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Original Article
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Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Cav1.2 splicing and RbFox1/Fox2 downregulation

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L-type voltage-gated Cav1.2 calcium channel regulates smooth muscle vascular contraction through calcium influx. Hypoxia downregulates and induces Cav1.2 alternative splicing (upregulating exon 9* and downregulating exon 33) in vascular smooth muscle cells, mediated by reduced RbFox1/2 expression. Hypoxia-induced Cav1.2 alternative splicing enhances sensitivity to calcium channel blocker, isradipine. RbFox1/2 overexpression during hypoxia prevents splicing changes and reduces isradipine sensitivity, suggesting a novel approach for managing ischemic diseases.

State‐of‐the‐Art Review
Open access

Structural and functional mechanisms of actin isoforms

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Actin isoforms are abundant cytoskeletal proteins that exhibit high structural and functional conservation yet have different cellular roles. This review discusses the structural and functional roles of actin isoforms, their biochemistries, and interactions with myosin motor proteins. Further, this review discusses the implications of post-translational modifications and disease-causing mutations on actin isoform biochemistry, function, and interactions.

Original Article
Open access

Functional characterization of Fur from the strict anaerobe Clostridioides difficile provides insight into its redox-driven regulatory capacity

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Iron homeostasis in Clostridium difficile is transcriptionally regulated by Fur and iron to avoid deleterious reactive radicals catalyzed by intracellular iron. We show a Fur reversible inactivation/activation mechanism dependent on Fur oligomerization, which responds to oxidizing conditions and is modulated by thioredoxin to control Fur binding to some of its regulon genes, also in an iron-independent manner. Fur regulatory ability may allow this bacterium to adapt to iron limitation.

Original Article

Essential residues in diterpene synthases for biosynthesis of oryzalexins A-F in rice phytoalexin

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Interconversion of enzymatic function between ent-kaurene synthase like 10 from domesticated rice (Oryza sativa) cv. Nipponbare (OsKSL10) and its homolog from wild rice (Oryza rufipogon) accession W1943 (OrKSL10) was achieved by amino acid substitution. These results imply that ent-miltiradiene synthase underwent a recent natural amino acid substitution of V546I/A654G during the cultivation of japonica rice and was converted to ent-sandaracopimaradiene synthase, leading to the acquisition of oryzalexin A-F biosynthesis.

Original Article

Inhibition of lactate dehydrogenase A by diclofenac sodium induces apoptosis in HeLa cells through activation of AMPK

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Lactate dehydrogenase A (LDHA) is overexpressed in multiple cancers and facilitates glycolysis by converting pyruvate to lactate for instant ATP production in cells. Diclofenac (DCF), an NSAID-group drug, is a specific LDHA inhibitor that decreases lactate, NAD+, and ATP production in cells. Cellular ATP deprivation leads to mitochondria-mediated oxidative stress and activates the sensor kinase AMPK, which further inhibits the phosphorylation of downstream S6K, leading to apoptosis-mediated cell death.

Original Article
Open access

Non-prime- and prime-side profiling of Pro-Pro endopeptidase specificity using synthetic combinatorial peptide libraries and mass spectrometry

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We profiled the full substrate specificity of Pro-Pro endopeptidases (PPEPs) in detail using a combination of synthetic combinatorial peptides and mass spectrometry. With this method, we determined the specificity of previously characterized PPEPs, PPEP mutants, and novel (putative) PPEPs. By combining this data with structural information, we shed more light on the structure–function relationship of this group of proteases. Adapted from Claushuis B et al. (2023 Anal Chem 95, 11621–11631), which is available under a Creative Commons Attribution 4.0 International License.

State‐of‐the‐Art Review
Open access

The role of compartmentalized β-AR/cAMP signaling in the regulation of lipolysis in white and brown adipocytes

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Adipocyte function is regulated by all three β-adrenergic receptor subtypes via the second messenger cAMP. This type of signaling is highly confined in subcellular microdomains or signalosomes by the action of various phosphodiesterase (PDE) families. This review highlights recent insights into cAMP compartmentation in white and brown adipocytes gained by live cell imaging techniques and how it regulates lipolysis under healthy and diabetic conditions as well as during adipocyte maturation.

Original Article
Open access

Nuclear patterns of phosphatidylinositol 4,5- and 3,4-bisphosphate revealed by super-resolution microscopy differ between the consecutive stages of RNA polymerase II transcription

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Quantitative dual-color direct stochastic optical reconstruction microscopy (dSTORM) revealed RNA polymerase II (RNAPII) transcription initiation marker phosphor-serine5 (P-S5) co-patterned with the nuclear phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in the nucleoplasm. However, P-S5 shifted its co-patterning from nucleoplasmic PI(4,5)P2 to the nuclear phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] at nuclear speckles. Additionally, the elongation marker phosphor-serine2 (P-S2) exhibited specific co-patterning with the nuclear speckle-associated PI(3,4)P2. This coincided with the movement of nascent RNA toward the nuclear speckle pool of PI(3,4)P2.

Original Article

ABCB1-mediated docetaxel resistance reversed by erastin in prostate cancer

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Erastin, can trigger the inhibition of the cystine–glutamate reverse transport system and other pathways leading to iron dependent cell death (ferroptosis). Here, we show that erastin reversed docetaxel resistance in prostate cancer by inhibiting the activity of multi-drug-resistant protein ATP-binding cassette subfamily B member 1 (ABCB1), thereby enhancing the extent of docetaxel-induced apoptosis.

Original Article

Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia

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Tau aggregates can be secreted into the extracellular space, thereby mediating propagation of tau pathology. Identifying mechanisms that prevent tau propagation is therefore critical for the development of therapeutic strategies for tauopathies. Microglia play an important role in clearing secreted tau. Here, we show that CR4, a previously undescribed receptor for tau fibrils, can mediate the clearance of extracellular tau fibrils, but not monomers by microglia. Moreover, inhibiting CR4 suppresses the clearance of extracellular tau fibrils and increases seed-competent tau fibrils in the extracellular space.

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