The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

Ion channels are a widespread class of membrane proteins that help establish and control cell membrane potential by allowing the passive diffusion of inorganic ions with high specificity through cell membrane. They are widely distributed in various cells and tissues, and their normal structure and function are of fundamental importance for all living organisms. The rapid advances in molecular cloning, protein structure analysis, patch clamp recordings and other technologies have greatly promoted the research on the biophysical and molecular properties of ion channels, and made significant progress in the study of the relationship between ion channels and pathophysiology as well. The immune system is made up of immune cells and organs that work together to protect the body and respond to infection and disease. Remarkably, recent basic and clinical research has revealed that ion channels are frequently and abundantly expressed in immune cells and have crucial roles in immune cell development and immune response. This review summarized recent progress in the roles of ion channels in immune cells, including the expression and regulation of ion channels in immune cells, the effects of ion flux mediated by ion channels on lymphocyte development, and functional roles of ion channels in both innate and adaptive immune responses. We also discussed some unresolved and insufficiently addressed issues in the current research, so as to provide an informative reference for better understanding the functional roles of ion channels in the immune system and further elucidation of their function from a physiological and pathological point of view.
Cell Membrane ; Immunity ; physiology ; Ion Channels ; immunology ; Membrane Proteins ; Research ; trends

OBJECTIVE: To investigate the effects of salvianolic acid A (SAA) on cardiomyocyte apoptosis and mitochondrial dysfunction in response to hypoxia/reoxygenation (H/R) injury and to determine whether the Akt signaling pathway might play a role. METHODS: An in vitro model of H/R injury was used to study outcomes on primary cultured neonatal rat cardiomyocytes. The cardiomyocytes were treated with 12.5, 25, 50 μg/mL SAA at the beginning of hypoxia and reoxygenation, respectively. Adenosine triphospate (ATP) and reactive oxygen species (ROS) levels were assayed. Cell apoptosis was evaluated by flow cytometry and the expression of cleaved-caspase 3, Bax and Bcl-2 were detected by Western blotting. The effects of SAA on mitochondrial dysfunction were examined by determining the mitochondrial membrane potential (△Ψm) and mitochondrial permeability transition pore (mPTP), followed by the phosphorylation of Akt (p-Akt) and GSK-3β (p-GSK-3β), which were measured by Western blotting. RESULTS: SAA significantly preserved ATP levels and reduced ROS production. Importantly, SAA markedly reduced the number of apoptotic cells and decreased cleaved-caspase 3 expression levels, while also reducing the ratio of Bax/Bcl-2. Furthermore, SAA prevented the loss of △Ψm and inhibited the activation of mPTP. Western blotting experiments further revealed that SAA significantly increased the expression of p-Akt and p-GSK-3β, and the increase in p-GSK-3β expression was attenuated after inhibition of the Akt signaling pathway with LY294002. CONCLUSION SAA has a protective effect on cardiomyocyte H/R injury; the underlying mechanism may be related to the preservation of mitochondrial function and the activation of the Akt/GSK-3β signaling pathway.
Adenosine Triphosphate ; analysis ; Animals ; Animals, Newborn ; Caffeic Acids ; pharmacology ; Cell Hypoxia ; Cells, Cultured ; Glycogen Synthase Kinase 3 beta ; physiology ; Lactates ; pharmacology ; Mitochondria, Heart ; drug effects ; physiology ; Mitochondrial Membrane Transport Proteins ; drug effects ; Myocytes, Cardiac ; drug effects ; Proto-Oncogene Proteins c-akt ; physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; metabolism ; Signal Transduction ; physiology

Proteins are the physical basis of life and perform all kinds of life activities. Proteins have different orientations and function in different tissues. The same protein, located in different subcellular regions, can perform different and even opposite functions. Both functional and structural proteins are capable of undergoing re-localization which can directly or indirectly participate in signal transduction. Due to abnormal transduction of signals during carcinogenesis, the proteins originally expressed in the cytoplasm are translocated into the nucleus and lead to functional changes in the tumor tissue. The changes of protein localization are affected by many factors, including the interaction between proteins, expression level of proteins and the cleaved intracellular domain of transmembrane protein.
Carcinogenesis ; pathology ; Cell Line, Tumor ; Cell Nucleus ; metabolism ; Cytoplasm ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins ; metabolism ; Protein Domains ; Protein Transport ; physiology ; Signal Transduction

Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtype-specific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affected GABAergic synapse formation more specifically than NL3, and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.
Animals ; Cell Adhesion Molecules, Neuronal ; physiology ; Cells, Cultured ; Cerebral Cortex ; embryology ; physiology ; GABAergic Neurons ; physiology ; Interneurons ; physiology ; Membrane Proteins ; physiology ; Nerve Tissue Proteins ; physiology ; Protein Isoforms ; physiology ; Pyramidal Cells ; physiology ; Rats, Sprague-Dawley ; Synapses ; physiology

Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and transporters. Studies have shown that hypoxia increases the release of a series of inflammatory cytokines which can modulate drug metabolism. Besides, both hypoxia inducible factor 1α (HIF-1α) and microRNA-mediated pathways play a role in regulating drug metabolism. This article reviewed the impact and single-factor modulating mechanisms of drug metabolism under hypoxia, and put forward the speculation and prospects of multi-factor modulating mechanisms.
Cell Hypoxia ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; physiology ; Membrane Transport Proteins ; physiology ; MicroRNAs ; physiology ; Pharmaceutical Preparations ; metabolism

Cell-to-cell connections provide conduits for signal exchanges, and play important functional roles in physiological and pathological processes of multicellular organisms. Membrane nanotubes are common long-distance connections between cells, not only transfer molecule signals and mitochondria, but also cooperate with gap junction and other cell-to-cell communications to transfer signals. During the last decade, there are many studies about membrane nanotubes, which focus on the similarities and differences between membrane nanotubes and other cell-to-cell communications, as well as their biological functions. In the present review, we summarized the latest findings about the structural diversity, the similarities and differences in signal transmission with other types of cell-to-cell communications, and physiological and pathological roles of membrane nanotubes.
Cell Communication ; Cell Membrane ; physiology ; Gap Junctions ; physiology ; Humans ; Mitochondria ; physiology ; Nanotubes

The study is aimed to explore the effects of stress at different temperatures( 35,45,55 ℃) on membrane permeability,active oxygen metabolism and accumulation of effective substances in Lonicera japonica,and provide theoretical basis for reducing deterioration and revealing browning mechanism during postharvest processing of L. japonica. The cell membrane permeability( relative conductivity,MDA content),active oxygen metabolism( SOD,POD,PPO,CAT activity) and the accumulation of effective substances( chlorogenic acid,luteolin,neochlorogenic acid,cryptochlorogenic acid,3,5-dicaffeoylquinic acid,3,4-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid) of L. japonica were all studied by constant temperature drying method,and the results were analyzed by the SPSS 17. 0 statistical software. The results showed that MDA content in L. japonica was increased by 151. 14% at 35 ℃,SOD,POD,PPO and CAT activity were 29. 73%,42. 86%,105. 02% and 10. 74% higher than at 45 ℃,respectively. The order of effective substance content in L. japonica was 35 ℃ >45 ℃ >55 ℃. The changes of membrane permeability,activity of active oxygen metabolizing enzyme and accumulation of active components were significantly affected by different temperature stress. The indexes showed that physiological and active oxygen metabolizing enzyme activity of L. japonica was the highest under 35 ℃ stress,chlorogenic acid and luteolin were effectively accumulated,which provides basic data for solving browning problem in the postharvest processing of L. japonica.
Cell Membrane Permeability ; Chlorogenic Acid/metabolism* ; Hot Temperature ; Lonicera/physiology* ; Luteolin/metabolism* ; Oxygen/metabolism* ; Stress, Physiological

OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) in mediating the protective effect of gastrodin against oxidative stress damage in H9c2 cardiac myocytes. METHODS: H9c2 cardiac myocytes were treated with HO, gastrodin, gastrodin+HO, cyclosporin A (CsA), or CsA+gas+HO group. MTT assay was used to detect the survival ratio of H9c2 cells, and flow cytometry with Annexin V-FITC/PI double staining was used to analyze the early apoptosis rate after the treatments. The concentration of ATP and level of reactive oxygen species (ROS) in the cells were detected using commercial kits. The mitochondrial membrane potential of the cells was detected with laser confocal microscopy. The expression of cytochrome C was detected with Western blotting, and the activity of caspase-3 was also assessed in the cells. RESULTS: Gastrodin pretreatment could prevent oxidative stress-induced reduction of mitochondrial membrane potential, and this effect was inhibited by the application of CsA. Gastrodin significantly lowered the levels of ROS and apoptosis-related factors in HO-exposed cells, and such effects were reversed by CsA. CsA significantly antagonized the protective effect of gastrodin against apoptosis in HO-exposed cells. CONCLUSIONS Gastrodin prevents oxidative stress-induced injury in H9c2 cells by inhibiting mPTP opening to reduce the cell apoptosis.
Adenosine Triphosphate ; analysis ; Apoptosis ; drug effects ; Benzyl Alcohols ; antagonists & inhibitors ; pharmacology ; Caspase 3 ; analysis ; Cell Line ; Cell Survival ; drug effects ; Cyclosporine ; pharmacology ; Cytochromes c ; analysis ; Glucosides ; antagonists & inhibitors ; pharmacology ; Humans ; Hydrogen Peroxide ; antagonists & inhibitors ; pharmacology ; Membrane Potential, Mitochondrial ; drug effects ; Mitochondrial Membrane Transport Proteins ; physiology ; Myocytes, Cardiac ; drug effects ; metabolism ; Oxidative Stress ; Reactive Oxygen Species ; analysis

Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.
Aging ; metabolism ; Animals ; Brain ; metabolism ; pathology ; Cell Line, Tumor ; Gene Expression ; physiology ; Huntingtin Protein ; genetics ; metabolism ; Membrane Glycoproteins ; metabolism ; Mice ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins ; metabolism ; RNA, Messenger ; metabolism ; Transcription, Genetic ; physiology