Biology subjects

Mathew, J.

Publications and source records attributed to Mathew, J..

9 recordsLinked to original sources

bioRxiv2025

Combination Treatment with NCX 4040 and Napabucasin Triggers Enhanced Oxidative Stress, STAT3 Inhibition and Plausible Immunogenic Activation in Metastatic Prostate Cancer Cells

Prostate cancer (PCa) remains a significant health concern, ranking as the second most common cancer after lung cancer, despite recent advances in diagnostics and therapeutics. Due to its heterogeneous nature, diverse etiology, and the limited efficacy of current treatments, developing a therapeutic approach that can address the multifaceted aspects of the disease is imperative. Combinatorial therapy has emerged as a promising strategy for addressing tumor heterogeneity and the limitations of current treatments across various cancer types. In our study, we investigated the potential of combining NCX 4040, a nitric oxide-releasing aspirin derivative, and Napabucasin, a STAT3 and cancer stemness inhibitor, as a novel PCa treatment strategy. We utilized two cellular models: BPH-Cd, a cadmium-transformed carcinogenic cell line, and DU145, a brain metastatic PCa cell line. Our findings demonstrate that the combination treatment exerted a synergistic and dose-dependent reduction in cell viability, tumorigenicity, and migratory capabilities in both BPH-Cd and DU145 cells, surpassing the effects observed with individual treatments. Furthermore, this combination treatment triggered a robust generation of cellular and mitochondrial reactive oxygen species (ROS), resulting in G2/M cell cycle arrest and late-stage apoptosis in both cell lines. Additionally, the combination treatment downregulated redox-sensitive transcription factors pSTAT3 Tyr705 and Ser727, as well as pro-survival proteins TRX1/2, TRXR1, and GPX4, while upregulating tumor suppressor proteins PRDX1 and TXNIP. This implies that inhibition of the pro-survival redox proteins leads to the accumulation of oxidized PRDX1 and TXNIP, thereby elevating oxidative stress and blocking STAT3-mediated transcription, ultimately impeding cell proliferation and survival. Moreover, increased expression of pH2AX protein, a DNA damage marker, indicated that the combination induced DNA damage, resulting in the activation of the cGAS-STING pathway, an anti-tumor immunogenic mechanism as confirmed with immunoblotting. Downregulation of various stem cell markers linked to Wnt/{beta}-catenin and Notch-1 signaling pathways highlight the combinations ability to also target cancer stemness. In summary, our study underscores the promise of combining NCX 4040 and Napabucasin as an innovative and multifaceted therapeutic approach for PCa. Abstract Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/675191v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@485f6dorg.highwire.dtl.DTLVardef@170f98forg.highwire.dtl.DTLVardef@1037b8org.highwire.dtl.DTLVardef@ba3f39_HPS_FORMAT_FIGEXP M_FIG C_FIG (A) The combination therapy modulates key markers of the redox signaling pathway, inducing excessive oxidative stress in PCa cells, which subsequently leads to DNA damage and late apoptotic cell death. DNA damage activates the cGAS-STING pathway, upregulating interferon regulatory factor 3 (IRF3), which may, in turn, trigger the activation of tumor-infiltrating lymphocytes, generating a potent anti-tumorigenic response. (B) The combination therapy inhibits stem-cell signaling pathways, including Wnt/{beta}-catenin, Notch-1, and STAT3, potentially suppressing cancer stemness and contributing to long-term disease control.

pharmacology and toxicology↗

bioRxiv2025

Exploring the C(2)M Cohesin Complex: Structure, Dynamics, and Ability to Facilitate Assembly of the Synaptonemal Complex

There are two meiotic cohesin pathways that regulate synaptonemal complex (SC) assembly in Drosophila. We previously proposed that C(2)M, which is required for SC assembly, is the only meiosis-specific component of a complex that includes Stromalin (SA), Nipped-B, SMC1 and SMC3. This model also predicts that specific residues within the C-terminus and N-terminus of C(2)M should interact with SMC1 and SMC3 to form a ring structure that may regulate the ability of C(2)M to facilitate SC assembly. Through mutant analysis, our results show several residues known to interact with SMC1 or SMC3 are critical for SC formation, suggesting that C(2)M may require a ring structure to perform meiosis-specific functions such as the formation of SC. We also show that SA colocalizes with and depends on C(2)M. However, the dynamics of C(2)M differ from SA and the SMCs in a way that suggests C(2)M regulates the dynamics and chromosome loading of the other cohesin proteins SMC1 and SA. Consistent with this conclusion, our results suggest that C(2)M can promote chromosome localization of the other cohesin components, and can induce SC assembly when ectopically expressed in germline mitotic cells.

genetics↗

bioRxiv2022

Pseudomonas aeruginosa Elicits Sustained IL-1β Upregulation in Alveolar Macrophages from Lung Transplant Recipients

BackgroundIsolation of Pseudomonas aeruginosa (PsA) is associated with increased BAL (bronchoalveolar lavage) inflammation and lung allograft injury in lung transplant recipients (LTR). However, the effect of PsA on macrophage responses in this population is incompletely understood. We examined human alveolar macrophage (AM) responses to PsA and Pseudomonas dominant microbiome in healthy lung transplant recipients (LTR). MethodsWe stimulated THP-1 derived macrophages (THP-1M) and human AM from LTR with different bacteria and LTR BAL derived microbiome characterized as Pseudomonas-dominant. Macrophage responses were assessed by high dimensional flow cytometry, including their intracellular production of cytokines (TNF-, IL-6, IL-8, IL-1{beta}, IL-10, IL-1RA, and TGF-{beta}). Pharmacological inhibitors were utilized to evaluate the role of the inflammasome in PsA-macrophages interaction. ResultsWe observed upregulation of pro-inflammatory cytokines (TNF-, IL-6, IL-8, IL-1{beta}) following stimulation by PsA compared to other bacteria (Staphylococcus aureus, Prevotella melaninogenica, Streptococcus pneumoniae) in both THP-1 derived and LTR AM, predominated by IL-1{beta}. IL-1{beta} production from THP-1 was sustained after PsA stimulation for up to 96 hours and 48 hours in LTR AM. Treatment with the inflammasome inhibitor BAY11-7082 abrogated macrophage IL-1{beta} and IL-18 production after PsA exposure. BAL Pseudomonas-dominant microbiota elicited an increased IL-1{beta}, similar to PsA, an effect abrogated by the addition of antibiotics. ConclusionPsA and PsA-dominant lung microbiota induce sustained IL-1{beta} production in LTR AM. Pharmacological targeting of the inflammasome reduces PsA-macrophage-IL1{beta} responses, underscoring their use in lung transplant recipients.

immunology↗

bioRxiv2022

Separability of Human Motor Memories during Reaching Adaptation with Force Cues

Judging by the breadth of our motor repertoire during daily activities, it is clear that acquiring multiple motor skills is a hallmark of the human motor system. However, for reaching movements the different planning conditions under which this is possible in laboratory settings have remained a challenging question. Considering the sensitivity of limb afferent feedback relative to externally applied forces, we hypothesised that independent cues delivered by means of background loads could support simultaneous formation of different motor memories of various velocity-dependent force fields. We demonstrate in a series of experiments that indeed healthy adults can form internal priors about opposite force fields, independently of the direction of the background force cue. However, when the cue and force field were only related by their magnitude, a separation was still observed but the associated mechanism was subject to interference. Finally, we highlight that this paradigm allows dissociating trial-by-trial acquisition of internal representations from within-trial feedback adaptation, as these two adaptation mechanisms are associated with different time scales that can be measured reliably. Significance StatementThe conditions under which humans can adapt to different contexts in parallel remain the subject of active debates. Mounting evidence highlights that contextual factors linked to movement planning are necessary to form different motor memories. Here we show that background forces indicative of the direction of a force field could play the role of contextual factors, and enable dual adaptation to different force fields. However, we uncovered that when the cue and the force field were in the same direction but of different magnitudes, the motor memories were still distinct but subject to interference. We further show that different timescales of adaptation observed can be explained by offline and online mechanisms in a model of reaching adaptation and control.

neuroscience↗

bioRxiv2021

Cancer missense mutations in the BRC repeats of BRCA2 protein disrupt RAD51 binding and activity leading to chemotherapeutic sensitivity

Pathogenic mutations in the BRCA2 tumor suppressor gene predispose to breast, ovarian, pancreatic, prostate, and other cancers. BRCA2 maintains genome stability through homology-directed repair (HDR) of DNA double-strand breaks (DSBs) and replication fork protection. Nonsense or frameshift mutations leading to truncation of the BRCA2 protein are typically considered pathogenic, however, missense mutations resulting in single amino acid substitutions can be challenging to functionally interpret. The majority of missense mutations in BRCA2 have been classified as Variants of Uncertain Significance (VUS) with unknown functional consequences. In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine their impact on canonical HDR and fork protection functions. We provide evidence that S1221P and T1980I, which map to conserved residues in the BRC2 and BRC7 repeats, compromise the cellular response to chemotherapeutics and ionizing radiation, and display deficits in fork protection. We further demonstrate biochemically that S1221P and T1980I disrupt RAD51 binding and diminish the ability of BRCA2 to stabilize RAD51-ssDNA complexes. The third variant, T1346I, located within the spacer region between BRC2 and BRC3 repeats, is fully functional. We conclude that T1346I is a benign allele whereas S1221P and T1980I are hypomorphic disrupting the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments. Our results underscore the importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer risk and guide therapy selection during cancer treatment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/461749v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1e5e3c6org.highwire.dtl.DTLVardef@1cd0e60org.highwire.dtl.DTLVardef@16adf4corg.highwire.dtl.DTLVardef@16a0089_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

A Fully Implantable Wireless Bidirectional Neuromodulation System for Mice

Novel research in the field of bioelectronic medicine requires systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced software signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such systems either preclude their use or impose significant constraints on experimental design. Here, we describe a fully-implantable neuromodulation system suitable for use in mice, measuring 2.2 cm3 and weighing 2.8 g. A bidirectional wireless interface allows simultaneous readout of multiple physiological signals and complete control over stimulation parameters, and a wirelessly rechargeable battery provides a lifetime of up to 5 days on a single charge. The device was successfully implanted (N=12) and a functional neural interface (capable of inducing acute bradycardia) is demonstrated with functional lifetimes exceeding to three weeks. The design utilizes only commercially-available components and 3D-printed packaging, with the goal of accelerating discovery and translation of future bioelectronic therapeutics.

bioengineering↗

bioRxiv2021

Savings in human force field learning supported by feedback adaptation

Savings have been described as the ability of healthy humans to relearn a previously acquired motor skill faster than the first time, which in the context of motor adaptation suggests that the learning rate in the brain could be adjusted when a perturbation is recognized. Alternatively, it has been argued that apparent savings were the consequence of a distinct process that instead of reflecting a change in the learning rate, revealed an explicit re-aiming strategy. Based on recent evidence that feedback adaptation may be central to both planning and control, we hypothesized that this component could genuinely accelerate relearning in human adaptation to force fields during reaching. Consistent with our hypothesis, we observed that upon re-exposure to a previously learned force field, the very first movement performed by healthy volunteers in the relearning context was better adapted to the external disturbance, and this occurred without any anticipation or cognitive strategy because the relearning session was started unexpectedly. We conclude that feedback adaptation is a medium by which the nervous system can genuinely accelerate learning across movements. Significance StatementSavings describe the ability of healthy humans to faster relearn a previously acquired motor skill. It is debated whether savings result from implicit changes in the learning rate or an explicit strategy. Given recent evidence that feedback control plays a key role in movement adaptation, we hypothesized that this component also contributed to savings in the context of force field adaptation. We confirm that relearning was faster and demonstrate that the very first relearning movement was better adapted to the external disturbance, i.e., the online corrections in the first re-exposure trial carried imprints of feedback adaptation from the previous sessions in the absence of any explicit strategy. We conclude that this non-explicit feedback component can genuinely accelerate motor learning.

neuroscience↗

bioRxiv2020

CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer

Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on colon cancer. Using HCT116 and HT29, with high and low CTDSP1 expression respectively and a retrospective analysis of patients receiving irinotecan with or without rabeprazole have indicated the effect of CTDSP1 in irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.

cancer biology↗

bioRxiv2019

Feedback adaptation to unpredictable force fields in 250ms

Motor learning and adaptation are important functions of the nervous system. Classical studies have characterized how humans adapt to changes in the environment during tasks such as reaching, and have documented improvements in behavior across movements. Yet little is known about how quickly the nervous system adapts to such disturbances. In particular, recent work has suggested that adaptation could be sufficiently fast to alter the control strategies of an ongoing movement. To further address the possibility that learning occurred within a single movement, we designed a series of human reaching experiments to extract in muscles recordings the latency of feedback adaptation. Our results confirmed that participants adapted their feedback responses to unanticipated force fields applied randomly. In addition, our analyses revealed that the feedback response was specifically and finely tuned to the ongoing perturbation not only across trials with the same force field, but also across different kinds of force fields. Finally, changes in muscle activity consistent with feedback adaptation occurred in about 250ms following reach onset. We submit this estimate as the latency of motor adaptation in the nervous system.

neuroscience↗