Chemo-resistance is one of the major causes of cancer-related deaths. Here we used single-cell transcriptomics to investigate divergent modes of chemo-resistance in tumor cells. We observed that ...higher degree of phenotypic intra-tumor heterogeneity (ITH) favors selection of pre-existing drug-resistant cells, whereas phenotypically homogeneous cells engage covert epigenetic mechanisms to trans-differentiate under drug-selection. This adaptation was driven by selection-induced gain of H3K27ac marks on bivalently poised resistance-associated chromatin, and therefore not expressed in the treatment-naïve setting. Mechanistic interrogation of this phenomenon revealed that drug-induced adaptation was acquired upon the loss of stem factor SOX2, and a concomitant gain of SOX9. Strikingly we observed an enrichment of SOX9 at drug-induced H3K27ac sites, suggesting that tumor evolution could be driven by stem cell-switch-mediated epigenetic plasticity. Importantly, JQ1 mediated inhibition of BRD4 could reverse drug-induced adaptation. These results provide mechanistic insights into the modes of therapy-induced cellular plasticity and underscore the use of epigenetic inhibitors in targeting tumor evolution.
Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side ...effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.
Direct and selective C−H methylation is a powerful tool with which to install methyl groups into organic molecules, and is particularly useful in pharmaceutical chemistry. However, practical methods ...for such modification of biologically interesting targets have been rarely developed. We here report an iron‐catalyzed C(sp3)−H methylation reaction of glycine derivatives, peptides and drug‐like molecules in an alcohol in the presence of di‐tert‐butyl peroxide. A readily available iron catalyst plays multiple roles in the transformation, which accelerates oxidation of C−N bonds to C=N double bonds, activates imine intermediates as Lewis acids by bidentate chelation, and at the same time facilitates cleavage of the peroxide to generate methyl radicals. A variety of methylated N‐aryl glycine derivatives and peptides were obtained in good yield and with excellent chemo‐ and site‐selectivity. This reaction is scalable, easily managed, and can be completed within 1–2 h. It features an economic, bio‐friendly catalyst, a green solvent and low toxic reagents, and will provide effective access to precise C−H modification of biomolecules and natural products.
A concise strategy relying on multifunctional iron catalysis in the presence of di‐tert‐butyl peroxide has been reported, allowing rapid and highly selective C(sp3)−H methylation of various glycine derivatives and peptides.
Sepsis-associated cerebral dysfunction is complex pathophysiology, generated from primary infections that are developed elsewhere in the body. The neonates, elderly population and chronically ill and ...long-term hospitalized patients are predominantly vulnerable to sepsis and related cerebral damage. Generally, electrophysiological recordings, severity and sedation scales, computerized imaging and spectroscopy techniques are used for its detection and diagnosis. About the underlying mechanisms, enhanced blood-brain barrier permeability and metalloprotease activity, tight junction protein loss and endothelial cell degeneration promote the influx of inflammatory and toxic mediators into the brain, triggering cerebrovascular damage. An altered neutrophil count and phenotype further dysregulate the normal neuroimmune responses and neuroendocrine stability via modulated activation of protein kinase C-delta, nuclear factor kappa-B and sphingolipid signaling. Glial activation, together with pro-inflammatory cytokines and chemokines and the Toll-like receptor, destabilize the immune system. Moreover, superoxides and hydroperoxides generate oxidative stress and perturb mitochondrial dynamics and ATP synthesis, propagating neuronal injury cycle. Activated mitochondrial apoptotic pathway, characterized by increased caspase-3 and caspase-9 cleavage and Bax/Bcl2 ratio in the hippocampal and cortical neurons, stimulate neurocognitive impairments. Additionally, altered LC3-II/I and P62/SQSTM1, p-mTOR, p-AMPK1 and p-ULK1 levels and dysregulated autophagosome-lysosome fusion decrease neuronal and glial energy homeostasis. The therapies and procedures for attenuating sepsis-induced brain damage include early resuscitation, cerebral blood flow autoregulation, implantable electric vagus nerve stimulation, antioxidants, statins, glucocorticoids, neuroimmune axis modulators and PKCδ inhibitors. The current review enumerates the pathophysiology of sepsis-induced brain damage, its diagnosis, the role of critical inducers and mediators and, ultimately, therapeutic measures attenuating cerebrovascular degeneration.
Over the past decades, asymmetric photochemical synthesis has garnered significant attention for its sustainability and unique ability to generate enantio‐enriched molecules through distinct reaction ...pathways. Photochemical asymmetric three‐component reactions have demonstrated significant potential for the rapid construction of chiral compounds with molecular diversity and complexity. However, noteworthy challenges persist, including the participation of high‐energy intermediates such as radical species, difficulties in precise control of stereoselectivity, and the presence of competing background and side reactions. Recent breakthroughs have led to the development of sophisticated strategies in this field. This review explores the intricate mechanisms, synthetic applications, and limitations of these methods. We anticipate that it will contribute towards advancing asymmetric catalysis, photochemical synthesis, and green chemistry.
This review primarily revolves around the photochemical asymmetric three‐component transformations facilitated by transition metal catalysis or organocatalysis. The intricate reaction mechanisms, diverse synthetic applications, and inherent limitations of these methods are thoroughly examined and discussed.
The formation progress of acidic tumor microenvironment, the mechanism of drug delivery systems and nanomaterials that responsive to acidic pH in tumor microenvironment are summarized in this review.
...Display omitted
Cancer is one of the diseases that have the highest mortality, which threatens the human health. Chemotherapy functions as the most widely used strategy in clinic to treat cancer, still exists urgent problems, like lacking selectivity and causing severe side effects. According to detailed researches on the metabolism, functions and histology of cancer tissues, many different features of cancer are uncovered, like lower pH in microenvironment, abnormal redox level in intracellular compartments and elevated expression level of several enzymes and receptors. Recently, the development of smart nanoparticles that response to tumor specific microenvironment has lighted up hope for selective cancer therapy. Herein, this review mainly focuses on pH-sensitive nanoscale materials for anti-cancer drug delivery. We summarized the formation progress of acidic tumor microenvironment, the mechanism of pH-responsive drug delivery system and nanomaterials that responsive to acidic pH in tumor microenvironment.
Chronic mitochondrial stress is a central problem associated with neurodegenerative diseases. Early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality ...control. Here we investigate axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in Amytrophic Lateral Sclerosis (ALS)- and Alzheimer’s disease (AD)-linked neurons. We show that stressed mitochondria are removed from axons triggered by the bulk release of mitochondrial anchoring protein syntaphilin via a new class of mitochondria-derived cargos independent of Parkin, Drp1, and autophagy. Immuno-electron microscopy and super-resolution imaging show the budding of syntaphilin cargos, which then share a ride on late endosomes for transport toward the soma. Releasing syntaphilin is also activated in the early pathological stages of ALS- and AD-linked mutant neurons. Our study provides new mechanistic insights into the maintenance of axonal mitochondrial quality through SNPH-mediated coordination of mitochondrial stress and motility before activation of Parkin-mediated mitophagy.
Display omitted
•Pathophysiological stress induces the removal of defective mitochondria from axons•Stressed mitochondria release SNPH cargos to enhance their retrograde transport•SNPH cargos undergo retrograde transport en route late endosomes to lysosomes•SNPH-mediated response is activated in the early disease stages of ALS and AD
Lin and Cheng et al. reveal a new mechanism maintaining axonal mitochondrial integrity by releasing anchoring protein syntaphilin from stressed mitochondria, thus facilitating the removal of dysfunctional mitochondria from axons before activation of Parkin-mediated mitophagy under physiological and pathological conditions.
The impermeable barrier of solid tumors due to the complexity of their components limits the treatment effect of nanomedicine and hinders its clinical translation. Several methods are available to ...increase the penetrability of nanomedicine, yet they are too complex to be effective, operational, or practical. Surface modification employs the characteristics of direct contact between multiphase surfaces to achieve the most direct and efficient penetration of solid tumors. Furthermore, their simple operation makes their use feasible. In this review, the latest surface modification strategies for the penetration of nanomedicine into solid tumors are summarized and classified into “bulldozer strategies” and “mouse strategies.” Additionally, the evaluation methods, existing problems, and the development prospects of these technologies are discussed.
This review provides a timely and comprehensive summary and discussion of the existing penetration‐promoting surface modification strategies and possible future development directions based on the tumor penetration dilemma caused by the interaction of components in the tumor microenvironment. In addition, the evaluation methods of nanomedicine penetrability are summarized, and the challenges of surface modification for tumor penetration are discussed.
A novel modulation scheme, called carrier mode shift keying (CMSK), is proposed. The information is conveyed through both constellation modulation and the parameter map of the weighted-type ...fractional Fourier transform (WFRFT). It enables additional information transmission without incremental resources. To reduce the complexity associated with the detection of additional information, a non-linear information detection algorithm based on statistical features is proposed. The simulations demonstrate that, at the same signal-to-noise ratio (SNR), the transmission of additional information exhibits higher reliability compared to the conventional transmission of modulated information. This concept of hierarchical transmission of information based on reliability will show potential for superior performance in specific scenarios.
PDF
