Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe through TRPML1 channel.

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe-prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages.

Action Potential Firing Patterns Regulate Dopamine Release via Voltage-Sensitive Dopamine D2 Autoreceptors in Mouse Striatum In Vivo.

Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown.

Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism.

The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes.

The ion channels of endomembranes.

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well as those in the degradative pathway (early endosomes, macropinosomes, phagosomes, autophagosomes, late endosomes, and lysosomes). These endomembrane organelles/vesicles work together to synthesize, modify, package, transport, and degrade proteins, carbohydrates, and lipids, regulating the balance between cellular anabolism and catabolism. Large ion concentration gradients exist across endomembranes: Ca gradients for most endomembrane organelles and H gradients for the acidic compartments.

Structural basis for sugar perception by gustatory receptors.

Insects rely on a family of seven transmembrane proteins called gustatory receptors (GRs) to encode different taste modalities, such as sweet and bitter. We report structures of sweet taste receptors GR43a and GR64a in the apo and sugar-bound states. Both GRs form tetrameric sugar-gated cation channels composed of one central pore domain (PD) and four peripheral ligand-binding domains (LBDs).

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.

Synaptotagmin-11 Inhibits Synaptic Vesicle Endocytosis via Endophilin A1.

Synaptic vesicle (SV) endocytosis is a critical and well-regulated process for the maintenance of neurotransmission. We previously reported that synaptotagmin-11 (Syt11), an essential non-Ca-binding Syt associated with brain diseases, inhibits neuronal endocytosis (Wang et al., 2016).

Characterization of the role of TMEM175 in an in vitro lysosomal H fluxes model.

Lysosome acidification is a dynamic equilibrium of H influx and efflux across the membrane, which is crucial for cell physiology. The vacuolar H ATPase (V-ATPase) is responsible for the H influx or refilling of lysosomes. TMEM175 was identified as a novel H permeable channel on lysosomal membranes, and it plays a critical role in lysosome acidification.

Lysosomal solute and water transport.

Lysosomes mediate hydrolase-catalyzed macromolecule degradation to produce building block catabolites for reuse. Lysosome function requires an osmo-sensing machinery that regulates osmolytes (ions and organic solutes) and water flux. During hypoosmotic stress or when undigested materials accumulate, lysosomes become swollen and hypo-functional.

The Acid Gate in the Lysosome.

The acidic environment within lysosomes is maintained within a narrow pH range (pH 4.5-5.0) optimal for digesting autophagic cargo macromolecules so that the resulting building block metabolites can be reused.

Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.

Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules.

A protocol to measure lysosomal Zn release through a genetically encoded Zn indicator.

Intracellular vesicles such as lysosomes contain micromolar to millimolar concentrations of Zn, and disturbing lysosomal Zn homeostasis via lysosomal Zn release leads to mitochondria damage and consequent lytic cell death. Methods have been developed to image cellular Zn dynamics. Here, we present a protocol using GZnP3, a genetically encoded fluorescent Zn indicator, to assess lysosomal Zn release in cultured cells by fluorescence microscopy imaging.

Application of intracavitary electrocardiogram classification in peripherally inserted central catheter localization in cancer patients.

Objective: This study aimed to analyze the application value of intracavitary electrocardiogram (ECG) classification in peripherally inserted central catheter (PICC) tip localization in patients with cancer.

Methods: Using a self-control study method, 325 patients with cancer underwent intracavitary ECGs to position the tip of a PICC catheter. The P wave, QRS wave amplitude, and waveform changes of each intracavitary ECG were recorded.

SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways.

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca-dependent and mediated by unconventional exocytosis.

Lysosomal Zn release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma.

During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca and Zn release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells.

Synaptotagmin-11 inhibits spontaneous neurotransmission through vti1a.

Recent work has revealed that spontaneous release plays critical roles in the central nervous system, but how it is regulated remains elusive. Here, we report that synaptotagmin-11 (Syt11), a Ca -independent Syt isoform associated with schizophrenia and Parkinson's disease, suppressed spontaneous release. Syt11-knockout hippocampal neurons showed an increased frequency of miniature excitatory post-synaptic currents while over-expression of Syt11 inversely decreased the frequency.

LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses.

LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions.

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes.

Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood.

Magnetic stir bars with hyperbranched aptamer as coating for selective, effective headspace extraction of trace polychlorinated biphenyls in soils.

It is challenging to greatly increase of the extraction selectivity and efficiency by stir bar sorptive extraction of ultra-trace polychlorinated biphenyls (PCBs) in complex environmental matrix, e.g., soils.

Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6.

Epithelial homeostasis and regeneration require a pool of quiescent cells. How the quiescent cells are established and maintained is poorly understood. Here, we report that Trpv6, a cation channel responsible for epithelial Ca absorption, functions as a key regulator of cellular quiescence.

Integrated analysis of circular RNA-associated ceRNA network in cervical cancer: Observational Study.

Background: Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in cervical cancer remains largely unknown. This study aimed to describe the regulatory mechanisms in cervical cancer.

[Application of intervertebral foramen endoscopy BEIS technique in the lumbar spine surgery failure syndrome over 60 years old].

Objective: To evaluate the mid-term efficacy of radiofrequency ablation of nucleus pulposus by intervertebral foramen endoscopy BEIS technique in the treatment of lumbar spine surgery failure syndrome over 60 years old.

Methods: The clinical data of 40 patients over 60 years old with lumbar spine surgery failure syndrome admitted from January 2010 to January 2015 were retrospectively analyzed. Among them, there were 34 males and 6 females, aged from 60 to 76 years old with an average of 66 years, the courses of disease ranged from 10 months to 4 years.

Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK.

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose.

Prognostic value of lymphocyte-to-monocyte ratio in ovarian cancer: a meta-analysis.

Introduction: Prognostic biomarkers are highly needed to properly manage patients with cancer and improve their clinical courses. The relationship between lymphocyte-to-monocyte ratio (LMR) at diagnosis and ovarian cancer prognosis has been extensively studied, but little consensus has been reached regarding its utility as a biomarker of poor outcome. Thus, this study aimed to investigate the potential prognostic value of pretreatment LMR in such patients to shed light on this issue.