitor treatments increased the activity of protective enzymes and the content of osmoregulatory substances in plants, suggesting that histone acetylation and deacetylation play a significant role in the response of B. rapa L. to low-temperature stress. The qRT-PCR analyses showed that the expression patterns of BrHATs were altered under different inhibitor treatments and low-temperature stress; meanwhile, we found three significantly differentially expressed genes. In sum, the process of histone acetylation is involved in the cold response and the BrHATs gene plays a role in the cold stress response.

Novel CAR-T Cells Specifically Targeting SIA-CIgG Demonstrate Effective Antitumor Efficacy in Bladder Cancer.

Chimeric Antigen Receptor (CAR) T-cell therapy is a promising cancer treatment method. However, its application in bladder cancer (BC) remains limited, partially because of the absence of appropriate target molecules. Sialylated cancer-derived IgG (SIA-CIgG) is highly expressed in BC and is closely associated with malignant biological behavior. However, its potential as a target for CAR-T cell therapy to treat BC is yet to be established. Here, it is found that SIA-CIgG is highly expressed in most BC samples but displayed limited expression in normal tissues. CAR-T cells specifically targeting SIA-CIgG can effectively lyse BC cells and the cytotoxicity depends on SIA-CIgG expression. Furthermore, SIA-CIgG CAR-T cells demonstrate milder tumor cell lysis and enhanced persistence compared with human epidermal growth factor receptor 2 (HER2) CAR-T cells, which have undergone extensive clinical trials. After repeated tumor antigen challenges, SIA-CIgG CAR-T cells display substantial alterations in both the transcriptome and chromatin accessibility. When combining SIA-CIgG CAR-T cell therapy with FDA-approved drugs to treat BC, the histone deacetylase inhibitor (HDACi), vorinostat, is found to enhance the ablility of CAR-T cells for tumor cell lysis. Therefore, the combination of SIA-CIgG CAR-T cells and vorinostat is promising for BC treatment.

Cotton Pectate Lyase GhPEL48_Dt Promotes Fiber Initiation Mediated by Histone Acetylation.

GhPEL48_Dt, a Pectate lyase (PEL, EC4.2.2.2), is a crucial enzyme involved in cell-wall modification and pectin degradation. Studies have shown that the GhPEL48_Dt also plays a significant role in cotton-fiber development; however, the specific function and regulatory mechanism of GhPEL48_Dt in cotton-fiber development are still not fully understood. Here, we found that the histone deacetylase inhibitor-Trichostatin A significantly reduces the transcript levels of GhPEL48_Dt and its enzyme activity. Further, silencing of GhPEL48_Dt significantly inhibits the initiation and elongation of cotton fibers by promoting pectin degradation, and the heterologous expression of GhPEL48_Dt promotes the development of trichomes and root hairs in Arabidopsis, which suggests that GhPEL48_Dt plays a positive and conserved role in single cell i.e., fiber, root hair, and leaf trichome development. Collectively, this paper provides a comprehensive analysis of the fundamental characteristics and functions of GhPEL48_Dt in fiber development, including the regulatory role of histone acetylation on GhPEL48_Dt, which contributes to the understanding of pectin degradation pathways and establishes a theoretical foundation for elucidating its regulatory mechanism.

Renal Fibrosis: SIRT1 Still of Value.

Chronic kidney disease (CKD) is a major global health concern. Renal fibrosis, a prevalent outcome regardless of the initial cause, ultimately leads to end-stage renal disease. Glomerulosclerosis and renal interstitial fibrosis are the primary pathological features. Preventing and slowing renal fibrosis are considered effective strategies for delaying CKD progression. However, effective treatments are lacking. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase belonging to class III histone deacetylases, is implicated in the physiological regulation and protection of the kidney and is susceptible to a diverse array of pathological influences, as demonstrated in previous studies. Interestingly, controversial conclusions have emerged as research has progressed. This review provides a comprehensive summary of the current understanding and advancements in the field; specifically, the biological roles and mechanisms of SIRT1 in regulating renal fibrosis progression. These include aspects such as lipid metabolism, epithelial-mesenchymal transition, oxidative stress, aging, inflammation, and autophagy. This manuscript explores the potential of SIRT1 as a therapeutic target for renal fibrosis and offers new perspectives on treatment approaches and prognostic assessments.

Effective enhancement of the ability of Monascus pilosus to produce lipid-lowering compound Monacolin K via perturbation of metabolic flux and histone acetylation modification

Monacolin K (MK), also known as lovastatin, is a polyketide compound with the ability to reduce plasma cholesterol levels and many other bio-activities. Red yeast rice (also named Hongqu) rich in MK derived from Monascus fermentation has attracted widespread attention due to its excellent performance in reducing blood lipids. However, industrial Monascus fermentation suffers from the limitations such as low yield of MK, long fermentation period, and susceptibility to contamination. In this study, we firstly blocked the competitive pathway of MK biosynthesis to create polyketide synthase gene pigA (the key gene responsible for the biosynthesis of Monascus azaphilone pigments) deficient strain A1. Then, based on the strategies to increase precursor supply for MK biosynthesis, acetyl-CoA carboxylase gene acc overexpression strains C1 and C2 were constructed with WT and A1 as the parent, respectively. Finally, histone deacetylase gene hos2 overexpression strain H1 was constructed by perturbation of histone acetylation modification. HPLC detection revealed all these four strains significantly increased their abilities to produce MK. After 14 days of solid-state fermentation, the MK yields of strains A1, C1, C2, and H1 reached 2.03 g/100 g, 1.81 g/100 g, 2.45 g/100 g and 2.52 g/100 g, which increased by 28.5 %, 14.7 %, 43.9 % and 36.1 % compared to WT, respectively. RT-qPCR results showed that overexpression of hos2 significantly increased the expression level of almost all genes responsible for MK biosynthesis after 5-day growth. Overall, the abilities of these strains to produce MK has been greatly improved, and MK production period has been shortened to 14 days from 20 days, providing new approaches for efficient production of Hongqu rich in MK.

Design and Synthesis of c-Met and HDAC Dual Inhibitors for the Treatment of Breast Cancer.

In recent years, it has been proposed that c-mesenchymal-to-epithelial transition factor (c-Met) and histone deacetylase (HDAC) dual inhibition is a promising cancer treatment strategy. Herein, a series of c-Met/HDAC dual inhibitors were designed and synthesized given their synergistic anticancer effect in breast cancer cells. Compound 12d exhibited excellent inhibitory activity against c-Met (IC50 = 28.92 nM) and HDAC (85.68%@1000 nM) and inhibited the proliferation of all three breast cancer cell lines. Moreover, a mechanism investigation demonstrated that 12d could simultaneously induce cell cycle arrest in the G0/G1 phase and cell apoptosis in MDA-MB-231 cells, which was endorsed by c-Met and HDAC pathway blockade. It could also suppress cell invasion. Our results suggest that developing promising c-Met/HDAC dual inhibitors is a novel strategy for breast cancer therapy.

Histone deacetylase inhibition expands cellular proteostasis repertoires to enhance neuronal stress resilience.

Neurons are long-lived, terminally differentiated cells with limited regenerative capacity. Cellular stressors such as endoplasmic reticulum (ER) protein folding stress and membrane trafficking stress accumulate as neurons age and accompany age-dependent neurodegeneration. Current strategies to improve neuronal resilience are focused on using factors to reprogram neurons or targeting specific proteostasis pathways. We discovered a different approach. In an unbiased screen for modifiers of neuronal membrane trafficking defects, we unexpectedly identified a role for histone deacetylases (HDACs) in limiting cellular flexibility in choosing cellular pathways to respond to diverse types of stress. Genetic or pharmacological inactivation of HDACs resulted in improved neuronal health in response to ER protein folding stress and endosomal membrane trafficking stress in C. elegans and mammalian neurons. Surprisingly, HDAC inhibition enabled neurons to activate latent proteostasis pathways tailored to the nature of the individual stress, instead of generalized transcriptional upregulation. These findings shape our understanding of neuronal stress responses and suggest new therapeutic strategies to enhance neuronal resilience.

MiRNA-449 family is epigenetically repressed and sensitizes to doxorubicin through ACSL4 downregulation in triple-negative breast cancer

Despite progress in breast cancer treatment, a significant portion of patients still relapse because of drug resistance. The involvement of microRNAs in cancer progression and chemotherapy response is well established. Therefore, this study aimed to elucidate the dysregulation of the microRNA-449 family (specifically, microRNA-449a, microRNA-449b-5p, and microRNA-449c-5p) and its impact on resistance to doxorubicin, a commonly used chemotherapeutic drug for the treatment of triple-negative breast cancer. We found that the microRNA-449 family is downregulated in triple-negative breast cancer and demonstrated its potential as a diagnostic biomarker. Besides, our findings indicate that the downregulation of the microRNA-449 family is mediated by the microRNAs-449/SIRT1-HDAC1 negative feedback loop. Moreover, it was found that the microRNA-449 family dysregulates the fatty acid metabolism by targeting ACSL4, which is a potential prognostic biomarker that mediates doxorubicin response through regulation of the drug extrusion pump ABCG2. Altogether, our results suggest that the microRNA-449 family might be a potential therapeutic target for the treatment of triple-negative breast cancer since it is implicated in doxorubicin response through ACSL4/ABCG2 axis regulation. Ultimately, our results also highlight the value of microRNAs-449 and ACSL4 as diagnostic and prognostic biomarkers in triple-negative breast cancer.Proposed model of miRNAs-449 downregulation in TNBC and doxorubicin response. MiRNAs-449 are downregulated in TNBC through a negative feedback loop with SIRT1 and HDAC1. Moreover, ACSL4 increases ABCG2 expression, thus diminishing the intracellular doxorubicin concentration and promoting doxorubicin resistance. MiRNAs-449 overexpression downregulates the ACSL4/ABCG2 axis and sensitizes doxorubicin-resistant cells to doxorubicin. Created with BioRender. TNBC: triple-negative breast cancer; DOX: doxorubicin; SIRT1: Sirtuin 1; HDAC1: Histone deacetylase 1; ACSL4: Acyl-CoA Synthetase Long-Chain Family Member 4; ABCG2: ATP-binding cassette superfamily G member 2.