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Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development.

Type IIA topoisomerases are essential DNA processing enzymes that must robustly and reliably relax DNA torsional stress. While cellular processes constantly create varying torsional stress, how this variation impacts type IIA topoisomerase function remains obscure. Using multiple single-molecule approaches, we examined the torsional dependence of eukaryotic topoisomerase II (topo II) activity on naked DNA and chromatin. We observed that topo II is ~50-fold more processive on buckled DNA than previously estimated. We further discovered that topo II relaxes supercoiled DNA prior to plectoneme formation, but with processivity reduced by ~100-fold. This relaxation decreases with diminishing torsion, consistent with topo II capturing transient DNA loops. Topo II retains high processivity on buckled chromatin (~10,000 turns) and becomes highly processive even on chromatin under low torsional stress (~1000 turns), consistent with chromatin’s predisposition to readily form DNA crossings. This work establishes that chromatin is a major stimulant of topo II function. Here the authors discover that chromatin stimulates topoisomerase II function by enabling the enzyme to achieve exceptionally high processivity and efficient supercoiling relaxation, even under low torsional stress.

The rapid digitalization of products and services has given rise to smart, technological products and services in various industries. While researchers recognize the complexity of digital components embedded in smart services, there exists scarce research on the evolution of product development, smart technology’s use, and the mechanisms wherein changes in products and services are triggered and implemented. In this research, grounded on the theoretical basis of layered modular architecture, we study a digital venture in an event management industry and offer a substantive look at the three mechanisms—system-environment fitness, data exploitation, and user expansion—that are responsible for transforming smart technology from a conceptual idea into a real product and from a simple digital device into an integrated smart system. Our research findings offer theoretical insight into the dynamics and fluidity of mechanisms that are relevant to smart technology’s design, use, and outcomes.

Type II topoisomerases modulate chromosome supercoiling, condensation, and catenation by moving one double-stranded DNA segment through a transient break in a second duplex. How DNA strands are chosen and selectively passed to yield appropriate topological outcomes – for example, decatenation vs. catenation – is poorly understood. Here, we show that at physiological enzyme concentrations, eukaryotic type IIA topoisomerases (topo IIs) readily coalesce into condensed bodies. DNA stimulates condensation and fluidizes these assemblies to impart liquid-like behavior. Condensation induces both budding yeast and human topo IIs to switch from DNA unlinking to active DNA catenation, and depends on an unstructured C-terminal region, the loss of which leads to high levels of knotting and reduced catenation. Our findings establish that local protein concentration and phase separation can regulate how topo II creates or dissolves DNA links, behaviors that can account for the varied roles of the enzyme in supporting transcription, replication, and chromosome compaction.

Etoposide is a broadly employed chemotherapeutic and eukaryotic topoisomerase II poison that stabilizes cleaved DNA intermediates to promote DNA breakage and cytotoxicity. How etoposide perturbs topoisomerase dynamics is not known. Here we investigated the action of etoposide on yeast topoisomerase II, human topoisomerase IIα and human topoisomerase IIβ using several sensitive single-molecule detection methods. Unexpectedly, we found that etoposide induces topoisomerase to trap DNA loops, compacting DNA and restructuring DNA topology. Loop trapping occurs after ATP hydrolysis but before strand ejection from the enzyme. Although etoposide decreases the innate stability of topoisomerase dimers, it increases the ability of the enzyme to act as a stable roadblock. Interestingly, the three topoisomerases show similar etoposide-mediated resistance to dimer separation and sliding along DNA but different abilities to compact DNA and chirally relax DNA supercoils. These data provide unique mechanistic insights into the functional consequences of etoposide on topoisomerase II dynamics. Using single-molecule biophysics methods, Le et al. discovered that etoposide, a chemotherapeutic poison of topoisomerase II (topo II), promotes topo II to compact DNA, trap DNA loops and pause DNA supercoiling relaxation, thus converting topo II into a strong roadblock to DNA processing.

Purpose The incorporation of molecular markers into neuro-oncology has transformed our understanding of adult diffuse gliomas. While surgical resection is the mainstay of treatment for many patients with gliomas, surgical management strategies warrant re-exploration in the context of characteristic molecular profiles. Methods We reviewed the neurosurgical and neuro-oncological literature for studies investigating surgery in molecularly defined cohorts of adult diffuse gliomas. Results We discuss key molecular markers associated with the three subtypes of adult diffuse glioma: glioblastoma IDH-wildtype, astrocytoma IDH-mutant, and oligodendroglioma IDH-mutant and 1p/19q codeleted. We additionally discuss surgical strategies and extent of resection in these tumors, framing them in the context of key molecular alterations. Finally, we briefly discuss the practical utility of molecular markers in guiding surgical decision making. Conclusion Molecular markers in gliomas are of growing relevance to surgical intervention. Advancements in preoperative and intraoperative molecular diagnostics will increase the utility of molecular biomarkers in informing surgical decision-making for patients with gliomas.

Abstract Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-β (transforming growth factor-β) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-β–stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-β–associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

Transforming growth factor-β (TGF-β) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on TGF-β1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 μg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-β1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-β1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes—including TGF-β1, fibronectin, elastin, and collagen1α1—in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-β receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-β1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-β1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.

CHI3L1, a chitinase-like protein, is implicated in pulmonary fibrosis, yet its mechanisms are incompletely understood. We demonstrated that CHI3L1 coordinates profibrotic macrophage activation and invasive myofibroblast differentiation, and their crosstalk. In vitro, CHI3L1 drove M2-like macrophage polarization with increased CD163, CD206, and PD-L1, and amplified TGF-β 1 –induced fibroblast responses, including myofibroblast transformation, migration, and invasion. Mechanistically, CHI3L1 enhanced TGF-β 1 signaling through SMAD, AKT, and ERK pathways, and PD-L1 was required for CHI3L1/TGF-β 1 –driven myofibroblast transformation. Coculture studies further demonstrated the ability of CHI3L1 to induce profibrotic macrophage activation that enhanced myofibroblast transformation mediated via a CD44/PD-L1 axis. In vivo, following bleomycin challenge, CHI3L1-transgenic mice exhibited increased PD-L1 + M2 macrophages, PD-L1 + PDGFRα + fibroblasts, and PD-1 + immune cells compared with WT controls. Therapeutically, combined anti-CHI3L1 and anti-PD-1 antibodies, or a bispecific anti-CHI3L1–anti-PD-1 antibody, produced greater antifibrotic efficacy than monotherapy. These findings demonstrate crosstalk between CHI3L1 and the PD-1/PD-L1 pathway that promotes profibrotic macrophage activation and invasive fibroblast differentiation and support dual targeting of CHI3L1 and PD-1/PD-L1 as a promising therapeutic strategy for pulmonary fibrosis.

Chitinase-3-like-1 (CHI3L1) is a potent immune modulator implicated in tumor progression and immune suppression, including melanoma lung metastasis. Kasugamycin (KSM) has been reported as a pan-chitinase inhibitor with antifibrotic activity, but its effects on CHI3L1-driven immune regulation remain poorly defined. This study aimed to determine whether KSM suppresses CHI3L1-mediated tumor progression by modulating tumor-associated macrophage (TAM) differentiation and to elucidate the underlying molecular mechanisms. The anti-tumor effects of KSM were evaluated using a B16/F10 melanoma lung metastasis model. CHI3L1 gain-of-function approaches were used to assess specificity. Lung immune populations were analyzed by flow cytometry. Human THP-1 monocytes were used to examine CHI3L1-induced macrophage differentiation in vitro. Bulk RNA sequencing was performed on differentiated macrophages to identify downstream signaling pathways. Pharmacologic inhibition studies were conducted using the epidermal growth factor receptor (EGFR) inhibitor gefitinib to validate mechanistic links. KSM treatment significantly reduced melanoma lung metastasis in a dose-dependent manner. CHI3L1 overexpression enhanced melanoma lung colony formation, which was effectively abrogated by KSM, indicating CHI3L1-specific anti-tumor activity. In melanoma-challenged lungs, KSM markedly decreased M2-like macrophages expressing CD206, CD163, and PD-L1. In vitro, CHI3L1 promoted M2 macrophage differentiation in THP-1 cells, which was strongly suppressed by KSM. Transcriptomic analysis revealed that EGFR expression was robustly induced by CHI3L1 and counter-regulated by KSM. Inhibition of EGFR signaling with gefitinib significantly attenuated CHI3L1-driven STAT3 activation and M2 macrophage polarization. These findings identify a previously unrecognized anti-tumor mechanism of KSM through inhibition of CHI3L1-EGFR-STAT3 signaling and suppression of M2-like TAM differentiation. KSM may therefore represent a promising immunomodulatory strategy for treating melanoma lung metastasis and other CHI3L1-driven malignancies.