The Current State of Charcot–Marie–Tooth Disease Treatment

Genes, Год журнала: 2023, Номер 14(7), С. 1391 - 1391

Опубликована: Июль 1, 2023

Charcot-Marie-Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts peripheral nerves causes lifelong disability, presents a significant barrier to development comprehensive treatments. An estimated 100 loci within human genome linked various forms CMT its related inherited neuropathies. This review delves into prospective therapeutic strategies used for frequently encountered variants, namely CMT1A, CMT1B, CMTX1, CMT2A. Compounds such as PXT3003, being clinically preclinically investigated, broad array agents their corresponding mechanisms discussed. Furthermore, progress in established gene therapy techniques, including replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, knockdown, appraised. Each these therapies has potential substantial advancements future research.

Язык: Английский

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HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy

Cancer Immunology Immunotherapy, Год журнала: 2024, Номер 73(1)

Опубликована: Янв. 1, 2024

Abstract The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit growth variety tumor. We previously revealed that HDAC family highly expressed in colorectal specimens and mouse models. In this study, was combined anti-PD1 treat tumor-bearing mice associated cancer. effectively inhibited tumor growth. expression PD-L1 were by treatment, whereas some biomarkers reflecting T cell activation upregulated. co-culture system cells cells, helped kill cells. Mechanically, HDAC6 enhanced acetylation STAT1 phosphorylation STAT1, thus preventing from entering nucleus activate transcription. This study reveals novel regulatory mechanism on non-histone substrates, especially protein acetylation. may be great significance immunotherapy related strategies.

Язык: Английский

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Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options

Journal of Pain Research, Год журнала: 2024, Номер Volume 17, С. 1005 - 1028

Опубликована: Март 1, 2024

Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that often misdiagnosed undertreated. The management painful DPN involves treating its underlying cause via lifestyle modifications intensive glucose control, targeting pathogenesis, providing symptomatic pain relief, thereby improving patient function health-related quality life. Four pharmacologic options are currently approved by the US Food Drug Administration (FDA) to treat DPN. These include three oral medications (duloxetine, pregabalin, tapentadol extended release) one topical agent (capsaicin 8% system). More recently, FDA several spinal cord stimulation (SCS) devices refractory Although not FDA-approved specifically DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, sodium channel blockers common first-line in clinical practice. Other strategies may be used as part individualized comprehensive plans. This article provides an overview most recent guidelines for managing with focus on two recently treatment (SCS capsaicin system), well evidence using guideline-supported drugs devices. Also discussed unmet needs this population, potential future treatments including novel mechanisms action, electrical devices, nutraceuticals.

Язык: Английский

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The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy

Science Advances, Год журнала: 2024, Номер 10(46)

Опубликована: Ноя. 15, 2024

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had effect in SM1 melanoma CT26 colon cancer models efficacy of anti–programmed cell death protein 1 treatment, leading to complete remission response cancer. treatment tumor-infiltrating macrophages CD8 effector T cells inflammatory gene signature. Acquired immunity long-term protection were evidenced as immunodominant clones after treatment. Last, showed no mutagenicity, toxicity, or adverse effects preclinical good laboratory practice studies, part package has led US Food Drug Administration clearance investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy pembrolizumab locally advanced metastatic solid tumors.

Язык: Английский

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Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein–Protein Interactions

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1274 - 1274

Опубликована: Фев. 1, 2025

Histone deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing numerous cellular processes. Both the catalytic and noncatalytic functions of HDAC6 have been implicated in cancer development progression. Over decade research domain inhibitors has shown these drugs are well tolerated, exhibit anticancer activity, can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness treating solid tumours remains uncertain. activity regulated by protein–protein interactions post-translational modifications, which may allosterically influence its domains. As result, effective inhibition using small molecule requires more sophisticated understanding role within tumour cells, including whether expression correlates with activity. A comprehensive cancer-specific expression, functional activation states will be critical for refining use therapy.

Язык: Английский

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Inhibition of histone deacetylase 6 activity mitigates neurological impairment and post-hemorrhagic hydrocephalus after intraventricular hemorrhage by modulating pyroptosis and autophagy pathways

Fluids and Barriers of the CNS, Год журнала: 2025, Номер 22(1)

Опубликована: Май 7, 2025

Posthemorrhagic hydrocephalus (PHH) is a frequent and significant complication that impacts the prognosis of patients suffering from intraventricular hemorrhage (IVH). However, underlying mechanism uncertain. Neuronal pyroptosis characterized by neuronal lysis destruction, along with release inflammatory factors. Autophagy known to inhibit inflammation, histone deacetylase-6 (HDAC6) implicated in regulation both autophagy NLRP3 inflammasome. role these proteins an IVH model has not been determined. In this study, mouse (6-8 weeks) was generated via intracerebroventricular administration autologous blood at volume 40 µL/animal. After surgical operation, we monitored mice various time points, assessing ventricle size MRI. Additionally, during acute (3 days) chronic (28 phases post-surgery, examined cell damage ventricular cilia, as well neurological function, using HE staining, Nissl scanning electron microscopy, behavioral experiments such function scoring water maze tests. Finally, detected activation pathway through western blotting immunofluorescence staining. induction attenuated cerebral caused acute-phase injection. HDAC6 regulating phase its influence on transcription nuclear factor kappa-B (NF-κB). Furthermore, regulates excessive autophagic neurons IVH. Treatment ricolinostat improved deficits Moreover, it alleviated mood, memory, learning while also improving PHH. Enhanced attenuates NOD-like receptor protein 3 (NLRP3) inflammasome inhibits plays important interaction between pyroptosis. Ricolinostat treatment significantly upregulation factors impairments induced addition, effectively reduced apoptosis formation

Язык: Английский

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Mechanistic Insights into the Anti-Hepatocellular Carcinoma Effects of ACY-1215: p53 Acetylation and Ubiquitination Regulation

Current Issues in Molecular Biology, Год журнала: 2025, Номер 47(5), С. 338 - 338

Опубликована: Май 8, 2025

As a major global health challenge, hepatocellular carcinoma (HCC) still faces substantial limitations in its treatment options. This study investigates the anti-HCC potential of ACY-1215, selective Histone deacetylase 6 (HDAC6) inhibitor, and mechanism targeting p53 regulation. In vitro studies conducted with HepG2 SMMC-7721 cells revealed that ACY-1215 markedly inhibited HCC cell proliferation, migratory capacity, invasive potential, as evidenced by CCK-8, colony formation, Transwell assays. Furthermore, induced caspase-dependent apoptosis. Mechanistically, enhanced acetylation disrupting HDAC6-p53 interaction, thereby stabilizing protein levels. Concurrently, it Murine Double Minute 2 (MDM2)-mediated ubiquitination, blocking proteasomal degradation prolonging half-life. dual modulation restored transcriptional activity, leading to upregulation downstream effector molecules associated cycle regulation Collectively, our findings reveal exerts potent effects through coordinated offering novel dual-targeting strategy for therapy.

Язык: Английский

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The Current State of Charcot–Marie–Tooth Disease Treatment

Опубликована: Июнь 13, 2023

Charcot–Marie–Tooth disease (CMT) and associated neuropathies constitute the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments remain elusive. The extensive genetic heterogeneity of CMT, which impacts peripheral nerves results in a lifelong disability, presents significant barrier to development comprehensive treatments. An estimated 100 loci within human genome are linked various forms CMT its related inherited neuropathies. This review delves into prospective therapeutic strategies used for frequently encountered variants, namely CMT1A, CMT1B, CMTX1, CMT2A. Compounds such as PXT3003, currently under clinical preclinical investigation, broad array agents their corresponding mechanisms have been discussed this review. Furthermore, progress established gene therapy techniques, including replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, knockdown, has appraised. Each these therapies potential substantial advancements future research.

Язык: Английский

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Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Ноя. 15, 2022

Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to lack of effective targeting drugs. The mechanisms non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 mostly located cytoplasm deacetylate substrates, which has been identified as critical promoter many oncogenic pathways cancers, including gastric Nevertheless, its inhibitor not applied clinically. In this study, we canagliflozin an active HDAC6-targeted from FDA-approved Drug Library by enzymatic assay. strong affinity compounds was further verified surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). addition, molecular docking showed could bind pocket form interactions residues. Further experiments revealed effectively inhibit migration epithelial-mesenchymal-transition (EMT) cells vitro vivo . These results reveal novel finding potential be agent inhibiting metastasis.

Язык: Английский

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Iron oxide nanoparticles induce ferroptosis via the autophagic pathway by synergistic bundling with paclitaxel

Molecular Medicine Reports, Год журнала: 2023, Номер 28(4)

Опубликована: Сен. 6, 2023

In recent years, inhibiting tumor cell activity by triggering ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non‑invasive applications. Currently, the potential mechanism underlying universal application paclitaxel (PTX)‑loaded iron oxide nanoparticles (IONP@PTX) to different types tumors is unclear. present study aimed prepare IONP@PTX cancer therapy and further explore mechanisms inhibitory effects this material on NCI‑H446 human small lung brain M059K malignant glioblastoma lines. First, CCK‑8 assay was performed determine viability, then combination index evaluating drug interaction effect evaluated. Intracellular reactive oxygen species (ROS) lipid peroxidation levels were monitored using DCFH‑DA fluorescent probe C11‑BODIPY™ probe, respectively. Furthermore, western blotting expression autophagy‑ death‑related proteins. experimental results showed that, compared with either IONP monotherapy, PTX or + PTX, exerted synergistic viability both types, significantly increased total ion concentration, ROS levels. autophagy‑related proteins Beclin 1 histone deacetylase 6 (HDAC6) in lines (P<0.05), light chain 3 (LC3)‑II/I cells (P<0.05) decreased that sequestosome1 (p62) (P<0.05). Moreover, addition rapamycin enhanced IONP@PTX‑induced upregulation 1, LC3‑II/I HDAC6 downregulation mTORC1 protein p62 suggesting induces ferroptosis, most likely through autophagy. Collectively, findings show works synergistically induce via autophagic pathway.

Язык: Английский

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