The successful treatment of cancer has significantly improved as a result of targeted therapy and immunotherapy. However, during chemotherapy, cancer cells evolve and can acquire “multidrug ...resistance” (MDR), which significantly limits the efficacy of cancer treatment and impacts patient survival and quality of life. Among the approaches to reverse MDR, modulating reactive oxidative species (ROS) may represent a strategy to kill MDR cancer cells that are mechanistically diverse. ROS in cancer cells play a central role in regulating and inducing apoptosis, thereby modulating cancer cells proliferation, survival and drug resistance. The levels of ROS and the activity of scavenging/anti-oxidant enzymes in drug resistant cancer cells are typically increased compared to non-MDR cancer and normal cells. Consequently, MDR cancer cells may be more susceptible to alterations in ROS levels. Numerous studies suggest that compounds modulating cellular ROS levels can enhance MDR cancer cell death and sensitize MDR cancer cells to certain chemotherapeutic drugs.
In the current review, we discuss the critical and targetable redox-regulating enzymes, including mitochondrial electron transport chain (ETC) complexes, NADPH oxidases (NOXs), enzymes related to glutathione metabolism, glutamate/cystine antiporter xCT, thioredoxin reductases (TrxRs), nuclear factor erythroid 2-related factor 2 (Nrf2), and their roles in regulating cellular ROS levels, drug resistance as well as their clinical significance. We also discuss and summarize the findings in the past decade regarding the efficacy of ROS modulators for the treatment of MDR cancer alone or as sensitizing compounds. Compounds that are efficacious in modulating ROS generation represent a prominent class of drug candidates that warrants evaluation in clinical trials for patients harboring MDR cancers.
Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use of copper‐based nanomaterials inducing cuproptosis for cancer ...treatment. Here, a glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate (Cu(tz)) coordination polymer (CP) nanoplatform, denoted as GOx@Cu(tz), for starvation‐augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be “turned on” for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@Cu(tz)‐mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper‐induced toxicity. The increased intracellular hydrogen peroxide (H2O2) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@Cu(tz). The in vivo experimental results indicate that GOx@Cu(tz) produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.
An enzyme‐engineered cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in cancer cells is reported, which may invigorate studies pursuing rational design of effective cancer therapy strategies based on cuproptosis.
Flexible and wearable pressure sensor may offer convenient, timely, and portable solutions to human motion detection, yet it is a challenge to develop cost-effective materials for pressure sensor ...with high compressibility and sensitivity. Herein, a cost-efficient and scalable approach is reported to prepare a highly flexible and compressible conductive sponge for piezoresistive pressure sensor. The conductive sponge, poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)@melamine sponge (MS), is prepared by one-step dip coating the commercial melamine sponge (MS) in an aqueous dispersion of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). Due to the interconnected porous structure of MS, the conductive PEDOT:PSS@MS has a high compressibility and a stable piezoresistive response at the compressive strain up to 80%, as well as good reproducibility over 1000 cycles. Thereafter, versatile pressure sensors fabricated using the conductive PEDOT:PSS@MS sponges are attached to the different parts of human body; the capabilities of these devices to detect a variety of human motions including speaking, finger bending, elbow bending, and walking are evaluated. Furthermore, prototype tactile sensory array based on these pressure sensors is demonstrated.
Recent studies in both mice and humans have suggested that gut microbiota could modulate tumor responsiveness to chemo- or immunotherapies. However, the underlying mechanism is not clear yet. Here, ...we found that gut microbial metabolites, especially butyrate, could promote the efficacy of oxaliplatin by modulating CD8+ T cell function in the tumor microenvironment. Butyrate treatment directly boosted the antitumor cytotoxic CD8+ T cell responses both in vitro and in vivo in an ID2-dependent manner by promoting the IL-12 signaling pathway. In humans, the oxaliplatin responder cancer patients exhibited a higher amount of serum butyrate than did non-responders, which could also increase ID2 expression and function of human CD8+ T cells. Together, our findings suggest that the gut microbial metabolite butyrate could promote antitumor therapeutic efficacy through the ID2-dependent regulation of CD8+ T cell immunity, indicating that gut microbial metabolites could be effective as a part of cancer therapy.
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•Gut microbial metabolites improve chemotherapy efficacy via regulating CD8+ T cells•The SCFA butyrate directly boosts the antitumor CD8+ T cell response via ID2•ID2 regulates the function of CD8+ T cells through IL-12 signaling•Butyrate supplementation improves the antitumor therapy efficacy
He et al. report that the gut microbial metabolite butyrate can directly modulate antitumor CD8+ T cell response and improve the chemotherapy efficacy through ID2-dependent IL-12 signaling, suggesting that manipulation of gut microbial metabolites could be effective as a part of cancer therapy.
Prefrontal cortex (PFC) mediates an assortment of cognitive functions including working memory, behavioral flexibility, attention, and future planning. Unlike the hippocampus, where induction of ...synaptic plasticity in the network is well-documented in relation to long-term memory, cognitive functions mediated by the PFC have been thought to be independent of long-lasting neuronal adaptation of the network. Nonetheless, accumulating evidence suggests that prefrontal cortical neurons possess the cellular machinery of synaptic plasticity and exhibit lasting changes of neural activity associated with various cognitive processes. Moreover, deficits in the mechanisms of synaptic plasticity induction in the PFC might be involved in the pathophysiology of psychiatric and neurological disorders such as schizophrenia, drug addiction, mood disorders, and Alzheimer's disease.
Motor behaviors are often planned long before execution but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. ...Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here, we investigate the multi-regional neural circuits that link an auditory “Go cue” and the transition from planning to execution of directional licking. Ascending glutamatergic neurons in the midbrain reticular and pedunculopontine nuclei show short latency and phasic changes in spike rate that are selective for the Go cue. This signal is transmitted via the thalamus to the motor cortex, where it triggers a rapid reorganization of motor cortex state from planning-related activity to a motor command, which in turn drives appropriate movement. Our studies show how midbrain can control cortical dynamics via the thalamus for rapid and precise motor behavior.
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•Distinct motor cortex activity patterns underlie planning and movement initiation•A contextual cue reorganizes motor cortex activity to initiate planned movements•Midbrain neurons transmit information to cortex via thalamus to release movements•Midbrain activity is causal for reorganizing cortical activity and releasing movements
Ascending midbrain neurons trigger rapid reorganization of motor cortex activity via thalamus to switch from planning-related activity to a motor command that initiates movement in mice
The emergence of drug resistance is a primary obstacle for successful chemotherapy. Drugs that target cryptic binding sites (CBSs) represent a novel strategy for overcoming drug resistance. In this ...short communication, we explain and discuss how the discovery of CBSs and their inhibitors can overcome drug resistance.
The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide ...association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (FtoKO
) or selectively in osteoblasts (FtoOc KO
). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H₂O₂) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-κB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of FtoOc KO
mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a–NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.
Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome ...cisplatin resistance, it is important to understand the mechanisms underlying the resistance.
A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway.
HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis.
Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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