Single-cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis.

Uncontrolled and excessive progression of liver fibrosis is thought to be the prevalent pathophysiological cause of liver cirrhosis and hepatocellular cancer, and there are currently no effective antifibrotic therapeutic options available. Intercellular communication and cellular heterogeneity in the liver are involved in the progression of liver fibrosis, but the exact nature of the cellular phenotypic changes and patterns of interregulatory remain unclear. Here, we performed single-cell RNA sequencing on nonparenchymal cells (NPCs) isolated from normal and fibrotic mouse livers.

A New Product of Bilirubin Degradation by HO and Its Formation in Activated Neutrophils and in an Inflammatory Mouse Model.

Bilirubin (BR) is a tetrapyrrolic compound stemming from heme catabolism with diverse physiological functions. It can be oxidized by HO to form several degradation products, some of which have been detected in vivo and may contribute to the pathogenesis of certain diseases. However, the oxidative degradation of BR is complex and the conditions that BR degradation occurs pathophysiologically remain obscure.

K2P1 leak cation channels contribute to ventricular ectopic beats and sudden death under hypokalemia.

Hypokalemia causes ectopic heartbeats, but the mechanisms underlying such cardiac arrhythmias are not understood. In reduced serum K concentrations that occur under hypokalemia, K2P1 two-pore domain K channels change ion selectivity and switch to conduct inward leak cation currents, which cause aberrant depolarization of resting potential and induce spontaneous action potential of human cardiomyocytes. K2P1 is expressed in the human heart but not in mouse hearts.

Bilirubin oxidation end product B prevents CoCl-induced primary cortical neuron apoptosis by promoting cell survival Akt/mTOR/p70S6K signaling pathway.

Bilirubin oxidation end products (BOXes) are associated with the late-developing neurological deficits after subarachnoid hemorrhage (SAH) possibly by direct constricting the cerebral arteries, but their specific impacts on neurons especially in the state of hypoxia, a prominent feature during the late stage of SAH, remain unclear. Here, we explored the effects of BOXes on the primary cortical neurons subjected to CoCl-induced hypoxia by evaluating the morphological and apoptotic changes of neurons. The present study showed that Z-BOX B but not Z-BOX A greatly alleviated CoCl-induced neuronal cell deterioration and apoptosis.

Bilirubin Oxidation End Products (BOXes) Induce Neuronal Oxidative Stress Involving the Nrf2 Pathway.

Delayed ischemic neurological deficit (DIND) is a severe complication after subarachnoid hemorrhage (SAH). Previous studies have suggested that bilirubin oxidation end products (BOXes) are probably associated with the DIND after SAH, but there is a lack of direct evidence yet even on cellular levels. In the present study, we aim to explore the potential role of BOXes and the involved mechanisms in neuronal function.

Clonal evolution in liver cancer at single-cell and single-variant resolution.

Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus.

Protein Kinase C δ (PKCδ) Attenuates Bleomycin Induced Pulmonary Fibrosis via Inhibiting NF-κB Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal interstitial lung disease characterized by consistent pulmonary inflammation. Although protein kinase C delta (PKCδ) is involved in broad scope cellular response, the role of PKCδ in IPF is complicated and has not been fully defined yet. Here, we reported that PKCδ deficiency (PKCδ) aggravated bleomycin (BLM)-induced pulmonary fibrosis and inflammation.

Activation of BK Channels Prevents Hepatic Stellate Cell Activation and Liver Fibrosis Through the Suppression of TGFβ1/SMAD3 and JAK/STAT3 Profibrotic Signaling Pathways.

Large-conductance and Ca-activated K (BK) channels are expressed in human hepatic stellate cells (HSCs), where they have roles in normal hepatic microcirculation, as well as in portal hypertension in liver cirrhosis through the regulation of contractility in activated HSCs. Nevertheless, whether BK channel activity exerts protective effects against aberrant HSC activation and hepatic fibrosis is unknown. Here, we report that BK channels are expressed in activated primary rat HSCs as well as in a human HSC line.

GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca signalling in a GABA-independent manner.

Background And Aims: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.

Capturing the Interaction Kinetics of an Ion Channel Protein with Small Molecules by the Bio-layer Interferometry Assay.

The bio-layer interferometry (BLI) assay is a valuable tool for measuring protein-protein and protein-small molecule interactions. Here, we first describe the application of this novel label-free technique to study the interaction of human EAG1 (hEAG1) channel proteins with the small molecule PIP2. hEAG1 channel has been recognized as potential therapeutic target because of its aberrant overexpression in cancers and a few gain-of-function mutations involved in some types of neurological diseases.

CSmiRTar: Condition-Specific microRNA targets database.

MicroRNAs (miRNAs) are functional RNA molecules which play important roles in the post-transcriptional regulation. miRNAs regulate their target genes by repressing translation or inducing degradation of the target genes' mRNAs. Many databases have been constructed to provide computationally predicted miRNA targets.

Eag1 K Channel: Endogenous Regulation and Functions in Nervous System.

1 (Eag1, Kv10.1, KCNH1) K channel is a member of the voltage-gated K channel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated K channels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family.

Nicotine facilitates VSMC dysfunction through a miR-200b/RhoGDIA/cytoskeleton module.

Nicotine can induce the abnormal migration and proliferation of vascular smooth muscle cells (VSMCs). We have previously shown that cytoskeletal proteins and RhoGDIA, a negative regulator of the Rho GTPase pathway, are involved in the nicotine-induced dysfunction of VSMCs. Here, we found that nicotine can activate the Rho GTPase pathway and induce the synthesis of the cytoskeletal proteins in VSMCs through the activation of intracellular downstream signaling pathways, including targets such as MYPT1, PAK1 and PI3K/AKT.

Human EAG channels are directly modulated by PIP2 as revealed by electrophysiological and optical interference investigations.

Voltage-gated ether à go-go (EAG) K(+) channels are expressed in various types of cancer cells and also in the central nervous system. Aberrant overactivation of human EAG1 (hEAG1) channels is associated with cancer and neuronal disorders such as Zimmermann-Laband and Temple-Baraitser syndromes. Although hEAG1 channels are recognized as potential therapeutic targets, regulation of their functional properties is only poorly understood.

Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels.

Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca(2+)- and voltage-dependent K(+) (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (β and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells.

A point mutation in the human Slo1 channel that impairs its sensitivity to omega-3 docosahexaenoic acid.

Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA) at nanomolar concentrations reversibly activate human large-conductance Ca(2+)- and voltage-gated K(+) (Slo1 BK) channels containing auxiliary β1 or β4 subunits in cell-free patches. Here we examined the action of DHA on the Slo1 channel without any auxiliary subunit and sought to elucidate the biophysical mechanism and the molecular determinants of the DHA sensitivity. Measurements of ionic currents through human Slo1 (hSlo1) channels reveal that the stimulatory effect of DHA does not require activation of the voltage or Ca(2+) sensors.

Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA.

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are well known for their functional versatility, which is bestowed in part by their rich modulatory repertoire. We recently showed that long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) found in oily fish lower blood pressure by activating vascular BK channels made of Slo1+β1 subunits. Here we examined the action of DHA on BK channels with different auxiliary subunit compositions.

Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca²⁺-dependent K⁺ channels.

Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA), found abundantly in oily fish, may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems. However, the mechanisms underlying the purported health-promoting effects of DHA remain largely unclear, in part because molecular signaling pathways and effectors of DHA are only beginning to be revealed. In vascular smooth muscle cells, large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels provide a critical vasodilatory influence.

Distinct functions of glial and neuronal dystroglycan in the developing and adult mouse brain.

Cobblestone (type II) lissencephaly and mental retardation are characteristic features of a subset of congenital muscular dystrophies that include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type congenital muscular dystrophy. Although the majority of clinical cases are genetically undefined, several causative genes have been identified that encode known or putative glycosyltransferases in the biosynthetic pathway of dystroglycan. Here we test the effects of brain-specific deletion of dystroglycan, and show distinct functions for neuronal and glial dystroglycan.

Bilirubin oxidation end products directly alter K+ channels important in the regulation of vascular tone.

The exact etiology of delayed cerebral vasospasm following cerebral hemorrhage is not clear, but a family of compounds termed 'bilirubin oxidation end products (BOXes)' derived from heme has been implicated. As proper regulation of vascular smooth muscle tone involves large-conductance Ca(2+)- and voltage-dependent Slo1 K(+) (BK, maxiK, K(Ca)1.1) channels, we examined whether BOXes altered functional properties of the channel.

Zn2+ activates large conductance Ca2+-activated K+ channel via an intracellular domain.

Zinc is an essential trace element and plays crucial roles in normal development, often as an integral structural component of transcription factors and enzymes. Recent evidence suggests that intracellular Zn(2+) functions as a signaling molecule, mediating a variety of important physiological phenomena. However, the immediate effectors of intracellular Zn(2+) signaling are not well known.

Comparative effects of H+ and Ca2+ on large-conductance Ca2+- and voltage-gated Slo1 K+ channels.

Large-conductance Ca(2+)- and voltage-gated Slo1 BK channels are allosterically activated by depolarization and intracellular ligands such as Ca(2+). Of the two high-affinity Ca(2+) sensors present in the channel, the RCK1 sensor also mediates H(+)-dependent activation of the channel. In this study, we examined the comparative mechanisms of the channel activation by Ca(2+) and H(+).

Modulation of BKCa channel gating by endogenous signaling molecules.

Large-conductance Ca(2+)- and voltage-activated K(+) (BK(Ca), MaxiK, or Slo1) channels are expressed in almost every tissue in our body and participate in many critical functions such as neuronal excitability, vascular tone regulation, and neurotransmitter release. The functional versatility of BK(Ca) channels owes in part to the availability of a spectacularly wide array of biological modulators of the channel function. In this review, we focus on modulation of BK(Ca) channels by small endogenous molecules, emphasizing their molecular mechanisms.