• 81960507 National Natural Science Foundation of China
• 82073087 National Natural Science Foundation of China
• QIAN KE HE JI CHU ZK (202) YI BAN 323 Science and Technology Plan Project of Guizhou Province
• 2020-39 Collaborative Innovation Center of the Chinese Ministry of Education
• ZUN SHI KE HE HZ ZI (2019)93 Hao Science and Technology Bureau fund of Zunyi City

• Mitochondrial function
• Ndufa8
• Oxidative stress
• Respiratory chain complex I
• White adipose tissue browning

• Animals
• Electron Transport Complex I/metabolism
• Obesity/metabolism
• Adipose Tissue, White/metabolism
• Mice
• Mitochondria/metabolism
• Mice, Inbred C57BL
• Adipose Tissue, Brown/metabolism
• Male
• Reactive Oxygen Species/metabolism
• Uncoupling Protein 1/metabolism
• Uncoupling Protein 1/genetics
• Dioxoles/pharmacology
• Diet, High-Fat
• Thermogenesis

• ATPase inhibitor
• anticancer agents
• bimolecular targets
• chemical proteomics
• ferroptosis

• National Natural Science Foundation of China
• Guangdong Basic and Applied Basic Research Foundation
• Fundamental Research Funds for the Central Universities

• Axon injury
• Axon regeneration
• CLIC1
• CLIC4
• Chloride intracellular channel protein
• Neuroprotection
• Optic neuropathy
• Retinal ganglion cells
• glaucoma

• Animals
• Retinal Ganglion Cells/metabolism
• Dependovirus/genetics
• Chloride Channels/genetics
• Chloride Channels/metabolism
• Cell Death/physiology
• Mice
• Mice, Inbred C57BL
• Male
• RNA, Small Interfering/genetics

• R01 EY032542 NEI NIH HHS
• R21 EY033060 NEI NIH HHS
• U01 EY027257 NEI NIH HHS

• Atherosclerosis
• Circular RNA
• Endothelial cell
• Signaling pathway

• Humans
• RNA, Circular
• Phosphatidylinositol 3-Kinases/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Signal Transduction
• Atherosclerosis/genetics

• H2020307041 Natural Science Foundation of Hebei Province

• Adenosine triphosphate homeostasis
• Adenosine triphosphate induced cell death
• Cancer signaling pathways
• Cancer treatment
• Mechanism
• Prognosis and clinical values

• ATP-induced cell death
• apoptosis
• autophagy
• bone marrow-derived mesenchymal stem cells
• complications
• osteoblasts
• osteoclasts
• osteoporosis

• Universiti Sains Malaysia
• National Natural Science Foundation of China
• Natural Science Foundation of Gansu Province

• RNA interference
• cell death
• chloride intracellular channel
• insect cell lines
• intracellular calcium ions

• National Natural Science Foundation of China

• HPV
• cancer
• ion channels
• molecular markers

• Humans
• Human Papillomavirus Viruses
• Papillomavirus Infections/complications
• Papillomavirus Infections/diagnosis
• Neoplasms/diagnosis
• Neoplasms/therapy
• Neoplasms/metabolism
• Ion Channels/metabolism
• Ions/metabolism

• Biomarker identification
• Differential expression analysis
• Differentially expressed gene
• Esophageal squamous cell carcinoma
• Microarray
• RNA-sequencing

• A9C, 9-Anthracenecarboxylic acid
• AMPhB, Amphotericin B
• Ad, Adenovirus
• Allosteric inhibition
• Bad, BCL2 associated agonist of cell death
• Bcl-2, B-cell lymphoma 2
• Bcl-xL, B-cell lymphoma-extra large
• CDK, Cyclin-dependent kinases
• CLIC, Chloride intracellular channel protein
• Chloride intracellular channel protein 4
• Computational high-throughput screening
• DAPI, 4′,6-diamidino-2-phenylindole
• DIDS, 4,4′-Diisothiocyano-2,2′-stilbenedisulfonic acid
• DMSO, Dimethyl sulfoxide
• DOPE, Discrete optimized protein energy
• GPU, Graphics Processing Unit
• GSH-like catalytic site
• GST, glutathione S-transferases
• GUI, Graphical User Interface
• HEPES, (4-(2-hydroxyethyl)− 1-piperazineethanesulfonic acid;
• HIF, Hypoxia-inducible factor
• HSQC, Heteronuclear single quantum coherence spectroscopy
• HUVEC, Human umbilical vein endothelial cells
• IKKβ, Inhibitor of nuclear kappa-B-kinase subunit beta
• JNK, c-Jun N-terminal kinase
• MKK6, Mitogen-activated protein kinase kinase-6
• MOI, Multiplicity of infection
• NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells
• NMR, Nuclear magnetic resonance
• NPT, The constant-temperature, constant-pressure ensemble
• NaCL, Sodium chloride
• Nuclear magnetic resonance
• PAH, Pulmonary arterial hypertension
• RAPA, Rapamycin
• SASA, Solvent accessible surface area
• SEK1, Dual specificity mitogen-activated protein kinase kinase 4
• Smad, Suppressor of Mothers against Decapentaplegic
• Structure-based drug discovery
• TEV, Tobacco etch virus
• TIP3P, Transferable intermolecular potential 3 P
• TROSY, Transverse relaxation optimized spectroscopy
• UCSF, University of California, San Francisco
• VEGF, Vascular endothelial growth factor
• p38, Mitogen activated protein kinases

• adipose tissues
• feed efficiency
• microRNA
• pig
• residual feed intake

• P01 HL147841 NHLBI NIH HHS
• R01 HL157453 NHLBI NIH HHS
• R01 HL121796 NHLBI NIH HHS
• R01 HL142588 NHLBI NIH HHS
• R01 HL139348 NHLBI NIH HHS
• K99 HL132123 NHLBI NIH HHS
• R01 HL136232 NHLBI NIH HHS
• R03 TR004178 NCATS NIH HHS
• R01 HL134824 NHLBI NIH HHS
• R01 HL113084 NHLBI NIH HHS
• R01 HL133050 NHLBI NIH HHS
• R01 AG057046 NIA NIH HHS
• R00 HL132123 NHLBI NIH HHS
• K99 HL155492 NHLBI NIH HHS
• R01 HL153164 NHLBI NIH HHS
• R01 HL156652 NHLBI NIH HHS
• R01 HL135096 NHLBI NIH HHS
• American Heart Association
• National Heart Lung and Blood Institute
• National of Aging

• CLIC4
• H(2)O(2)-induced apoptosis
• antioxidant
• cancer cells
• cancer redox
• mitochondrial ROS

• Animals
• Apoptosis/drug effects
• Apoptosis/genetics
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Chloride Channels/genetics
• Chloride Channels/metabolism
• Female
• Gene Deletion
• Glutaredoxins/metabolism
• Hydrogen Peroxide/metabolism
• Hydrogen Peroxide/pharmacology
• Mice
• Mitochondria/metabolism
• Mitochondrial Proteins/genetics
• Mitochondrial Proteins/metabolism
• Necrosis
• Proto-Oncogene Proteins c-bcl-2/metabolism
• RNA, Messenger/metabolism
• Superoxides/metabolism

• Z01 BC005445 Intramural NIH HHS
• ZIA BC005445 Intramural NIH HHS

• Apoptosis
• IL-17
• Lung epithelial cell
• Mycoplasma pneumoniae pneumonia
• S100A8/S100A9

• TDRG1
• breast cancer
• clic4
• miR-214-5p

Glioblastoma multiforme is an aggressive grade IV lethal brain tumour with a median survival of 14 months. Despite surgery to remove the tumour, and subsequent concurrent chemotherapy and radiotherapy, there is little in terms of effective treatment options. Because of this, exploring new treatment avenues is vital. Brain tumours are intrinsically electrically active; expressing unique patterns of ion channels, and this is a characteristic we can exploit. Ion channels are specialised proteins in the cell’s membrane that allow for the passage of positive and negatively charged ions in and out of the cell, controlling membrane potential. Membrane potential is a crucial biophysical signal in normal and cancerous cells. Research has identified that specific classes of ion channels not only move the cell through its cell cycle, thus encouraging growth and proliferation, but may also be essential in the development of brain tumours. Inhibition of sodium, potassium, calcium, and chloride channels has been shown to reduce the capacity of glioblastoma cells to grow and invade. Therefore, we propose that targeting ion channels and repurposing commercially available ion channel inhibitors may hold the key to new therapeutic avenues in high grade gliomas.

Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

• glioblastoma multiforme
• glioma
• ion channel
• ion channel inhibitor
• membrane potential

Pancreatic beta‐cells are central regulators of glucose homeostasis. By tightly coupling nutrient sensing and granule exocytosis, beta‐cells adjust the secretion of insulin to the circulating blood glucose levels. Failure of beta‐cells to augment insulin secretion in insulin‐resistant individuals leads progressively to impaired glucose tolerance, Type 2 diabetes, and diabetes‐related diseases. Mitochondria play a crucial role in β‐cells during nutrient stimulation, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion. Mitochondria are double‐membrane organelles containing numerous channels allowing the transport of ions across both membranes. These channels regulate mitochondrial energy production, signalling, and cell death. The mitochondria of β‐cells express ion channels whose physio/pathological role is underappreciated. Here, we describe the mitochondrial ion channels identified in pancreatic β‐cells, we further discuss the possibility of targeting specific β‐cell mitochondrial channels for the treatment of Type 2 diabetes, and we finally highlight the evidence from clinical studies.

This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc

• autosomal recessive nonsyndromic hearing impairment
• cancer
• cell signaling
• chloride channel
• chloride intracellular channel
• mitochondria
• physiology
• pulmonary hyperetnsion

• Cancer risk marker
• Head and neck cancers
• Ion channel
• Prognostic marker
• Squamous cell carcinoma
• Therapeutic target

• immune infiltration
• in situ hybridization
• miRNA
• single-cell RNA-sequencing
• stroma

• ZIA BC005445 Intramural NIH HHS

• Apoptosis
• CRISPR/Cas9
• LPS
• Neurodegenerative diseases
• c-Myc/chloride intracellular channel 4 pathway

• Animals
• Apoptosis/physiology
• Chloride Channels/genetics
• Chloride Channels/metabolism
• Disease Models, Animal
• Disease Progression
• Gene Knockout Techniques
• Lipopolysaccharides/toxicity
• Male
• Mitochondria/metabolism
• Mitochondrial Proteins/metabolism
• Neurodegenerative Diseases/physiopathology
• PC12 Cells
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• Rats
• Rats, Sprague-Dawley

Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process.

In the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model.

These results indicated that resveratrol reduced store-operated Ca²⁺ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1–STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.

The online version of this article (10.1186/s40659-019-0250-7) contains supplementary material, which is available to authorized users.

• Apoptosis
• ORAI1
• Resveratrol
• STIM1
• Store-operated calcium entry

Resveratrol, a bioactive compound predominantly found in grapes and red wine, provides a wide range of properties that are beneficial for health, including anticancer and anti-inflammatory activities. Previously published studies have addressed the potential therapeutic effects of resveratrol on rheumatoid arthritis (RA); however, the subcellular mechanism remains to be fully elucidated. In the present study, the therapeutic effects of resveratrol on adjuvant arthritis (AA) in Sprague-Dawley rats were investigated, and the mechanisms of resveratrol-induced apoptosis in fibroblast-like synoviocytes (FLSs) were further examined. Based on the findings, resveratrol treatment over a 12-day period led to a reduction in paw swelling and arthritis scores at the macroscopic level, and an attenuation of inflammatory cell infiltration and synovial hyperplasia, upon a histopathological examination of the AA rats. Furthermore, the administration of resveratrol triggered decreases in the expression of interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) and an increase in the expression of IL-10, alleviating inflammatory injury in AA rats in a dose-dependent manner. In addition, resveratrol was revealed to induce the apoptosis of FLSs when administered with 5 µM H₂O₂ as determined by elevated levels of Bax, caspase-3, caspase-12 and C/EBP-homologous protein, and the downregulation of B-cell lymphoma 2 (Bcl-2), suggesting that resveratrol is able to induce apoptosis in FLSs via the mitochondrial pathway and endoplasmic reticulum (ER) stress in a milieu containing 5 µM H₂O₂. Furthermore, JC-1 was used as a fluorescent probe to detect the mitochondrial membrane potential (Δψm), and resveratrol was shown to reduce the Δψm in FLSs in the presence of 5 µM H₂O₂. However, resveratrol was not able to trigger intracellular calcium overload, although it did suppress ATP- and thapsigargin-induced calcium release from the ER. In conclusion, the present study revealed that resveratrol was able to alleviate inflammatory injury in AA rats, triggering the apoptosis of FLSs via the mitochondrial pathway and ER stress. These results provide a theoretical basis for future treatments using resveratrol for RA.

Cutaneous squamous cell carcinoma (CSCC) is the second most common carcinoma worldwide. Clinical treatment for patients with CSCC remains non-ideal. Insulin-like growth factor binding protein 3 (IGFBP3), a member of the insulin-like growth (IGF) system, participates in several biological processes, including cellular proliferation and apoptosis. Here, we explored the functional role of IGFBP3 in apoptosis and proliferation of A431 cells, a human CSCC cell line.

Differential expression analysis, immunohistochemistry, immunoblotting, TUNEL assay, and CCK8 assay techniques were used to investigate the IGFBP3 expression levels in both A431 cells and CSCC tissue surgically obtained from humans as well as to explore the functional role of IGFBP3 in the apoptosis and proliferation of A431 cells.

By using normal epidermal keratinocytes for comparison, we identified the top 10 ranked differentially upregulated genes expressed in human cutaneous squamous cell carcinoma cell lines. Among these 10 genes, IGFBP3 was ranked number 1. By using immunohistochemistry, we found that the expression level of IGFBP3 was significantly elevated in CSCC tissue compared with that in normal human skin tissue. Knockdown of IGFBP3 in A431 cells by transfection with IGFBP3-specific siRNA markedly altered the expression of proteins that contribute to apoptosis via mitochondrial pathways, significantly suppressing the expression of Bax and active caspase-3, while significantly increasing B-cell lymphoma-2 expression. TUNEL assay confirmed the effect of knockdown of IGFBP3 on the apoptosis as well. In addition, knockdown of IGFBP3 inhibited the proliferation of A431 cells.

IGFBP3 is overexpressed in both CSCC cell lines and tissue. Knockdown of IGFBP3 enhanced the apoptosis via a mitochondrial pathway and inhibited the proliferation of A431 cells. These findings indicate that IGFBP3 may be a biomarker and a potential therapeutic target for CSCC.

• CSCC
• IGFBP3
• mitochondria
• proliferation

New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.

To investigate the molecular mechanisms of gastric carcinogenesis.

We used label-free quantification technology integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify differentially expressed proteins in 160 specimens of normal gastric mucosa, gastric mucosa with mild dysplasia, moderate dysplasia, severe dysplasia, and early mucosal gastric cancer (GC) collected at the Second Hospital of Lanzhou University from 2010 to 2015. Immunohistochemistry was used to verify the differentially expressed proteins detected by LC-MS/MS.

With a threshold of a 1.2-fold change and a P-value < 0.05 between mild dysplasia, moderate dysplasia, severe dysplasia or early mucosal GC and matched normal gastric mucosa tissues, proteomic analysis identified 365 significantly differentially expressed proteins. ERGIC1 expression decreased, while DNA-PKcs expression increased gradually along with different stages of GC initiation based on the tendency of fold change. The expression patterns of ERGIC1 and DNA-PKcs revealed by immunohistochemistry were consistent with the LC-MS/MS results.

The results suggest that aberrant ERGIC1 and DNA-PKcs expression may be involved in GC initiation.

• DNA-PKcs
• ERGIC1
• Dysplasia
• Proteomics
• Gastric cancer

• Adult
• Aged
• Carcinogenesis/pathology
• Cell Differentiation
• Chromatography, High Pressure Liquid/methods
• DNA-Activated Protein Kinase/metabolism
• Down-Regulation
• Female
• Gastric Mucosa/pathology
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Nuclear Proteins/metabolism
• Proteomics/methods
• Stomach Neoplasms/pathology
• Tandem Mass Spectrometry/methods
• Up-Regulation
• Vesicular Transport Proteins/metabolism

• Animals
• Apoptosis/drug effects
• Benzaldehydes/administration & dosage
• Benzaldehydes/pharmacology
• Brain Ischemia/genetics
• Brain Ischemia/prevention & control
• Cell Line
• Disease Models, Animal
• Endothelial Cells/cytology
• Endothelial Cells/drug effects
• Glucose/deficiency
• Human Umbilical Vein Endothelial Cells
• Humans
• Membrane Potential, Mitochondrial/drug effects
• MicroRNAs/genetics
• Proto-Oncogene Proteins c-bcl-2/genetics
• Rats
• Rats, Sprague-Dawley
• Up-Regulation