To maximize therapeutic effects and minimize unwanted effects, the interest in drug targeting to the endoplasmic reticulum (ER) or Golgi apparatus (GA) has been recently growing because two organelles are distributing hubs of cellular building/signaling components (e.g., proteins, lipids, Ca) to other organelles and the plasma membrane. Their structural or functional damages induce organelle stress (i.e., ER or GA stress), and their aggravation is strongly related to diseases (e.g., cancers, liver diseases, brain diseases). Many efforts have been developed to image (patho)physiological functions (e.g., oxidative stress, protein/lipid-related processing) and characteristics (e.g., pH, temperature, biothiols, reactive oxygen species) in the target organelles and to deliver drugs for organelle disruption using organelle-targeting moieties. Therefore, this review will overview the structure, (patho)physiological functions/characteristics, and related diseases of the organelles of interest. Future direction on ER or GA targeting will be discussed by understanding current strategies and investigations on targeting, imaging/sensing, and therapeutic systems.
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http://dx.doi.org/10.1016/j.addr.2024.115386 | DOI Listing |
Cell Commun Signal
January 2025
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Background: Bok is a poorly characterized Bcl-2 protein family member with roles yet to be clearly defined. It is clear, however, that Bok binds strongly to inositol 1,4,5-trisphosphate (IP) receptors (IPRs), which govern the mobilization of Ca from the endoplasmic reticulum, a signaling pathway required for many cellular processes. Also known is that Bok has a highly conserved phosphorylation site for cAMP-dependent protein kinase at serine-8 (Ser-8).
View Article and Find Full Text PDFSignal Transduct Target Ther
January 2025
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
The excessive cytokine release and limited persistence represent major challenges for chimeric antigen receptor T (CAR-T) cell therapy in diverse tumors. Conventional CARs employ an intracellular domain (ICD) from the ζ subunit of CD3 as a signaling module, and it is largely unknown how alternative CD3 chains potentially contribute to CAR design. Here, we obtained a series of CAR-T cells against HER2 and mesothelin using a domain comprising a single immunoreceptor tyrosine-based activation motif from different CD3 subunits as the ICD of CARs.
View Article and Find Full Text PDFEur J Heart Fail
January 2025
Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Aims: Hyperglycaemic conditions increase cardiac stress, a common phenomenon associated with inflammation, aging, and metabolic imbalance. Sodium-glucose cotransporter 2 inhibitors, a class of anti-diabetic drugs, showed to improve cardiovascular functions although their mechanism of action has not yet been fully established. This study investigated the effects of empagliflozin on cardiomyocytes following high glucose exposure, specifically focusing on inflammatory and metabolic responses.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
Key Laboratory of National Forestry and Grassland Administration on Biodiversity Conservation in Karst Mountainous Areas of Southwestern China, School of Life Sciences, Guizhou Normal University, Guiyang 550025, China. Electronic address:
ER stress activates the unfolded protein response (UPR), a critical mechanism for maintaining cellular homeostasis in plants. The p24 protein family is known to be involved in protein trafficking between the endoplasmic reticulum (ER) and the Golgi apparatus, but its role in ER stress remains unclear in plants. In this study, we found that Atp24δ8(delta8), a member of the δ-2 subclass of the p24 family, is significantly upregulated in response to tunicamycin-induced ER stress.
View Article and Find Full Text PDFCell Rep Med
January 2025
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address:
Alpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding of AAT variants resulting in gain-of-toxic aggregation in the liver and loss of monomer activity in the lung leading to chronic obstructive pulmonary disease (COPD). Using high-throughput screening, we discovered a bioactive natural product, phenethyl isothiocyanate (PEITC), highly enriched in cruciferous vegetables, including watercress and broccoli, which improves the level of monomer secretion and neutrophil elastase (NE) inhibitory activity of AAT-Z through the endoplasmic reticulum (ER) redox sensor protein disulfide isomerase (PDI) A4 (PDIA4). The intracellular polymer burden of AAT-Z can be managed by combination treatment of PEITC and an autophagy activator.
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