Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment.

Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics.

Beyond the bulk: overview and novel insights into the dynamics of muscle satellite cells during muscle regeneration.

Skeletal muscle possesses remarkable regenerative capabilities, fully recovering within a month following severe acute damage. Central to this process are muscle satellite cells (MuSCs), a resident population of somatic stem cells capable of self-renewal and differentiation. Despite the highly predictable course of muscle regeneration, evaluating this process has been challenging due to the heterogeneous nature of myogenic precursors and the limited insight provided by traditional markers with overlapping expression patterns.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers.

ISG15-USP18 Dysregulation by Oxidative Stress Promotes IFN-γ Secretion from CD8+ T Cells in Vitiligo.

Excessive oxidative stress is thought to play pathologic roles in cellular senescence and autoimmune disorders by inducing inflammation and breaking down immune tolerance. In this study, we sought to identify the factors linking oxidative stress to autoimmunity and cellular senescence in vitiligo, where elevated oxidative stress plays an important role. RNA sequencing analysis of hydrogen peroxide-treated melanocytes revealed upregulation of ISG15.

DNA double-strand break-free CRISPR interference delays Huntington's disease progression in mice.

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. CRISPR-Cas9 nuclease causes double-strand breaks (DSBs) in the targeted DNA that induces toxicity, whereas CRISPR interference (CRISPRi) using dead Cas9 (dCas9) suppresses the target gene expression without DSBs. Delivery of dCas9-sgRNA targeting CAG repeat region does not damage the targeted DNA in HEK293T cells containing CAG repeats.

7-desacetoxy-6,7-dehydrogedunin discovered by high-throughput screening system suppresses melanogenesis through ATP-P2X7 signaling inhibition.

Background: Hyperpigmented skin disorders such as melasma and lentigo are common photoaging diseases that cause cosmetic problems. The pigmentation is usually exacerbated by ultraviolet (UV) radiation, and various factors and pathways are involved in UV-mediated melanogenesis. Adenosine 5'-triphosphate (ATP), a well-known molecular unit of intracellular energy, is also regarded as a mediator of UV-mediated melanogenesis via the P2X7 purinergic receptor.

Antibody-dependent cellular cytotoxicity-null effector developed using mammalian and plant GlycoDelete platform.

Cancer therapy using immune checkpoint inhibitor antibodies has markedly shifted the paradigm of cancer treatment. However, methods completely eliminating the effector function of these signal-regulating antibodies is urgently required. The heterogeneity of glycan chains in antibodies limits their use as therapeutic agents due to their variability; thus, the development of uniform glycan chains is necessary.

Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer.

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect.

Nephrin expression in human epidermal keratinocytes and its implication in poor wound closure.

Nephrin is a type-1 transmembrane protein and a component of the slit diaphragm renal-filtration barrier. It has several functions in actin remodeling and cell-cell adhesion. Nephrin is principally located in the kidney glomerulus, but several studies have reported that nephrin is found in the pancreas, brain, and placenta.

Endogenous pannexin1 channels form functional intercellular cell-cell channels with characteristic voltage-dependent properties.

The occurrence of intercellular channels formed by pannexin1 has been challenged for more than a decade. Here, we provide an electrophysiological characterization of exogenous human pannexin1 (hPanx1) cell–cell channels expressed in HeLa cells knocked out for connexin45. The observed hPanx1 cell–cell channels show two phenotypes: O-state and S-state.

Evaluation of Subchronic Toxicity and Genotoxicity of Ethanolic Extract of Leaves and Stems.

, a traditional plant on Ulleung Island in the Republic of Korea, has been recognized for its multiple medicinal properties. However, potential toxicity and safety analyses of have not been previously investigated. Therefore, this study aimed to evaluate the safety profile of ethanolic extract of leaves and stems (EAG) in terms of genotoxicity and subchronic oral animal toxicity under OECD guidelines and GLP conditions.

Particulate Matter Promotes Melanin Production through Endoplasmic Reticulum Stress‒Mediated IRE1α Signaling.

Particulate matter (PM) is believed to be related to cardiovascular and respiratory diseases. The skin is also known to be affected by PM exposure as a result of skin barrier dysfunction, cutaneous inflammation, and apoptotic cell death. Epidemiological studies have suggested that PM is related to pigment spots.

Interaction between CD36 and FABP4 modulates adipocyte-induced fatty acid import and metabolism in breast cancer.

Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness.

Phospholipase D2 is a positive regulator of sirtuin 1 and modulates p53-mediated apoptosis via sirtuin 1.

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase that plays diverse physiological roles. However, little is known about the regulation of SIRT1 activity. Here, we show that phospholipase D2 (PLD2), but not PLD1, selectively interacts with SIRT1 and increases the deacetylase activity of SIRT1.

Comparison of CD20 Binding Affinities of Rituximab Produced in Nicotiana benthamiana Leaves and Arabidopsis thaliana Callus.

Plants are promising drug-production platforms with high economic efficiency, stability, and convenience in mass production. However, studies comparing the equivalency between the original antibodies and those produced in plants are limited. Amino acid sequences that constitute the Fab region of an antibody are diverse, and the post-transcriptional modifications that occur according to these sequences in animals and plants are also highly variable.

Identification of Cx45 as a Major Component of GJs in HeLa Cells.

 Gap junctions (GJs) are intercellular channels that connect adjacent cells electrically and metabolically. The iodide-yellow fluorescent protein (I-YFP) gap junctional intercellular communication (GJIC) assay is a recently developed method with high sensitivity. HeLa cells have been widely used as GJ-deficient cells for GJ-related research.

Distinct roles of stereociliary links in the nonlinear sound processing and noise resistance of cochlear outer hair cells.

Outer hair cells (OHCs) play an essential role in hearing by acting as a nonlinear amplifier which helps the cochlea detect sounds with high sensitivity and accuracy. This nonlinear sound processing generates distortion products, which can be measured as distortion-product otoacoustic emissions (DPOAEs). The OHC stereocilia that respond to sound vibrations are connected by three kinds of extracellular links: tip links that connect the taller stereocilia to shorter ones and convey force to the mechanoelectrical transduction channels, tectorial membrane-attachment crowns (TM-ACs) that connect the tallest stereocilia to one another and to the overlying TM, and horizontal top connectors (HTCs) that link adjacent stereocilia.

O-GlcNAcylation of light chain serine 12 mediates rituximab production doubled by thiamet G.

O-Glycosylation occurs in recombinant proteins produced by CHO cells, but this phenomenon has not been studied extensively. Here, we report that rituximab is an O-linked N-acetyl-glucosaminylated (O-GlcNAcylated) protein and the production of rituximab is increased by thiamet G, an inhibitor of O-GlcNAcase. The production of rituximab doubled with OGA inhibition and decreased with O-GlcNAc transferase inhibition.

A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells.

Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria.

Inhibition of gap junctional intercellular communication by an anti-migraine agent, flunarizine.

Gap junctions (GJs), which consist of proteins called connexins, are intercellular channels that allow the passage of ions, second messengers, and small molecules. GJs and connexins are considered as emerging therapeutic targets for various diseases. Previously, we screened numerous compounds using our recently developed iodide yellow fluorescent protein gap junctional intercellular communication (I-YFP GJIC) assay and found that flunarizine (FNZ), used for migraine prophylaxis and as an add-on therapy for epilepsy, inhibits GJIC in LN215 human glioma cells.

Critical Role of ATP-P2X7 Axis in UV-Induced Melanogenesis.

Purinergic signaling participates in skin physiology and pathology, such as hair growth, wound healing, inflammation, pain, and skin cancer. However, few studies have investigated the involvement of purinergic signaling in skin pigmentation. This study demonstrated that extracellular adenosine 5'-triphosphate (ATP) released from keratinocytes by UVB radiation promotes melanin production in primary human epidermal melanocytes and ex vivo skin cultures.

Low binding affinity and reduced complement-dependent cell death efficacy of ofatumumab produced using a plant system (Nicotiana benthamiana L.).

The plant protein production system is a platform that can not only reduce production costs but also produce monoclonal antibodies that do not have the risk of residual proteins from the host. However, due to the difference between post-translational processes in plants and animals, there may be a modification in the Fab region of the monoclonal antibody produced in the plant; thus, it is necessary to compare the antigen affinity of this antibody with that of the prototype. In this study, ofatumumab, a fully human anti-CD20 IgG1κ monoclonal antibody used for its non-cross resistance to rituximab, was expressed in Nicotiana benthamiana, and its affinities and efficacies were compared with those of native ofatumumab produced from CHO cells.