Uterine fibroids (leiomyomas), the most common tumors in women and those assigned female at birth, originate from myometrial smooth muscle cells and cause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction of labor in approximately a quarter of reproductive-age women. During each ovulatory cycle, the myometrium responds to the ovarian steroids, estradiol, and progesterone, via increased tissue stem cell proliferation to prepare for impending pregnancy, during which a somatic mutation may arise to initiate a tumor. Both the mutated smooth muscle cells and the adjacent tumor-associated fibroblasts lay down excessive quantities of extracellular matrix, providing a unique feature that led to naming these tumors “fibroids.” The most common somatic mutations in fibroids affect the Mediator complex subunit 12 ( MED12; 77%) and high-mobility group AT-hook 2/1 ( HMGA2/1; 10%) genes. Heterozygous mutations in MED12, a chromatin-associated protein, disrupt the attached CDK8 kinase module in the Mediator complex. MED12 mutations are associated with increased genomic instability, altered chromatin landscape and enhancer engagement, and increased responsiveness to progesterone. Progesterone and a small stem cell population in a fibroid are essential for tumor survival and growth. Progesterone, via its receptors in differentiated fibroid cell populations, activates the production of Wingless-type MMTV integration site family (WNT) ligands, cytokines, and other growth substances to act on adjacent stem cells in a paracrine fashion to support tumor growth. Suppression of estrogen or progesterone production and progesterone antagonists have been used for temporary shrinkage of these tumors and symptom relief. Here we provide an overview of these mechanisms and future approaches for prevention and medical management of uterine fibroids.

Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in millions of women worldwide. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyomas that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant MED12 (mut-MED12) versus WT-MED12 leiomyomas. Integration of cistromic and transcriptomics data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene that was significantly upregulated in mut-MED12 leiomyomas when compared with adjacent myometrium and WT-MED12 leiomyomas. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyomas. Treatment of primary mut-MED12 leiomyoma cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis, and induced AHR-target gene expression, whereas blocking the TDO2/kynurenine/AHR pathway by siRNA or pharmacological treatment abolished these effects. Progesterone receptors regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for leiomyoma growth. In summary, activation of the TDO2/kynurenine/AHR pathway selectively in mut-MED12 leiomyomas promoted tumor growth and may inform the future development of targeted treatments and precision medicine.

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. Methods: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. Results: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein–ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6–ligand complexes, confirming the stability of their interactions. Conclusions: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.

Lactoferrin (LTF), a multifunctional glycoprotein, plays a critical role in iron metabolism, host defense mechanisms, and the regulation of inflammatory pathways. It is widely present in various mammalian secretions, including saliva, tears, and nasal fluids, and exhibits potent antimicrobial, immunomodulatory, and neuroprotective properties. Emerging evidence suggests that LTF may be pivotal in mitigating neurodegenerative diseases (NDs) by modulating oxidative stress and neuroinflammation. This study investigates the interaction of LTF with Noscapine, a benzylisoquinoline alkaloid known for its therapeutic potential, including anticancer and neuroprotective effects. Fluorescence binding studies revealed a strong binding affinity between LTF and Noscapine with a binding constant (K) of 0.1 × 10⁵ M^-1. Circular dichroism (CD) spectroscopy revealed subtle changes in LTF's secondary structure and a strong binding affinity between LTF and Noscapine, indicative of specific molecular interactions and conformational adjustments. Additionally, in silico studies were performed to complement the experimental findings. Molecular docking studies identified potential binding sites and highlighted key interactions stabilizing the LTF-Noscapine complex. Molecular dynamic (MD) simulation studies demonstrated that structural compactness is well preserved with only minimal structural alterations observed in the protein upon binding of Noscapine. Together, these results provide comprehensive insights into the molecular basis of LTF-Noscapine interaction, with potential implications for therapeutic applications in NDs. This study lays the groundwork for further exploration of Noscapine's potential in combating NDs and other biomedical challenges.