The Current State of Charcot–Marie–Tooth Disease Treatment

Genes, Journal Year: 2023, Volume and Issue: 14(7), P. 1391 - 1391

Published: July 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.

Language: Английский

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

Cancer Immunology Immunotherapy, Journal Year: 2024, Volume and Issue: 73(1)

Published: Jan. 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.

Language: 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, Journal Year: 2024, Volume and Issue: Volume 17, P. 1005 - 1028

Published: March 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.

Language: Английский

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

Science Advances, Journal Year: 2024, Volume and Issue: 10(46)

Published: Nov. 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.

Language: 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, Journal Year: 2025, Volume and Issue: 26(3), P. 1274 - 1274

Published: Feb. 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.

Language: 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, Journal Year: 2025, Volume and Issue: 22(1)

Published: May 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

Language: 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, Journal Year: 2025, Volume and Issue: 47(5), P. 338 - 338

Published: May 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.

Language: Английский

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The Current State of Charcot–Marie–Tooth Disease Treatment

Published: June 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.

Language: Английский

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

Molecular Medicine Reports, Journal Year: 2023, Volume and Issue: 28(4)

Published: Sept. 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.

Language: Английский

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Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer

Pharmaceutics, Journal Year: 2023, Volume and Issue: 16(1), P. 54 - 54

Published: Dec. 29, 2023

Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, angiogenesis. Due its ability remove misfolded induce autophagy, regulate unfolded protein response, HDAC6 plays a protective role responses stress enables tumor survival. The scope this review is discuss the roles HDCA6 implications for therapy colorectal (CRC). As overexpressed CRC, correlates poor disease prognosis, not essential normal mammalian development, it represents good therapeutic target. Selective inhibition impairs growth progression without inducing major adverse events experimental animals. In inhibitors have shown potential reduce enhance effect other drugs. regulation immune responses, improve antitumor immunity increasing immunogenicity cells, augmenting activity, alleviating immunosuppression microenvironment. Therefore, may represent promising candidates overcome resistance immunotherapy.

Language: Английский

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