scholarly journals Novel strategy for treating neurotropic viral infections using hypolipidemic drug Atorvastatin

2019 ◽  
Author(s):  
Suvadip Mallick ◽  
Surajit Chakraborty ◽  
Bibhabasu Hazra ◽  
Sujata Dev ◽  
Sriparna Mukherjee ◽  
...  
Keyword(s):  
Er Stress ◽  
Viral Genome ◽  
Viral Infections ◽  
Host Protein ◽  
Dependent Manner ◽  
Neuro2a Cell ◽  
Novel Strategy ◽  
Related Proteins

AbstractChandipura virus (CHPV) and Japanese Encephalitis Virus (JEV) are known to infect neurons followed by their successful propagation. Increased incidences of central nervous system invasion by the abovementioned viruses have been reported in case of children and elderly thus culminating into severe neurological damage. Literature suggests induction of endoplasmic reticulum (ER)-stress related proteins upon CHPV and JEV infection which help promote viral reproduction. Since earlier studies underscore the pleotropic role of atorvastatin (AT) in neuroprotection against flaviviruses like Hepatitis C and dengue, it was hypothesized that AT might also act as a neuroprotective agent against RNA viruses like CHPV and JEV. AT-mediated antiviral activity was evaluated by assessing survivability of virus-infected mouse pups treated with the drug. Balb C mice were used for in vivo experiments. Neuro2A cell line was used as the model for in vitro experiments. Cells subjected to AT treatment were infected by CHPV and JEV followed by evaluation of ER stress-related and apoptosis-related proteins by immunoblotting technique and immunofluorescence microscopy. Interaction of host protein with viral genome was assessed by RNA-Co-IP. AT treatment exhibited significant anti-viral activity against CHPV and JEV infections via hnRNPC-dependent manner. Viral genome-hnRNPC interaction was found to be abrogated upon AT action. AT was also observed to reduce secretion of proinflammatory cytokines by the neurons in response to viral infection. Moreover, AT treatment was also demonstrated to reduce neuronal death by abrogating virus-induced miR-21 upregulation in hnRNPC-dependent fashion. This study thus suggests probable candidature of AT as antiviral against CHPV and JEV infections.

scholarly journals N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

2020 ◽  
Vol 21 (16) ◽  
pp. 5815
Author(s):  
Hongqing Xie ◽  
Xiaotong Li ◽  
Weiwei Yang ◽  
Liping Yu ◽  
Xiasen Jiang ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Er Stress ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Antineoplastic Effect ◽  
Tumor Tissues ◽  
Induced Apoptosis ◽  
Species Production

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

scholarly journals Curcumin Oxidation Is Required for Inhibition of Helicobacter pylori Growth, Translocation and Phosphorylation of Cag A

2021 ◽  
Vol 11 ◽  
Author(s):  
Ashwini Kumar Ray ◽  
Paula B. Luis ◽  
Surabhi Kirti Mishra ◽  
Daniel P. Barry ◽  
Mohammad Asim ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Growth Inhibition ◽  
Mrna Expression ◽  
Host Protein ◽  
Dependent Manner ◽  
Gene Encoding ◽  
E Coli ◽  
H Pylori

Curcumin is a potential natural remedy for preventing Helicobacter pylori-associated gastric inflammation and cancer. Here, we analyzed the effect of a phospholipid formulation of curcumin on H. pylori growth, translocation and phosphorylation of the virulence factor CagA and host protein kinase Src in vitro and in an in vivo mouse model of H. pylori infection. Growth of H. pylori was inhibited dose-dependently by curcumin in vitro. H. pylori was unable to metabolically reduce curcumin, whereas two enterobacteria, E. coli and Citrobacter rodentium, which efficiently reduced curcumin to the tetra- and hexahydro metabolites, evaded growth inhibition. Oxidative metabolism of curcumin was required for the growth inhibition of H. pylori and the translocation and phosphorylation of CagA and cSrc, since acetal- and diacetal-curcumin that do not undergo oxidative transformation were ineffective. Curcumin attenuated mRNA expression of the H. pylori virulence genes cagE and cagF in a dose-dependent manner and inhibited translocation and phosphorylation of CagA in gastric epithelial cells. H. pylori strains isolated from dietary curcumin-treated mice showed attenuated ability to induce cSrc phosphorylation and the mRNA expression of the gene encoding for IL-8, suggesting long-lasting effects of curcumin on the virulence of H. pylori. Our work provides mechanistic evidence that encourages testing of curcumin as a dietary approach to inhibit the virulence of CagA.

scholarly journals β-TrCP-mediated ubiquitination and degradation of Dlg5 regulates hepatocellular carcinoma cell proliferation

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Dongping Wang ◽  
Qi Zhang ◽  
Fenfen Li ◽  
Chan Wang ◽  
Changming Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Xenograft Model ◽  
Ubiquitin Proteasome System ◽  
Tumor Xenograft ◽  
Dependent Manner ◽  
Ubiquitin Proteasome ◽  
Novel Strategy ◽  
Hcc Cells

Abstract Background Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase (MAGUK) adaptor family of proteins and its deregulation has been implicated in the malignancy of several cancer types. Dlg5 was down-regulated in hepatocellular carcinoma (HCC) and lower Dlg5 expression was associated with poor survival of HCC patients. However, how to regulate Dlg5 remains largely unknown. Methods The co-immunoprecipitation assay was used to determine the interaction between Dlg5 and β-TrCP. The in vivo ubiquitination assay was performed to determine the regulation of Dlg5 by β-TrCP. CCK-8 and colony formation assay were implemented to detect the biological effect of Dlg5 on the growth of HCC cells in vitro. The effect of Dlg5 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. Results Here we report that Dlg5 is regulated by the ubiquitin proteasome system and depletion of either Cullin 1 or β-TrCP led to increased levels of Dlg5. β-TrCP regulated Dlg5 protein stability by targeting it for ubiquitination and subsequent destruction in a phosphorylation-dependent manner. We further demonstrated a crucial role of Ser730 in the non-canonical phosphodegron of Dlg5 in governing β-TrCP-mediated Dlg5 degradation. Importantly, failure to degrade Dlg5 significantly inhibited HCC cells proliferation both in vitro and in vivo. Conclusion Collectively, our finding provides a novel molecular mechanism for the negative regulation of Dlg5 by β-TRCP in HCC cells. It further suggests that preventing Dlg5 degradation could be a possible novel strategy for clinical treatment of HCC.

scholarly journals The Effects of Yuan-Zhi Decoction and Its Active Ingredients in Both In Vivo and In Vitro Models of Chronic Cerebral Hypoperfusion by Regulating the Levels of Aβ and Autophagy

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Yan Liu ◽  
Xiaobo Huang ◽  
Wenqiang Chen ◽  
Yujing Chen ◽  
Ningqun Wang ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Hippocampal Neurons ◽  
The Elderly ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Dependent Manner ◽  
Active Ingredients ◽  
Related Proteins

Chronic cerebral hypoperfusion (CCH) is closely related to the occurrence of Alzheimer’s disease (AD) in the elderly. CCH can induce overactivation of autophagy, which increases the deposition of amyloid-β (Aβ) plaques in the brain, eventually impairing the cognitive function. Yuan-Zhi decoction (YZD) is a traditional Chinese medicine (TCM) formulation that is used to treat cognitive dysfunction in the elderly, but the specific mechanism is still unclear. In this study, we simulated CCH in a rat model through bilateral common carotid artery occlusion (BCCAO) and treated the animals with YZD. Standard neurological tests indicated that YZD significantly restored the impaired cognitive function after BCCAO in a dose-dependent manner. Furthermore, YZD also decreased the levels of Aβ aggregates and the autophagy-related proteins ATG5 and ATG12 in their hippocampus. An in vitro model of CCH was also established by exposing primary rat hippocampal neurons to hypoxia and hypoglycemia (H-H). YZD and its active ingredients increased the survival of these neurons and decreased the levels of Aβ1-40 and Aβ1-42, autophagy-related proteins Beclin-1 and LC3-II, and the APP secretases BACE1 and PS-1. Finally, both Aβ aggregates showed a positive statistical correlation with the expression levels of the above proteins. Taken together, YZD targets Aβ, autophagy, and APP-related secretases to protect the neurons from hypoxic-ischemic injury and restore cognitive function.

scholarly journals Selenoprotein V Protects Against Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1858-1858
Author(s):  
Xu Zhang ◽  
Wei Xiong ◽  
Jiaqiang Huang ◽  
Xin Gen Lei
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Caspase 9 ◽  
Funding Sources ◽  
Control Plasmid ◽  
Selenoprotein V ◽  
Related Proteins

Abstract Objectives Selenoprotein V (SELENOV) contains a thioredoxin-like fold and a conserved CxxU motif with a potential redox function. Three experiments were performed to assess its in vivo and in vitro roles and mechanisms in coping with different oxidant insults. Methods In Expt.1, SELENOV knockout (KO) and wildtype (WT) mice (male, 8-wk old) were given an IP injection of saline, diquat (DQ, 12.5 mg/kg), or acetaminophen (APAP, 300 mg/kg) (n = 10), and killed 5 h after the injection to collect liver and blood. In Expt. 2, primary hepatocytes were isolated from the 2 genotypes, cultured in complete Williams's medium E, and treated with DQ (0, 0.25 and 0.75 mM) and APAP (0, 1, 3, and 6 mM) for 12 h. In Expt. 3, 293 T cells were transfected with a control plasmid (GFP) or the plasmid containing Selenov gene (full length, OE) and treated with APAP (0, 1, 2, and 4 mM) for 24 h or H2O2 (0.1, 0.2, and 0.4 mM) for 12 h. Results In Expt. 1, the DQ and APAP injections caused greater (P < 0.05) rises in serum alanine aminotransferase activities, hepatic malondialdehyde (MDA) and carbonyl contents, endoplasmic reticulum (ER) stress-related proteins (BIP and CHOP), apoptosis-related proteins (FAK and caspase 9), and 3-nitrotyrosine, along with lower total anti-oxidizing-capability (T-AOC) and severer hepatocyte necrosis in the central lobular areas, in the KO than in the WT. In Expt. 2, the DQ and APAP treatments induced elevated (P < 0.05) cell death (20–40%), MDA contents (25–35%), and decreased (P < 0.05) T-AOC (50–65%) in the KO hepatocytes than in the WT cells. The KO hepatocytes treated with APAP displayed a sharp decline (P < 0.05) in cellular total respiration ability than the WT cells. In Expt. 3, the OE cells had greater viability and T-AOC and lower reactive oxygen species, MDA, and carbonyl contents after the APAP and H2O2 exposures (all at P < 0.05) than the controls. Moreover, the OE cells had greater (P < 0.05) redox enzyme activities (GPX, TrxR, and SOD), and lower (P < 0.05) expressions of ER stress-related genes (Atf4, Atf6, Bip, Xpp1t, Xbp1s, and Chop) and proteins (BIP, CHOP, FAK, caspase 9) than the controls after the treatment of H2O2 (0.4 mM). Conclusions Our data revealed the in vivo and in vitro roles and mechanisms of SELENOV in protecting against oxidative stress, ER stress, and apoptosis induced by pro-oxidants. Funding Sources This research is supported in part by an NSFC grant #31,320,103,920.

scholarly journals RIPK3-mediated inflammation is a conserved β cell response to ER stress

2020 ◽  
Vol 6 (51) ◽  
pp. eabd7272
Author(s):  
Bingyuan Yang ◽  
Lisette A. Maddison ◽  
Karolina E. Zaborska ◽  
Chunhua Dai ◽  
Linlin Yin ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Response ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Proinflammatory Mediators ◽  
Islet Inflammation

Islet inflammation is an important etiopathology of type 2 diabetes; however, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered RIPK3-dependent IL1B induction in β cells as an instigator of islet inflammation. In cultured β cells, ER stress activated RIPK3, leading to NF-kB–mediated proinflammatory gene expression. In a zebrafish muscle insulin resistance model, overnutrition caused islet inflammation, β cell dysfunction, and loss in an ER stress–, ripk3-, and il1b-dependent manner. In mouse islets, high-fat diet triggered the IL1B expression in β cells before macrophage recruitment in vivo, and RIPK3 inhibition suppressed palmitate-induced β cell dysfunction and Il1b expression in vitro. Furthermore, in human islets grafted in hyperglycemic mice, a marked increase in ER stress, RIPK3, and NF-kB activation in β cells were accompanied with murine macrophage infiltration. Thus, RIPK3-mediated induction of proinflammatory mediators is a conserved, previously unrecognized β cell response to metabolic stress and a mediator of the ensuing islet inflammation.

Inhibition of geranylgeranyltransferase inhibits bronchial smooth muscle hyperresponsiveness in mice

2009 ◽  
Vol 297 (5) ◽  
pp. L984-L991 ◽  
Author(s):  
Yoshihiko Chiba ◽  
Shunsuke Sato ◽  
Motohiko Hanazaki ◽  
Hiroyasu Sakai ◽  
Miwa Misawa
Keyword(s):  
Smooth Muscle ◽  
Rho Kinase ◽  
Selective Inhibition ◽  
Dependent Manner ◽  
Bronchial Smooth Muscle ◽  
Concentration Dependent Manner ◽  
Characteristic Features ◽  
Novel Strategy

Recent studies revealed an involvement of RhoA/Rho-kinase in the contraction of bronchial smooth muscle (BSM), and this pathway has now been proposed as a new target for asthma therapy. A posttranslational geranylgeranylation of RhoA is required for its activation. Thus selective inhibition of geranylgeranyltransferase may be a novel strategy for treatment of the BSM hyperresponsiveness in asthmatics. To test this hypothesis, we investigated the effect of a geranylgeranyltransferase inhibitor, GGTI-2133, on antigen-induced BSM hyperresponsiveness by using mice with experimental asthma. Mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also were treated with GGTI-2133 (5 mg/kg ip) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused a BSM hyperresponsiveness to acetylcholine with the increased expressions of RhoA and the anti-farnesyl-positive 21-kDa proteins, probably geranylgeranylated RhoA. The in vivo GGTI-2133 treatments significantly inhibited BSM hyperresponsiveness induced by antigen exposure. In another series of experiments, BSM tissues isolated from the repeatedly antigen-challenged mice were cultured for 48 h in the absence or presence of GGTI-2133. Under these conditions, the putative geranylgeranylated RhoA was decreased in a GGTI-2133 concentration-dependent manner. The in vitro incubation with GGTI-2133 also inhibited BSM hyperresponsiveness induced by antigen exposure. These findings suggest that GGTI-2133 inhibits antigen-induced BSM hyperresponsiveness, probably by reducing downstream signal transduction of RhoA. Selective geranylgeranyltransferase inhibitors may be beneficial for the treatment of airway hyperresponsiveness, one of the characteristic features of allergic bronchial asthma.

scholarly journals Substrate priming enhances phosphorylation by the budding yeast kinases Kin1 and Kin2

2018 ◽  
Vol 293 (47) ◽  
pp. 18353-18364
Author(s):  
Grace R. Jeschke ◽  
Hua Jane Lou ◽  
Keith Weise ◽  
Charlotte I. Hammond ◽  
Mallory Demonch ◽  
...  
Keyword(s):  
Er Stress ◽  
Secretory Pathway ◽  
Consensus Sequence ◽  
Phosphorylation Site ◽  
Growth Defect ◽  
Common Mechanism ◽  
Sequence Motif ◽  
Dependent Manner

Multisite phosphorylation of proteins is a common mechanism for signal integration and amplification in eukaryotic signaling networks. Proteins are commonly phosphorylated at multiple sites in an ordered manner, whereby phosphorylation by one kinase primes the substrate by generating a recognition motif for a second kinase. Here we show that substrate priming promotes phosphorylation by Saccharomyces cerevisiae Kin1 and Kin2, kinases that regulate cell polarity, exocytosis, and the endoplasmic reticulum (ER) stress response. Kin1/Kin2 phosphorylated substrates within the context of a sequence motif distinct from those of their most closely related kinases. In particular, the rate of phosphorylation of a peptide substrate by Kin1/Kin2 increased >30-fold with incorporation of a phosphoserine residue two residues downstream of the phosphorylation site. Recognition of phosphorylated substrates by Kin1/Kin2 was mediated by a patch of basic residues located in the region of the kinase αC helix. We identified a set of candidate Kin1/Kin2 substrates reported to be dually phosphorylated at sites conforming to the Kin1/Kin2 consensus sequence. One of these proteins, the t-SNARE protein Sec9, was confirmed to be a Kin1/Kin2 substrate both in vitro and in vivo. Sec9 phosphorylation by Kin1 in vitro was enhanced by prior phosphorylation at the +2 position. Recognition of primed substrates was not required for the ability of Kin2 to suppress the growth defect of secretory pathway mutants but was necessary for optimal growth under conditions of ER stress. These results suggest that at least some endogenous protein substrates of Kin1/Kin2 are phosphorylated in a priming-dependent manner.

scholarly journals H2S attenuates endoplasmic reticulum stress in hypoxia-induced pulmonary artery hypertension

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Jianjun Wu ◽  
Weili Pan ◽  
Chao Wang ◽  
Hui Dong ◽  
Lei Xing ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Er Stress ◽  
Biological Effects ◽  
Pulmonary Artery Hypertension ◽  
Dependent Manner ◽  
Systemic Hemodynamic

Abstract Background: Previous studies have found that hydrogen sulfide (H2S) has multiple functions such as anti-inflammatory, antioxidative in addition to biological effects among the various organs. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. We hypothesized that endogenous bioactive molecular known to suppress endoplasmic reticulum (ER) stress signaling, like H2S, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension (PAH). Methods and results: A hypoxic model was established with PASMCs to investigate the possible role of H2S in PAH. Effects of H2S on proliferation of PASMCs were evaluated by CCK-8 and EdU assay treated with or without GYY4137 (donor of H2S). H2S significantly inhibited hypoxia-induced increase in PASMCs proliferation in a dose-dependent manner. H2S by intraperitoneal injection with rats both prevented and reversed chronic hypoxia-induced pulmonary hypertension in rats, decreasing pulmonary vascular resistance, pulmonary artery remodeling and right ventricular hypertrophy, and improving functional capacity without affecting systemic hemodynamic. Exogenous H2S suppressed ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation, and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. Conclusion: H2S effectively inhibits hypoxia-induced increase in cell proliferation, migration, and oxidative stress in PASMCs, and NOX-4 might be the underlying mechanism of PAH. Attenuating ER stress with exogenous H2S may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.

scholarly journals Cepharanthine as a Potential Novel Tumor-Regional Therapy in Treating Cutaneous Melanoma: Altering the Expression of Cathepsin B, Tumor Suppressor Genes and Autophagy-Related Proteins

2020 ◽  
Vol 8 ◽  
Author(s):  
Yufang Liu ◽  
Yang Xie ◽  
Yao Lin ◽  
Qingfang Xu ◽  
Yunfen Huang ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Cathepsin B ◽  
Skin Irritation ◽  
Melanoma Cells ◽  
Dependent Manner ◽  
Primary Cutaneous Melanoma ◽  
Regional Therapy ◽  
Related Proteins

The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans and need to develop more novel non-surgical therapies. Autophagy and cathepsin B targeted therapy was reported to improve melanoma treatment. Cepharanthine (CEP), a natural alkaloid extracted from the genus Cephalophyllum has been reported to have the function of inhibiting cancers. We found that CEP inhibited human primary cutaneous melanoma cells viability and proliferation in 24 h in vitro, and topical application or intra-tumoral injection of CEP decreased the growth of cutaneous melanoma in mice within 4 weeks. CEP preparations below 50% concentration did not induce skin irritation and allergy reaction on human skin in vivo. Primary cutaneous melanoma cells incubated with CEP, the expression of cathepsin B was decreased and the LC3-I and LC3-II expression changed in a dose-dependent manner, while p53, p21Cip1p, and p16Inka gene expression was up-regulated. We demonstrated the effects of CEP as a novel tumor-regional therapy for cutaneous melanoma and provided a preliminary research basis for future clinical treatment researches and the exploration of integrated treatments with systemic therapy, radiotherapy, and surgery for human primary cutaneous melanoma.

Sign in / Sign up

Export Citation Format

Share Document