scholarly journals The two-cell model of glucose metabolism: a hypothesis of schizophrenia

2021 ◽  
Author(s):  
Dirk Roosterman ◽  
Graeme Stuart Cottrell
Keyword(s):  
Glucose Metabolism ◽  
Signaling Pathway ◽  
Cell Model ◽  
General Mechanism ◽  
Regulation Of Transcription ◽  
Self Awareness ◽  
Glucose Signaling ◽  
Schizophrenic Patients ◽  
The Central Nervous System ◽  
Glucose Metabolites

AbstractSchizophrenia is a chronic and severe mental disorder that affects over 20 million people worldwide. Common symptoms include distortions in thinking, perception, emotions, language, and self awareness. Different hypotheses have been proposed to explain the development of schizophrenia, however, there are no unifying features between the proposed hypotheses. Schizophrenic patients have perturbed levels of glucose in their cerebrospinal fluid, indicating a disturbance in glucose metabolism. We have explored the possibility that disturbances in glucose metabolism can be a general mechanism for predisposition and manifestation of the disease. We discuss glucose metabolism as a network of signaling pathways. Glucose and glucose metabolites can have diverse actions as signaling molecules, such as regulation of transcription factors, hormone and cytokine secretion and activation of neuronal cells, such as microglia. The presented model challenges well-established concepts in enzyme kinetics and glucose metabolism. We have developed a ‘two-cell’ model of glucose metabolism, which can explain the effects of electroconvulsive therapy and the beneficial and side effects of olanzapine treatment. Arrangement of glycolytic enzymes into metabolic signaling complexes within the ‘two hit’ hypothesis, allows schizophrenia to be formulated in two steps. The ‘first hit’ is the dysregulation of the glucose signaling pathway. This dysregulation of glucose metabolism primes the central nervous system for a pathological response to a ‘second hit’ via the astrocytic glycogenolysis signaling pathway.

scholarly journals Role of cAMP in Double Switch of Glucagon Secretion

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 896
Author(s):  
Jan Zmazek ◽  
Vladimir Grubelnik ◽  
Rene Markovič ◽  
Marko Marhl
Keyword(s):  
Glucose Metabolism ◽  
Signaling Pathway ◽  
Cell Model ◽  
Dominant Role ◽  
Glucagon Secretion ◽  
Camp Signaling ◽  
Independent Manner ◽  
Metabolic Switch ◽  
Camp Signaling Pathway ◽  
Double Switch

Glucose metabolism plays a crucial role in modulating glucagon secretion in pancreatic alpha cells. However, the downstream effects of glucose metabolism and the activated signaling pathways influencing glucagon granule exocytosis are still obscure. We developed a computational alpha cell model, implementing metabolic pathways of glucose and free fatty acids (FFA) catabolism and an intrinsically activated cAMP signaling pathway. According to the model predictions, increased catabolic activity is able to suppress the cAMP signaling pathway, reducing exocytosis in a Ca2+-dependent and Ca2+ independent manner. The effect is synergistic to the pathway involving ATP-dependent closure of KATP channels and consequent reduction of Ca2+. We analyze the contribution of each pathway to glucagon secretion and show that both play decisive roles, providing a kind of “secure double switch”. The cAMP-driven signaling switch plays a dominant role, while the ATP-driven metabolic switch is less favored. The ratio is approximately 60:40, according to the most recent experimental evidence.

scholarly journals Gambogic acid protects LPS-induced apoptosis and inflammation in a cell model of neonatal pneumonia through the regulation of TrkA/Akt signaling pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xu Gao ◽  
Jingya Dai ◽  
Guifang Li ◽  
Xinya Dai
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Cell Model ◽  
Akt Signaling ◽  
Gambogic Acid ◽  
Akt Signaling Pathway ◽  
Western Blot Assay ◽  
A Cell ◽  
Induced Apoptosis ◽  
Apoptosis And Inflammation

Abstract Objective In this work, we investigated the effects of gambogic acid (GA) on lipopolysaccharide (LPS)-induced apoptosis and inflammation in a cell model of neonatal pneumonia. Method Human WI-38 cells were maintained in vitro and incubated with various concentrations of GA to examine WI-38 survival. GA-preincubated WI-38 cells were then treated with LPS to investigate the protective effects of GA on LPS-induced death, apoptosis and inflammation. Western blot assay was utilized to analyze the effect of GA on tropomyosin receptor kinase A (TrkA) signaling pathway in LPS-treated WI-38 cells. In addition, human AKT serine/threonine kinase 1 (Akt) gene was knocked down in WI-38 cells to further investigate the associated genetic mechanisms of GA in protecting LPS-induced inflammation and apoptosis. Results Pre-incubating WI-38 cells with low and medium concentrations GA protected LPS-induced cell death, apoptosis and inflammatory protein productions of IL-6 and MCP-1. Using western blot assay, it was demonstrated that GA promoted TrkA phosphorylation and Akt activation in LPS-treated WI-38 cells. Knocking down Akt gene in WI-38 cells showed that GA-associated protections against LPS-induced apoptosis and inflammation were significantly reduced. Conclusions GA protected LPS-induced apoptosis and inflammation, possibly through the activations of TrkA and Akt signaling pathway. This work may broaden our understanding on the molecular mechanisms of human neonatal pneumonia.

scholarly journals In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine

2021 ◽  
Author(s):  
Antonio Munafò ◽  
Stefano Frara ◽  
Norberto Perico ◽  
Rosaria Di Mauro ◽  
Monica Cortinovis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Options ◽  
Public Health Problem ◽  
Cardiovascular Death ◽  
Regulation Of Transcription ◽  
Major Public Health Problem ◽  
Obese Patients ◽  
Ephedra Sinica ◽  
The Central Nervous System ◽  
Treatment Of Obesity

AbstractObesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with β3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.

scholarly journals Anxa2 gene silencing attenuates obesity-induced insulin resistance by suppressing the NF-κB signaling pathway

2019 ◽  
Vol 316 (2) ◽  
pp. C223-C234 ◽  
Author(s):  
Yong Wang ◽  
Yun-Sheng Cheng ◽  
Xiao-Qiang Yin ◽  
Gang Yu ◽  
Ben-Li Jia
Keyword(s):  
Insulin Resistance ◽  
Gene Silencing ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Cell Model ◽  
Global Scale ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Insulin resistance (IR) continues to pose a major threat to public health due to its role in the pathogenesis of metabolic syndrome and its ever-increasing prevalence on a global scale. The aim of the current study was to investigate the efficacy of Anxa2 in obesity-induced IR through the mediation of the NF-κB signaling pathway. Microarray analysis was performed to screen differentially expressed genes associated with obesity. To verify whether Anxa2 was differentially expressed in IR triggered by obesity, IR mouse models were established in connection with a high-fat diet (HFD). In the mouse IR model, the role of differentially expressed Anxa2 in glycometabolism and IR was subsequently detected. To investigate the effect of Anxa2 on IR and its correlation with inflammation, a palmitic acid (PA)-induced IR cell model was established, with the relationship between Anxa2 and the NF-κB signaling pathway investigated accordingly. Anxa2 was determined to be highly expressed in IR. Silencing Anxa2 was shown to inhibit IR triggered by obesity. When Anxa2 was knocked down, elevated expression of phosphorylated insulin receptor substrate 1 (IRS1), IRS1 and peroxisome proliferator-activated receptor coactivator-1a, and glucose tolerance and insulin sensitivity along with 2-deoxy-d-glucose uptake was detected, whereas decreased expression of suppressor of cytokine signaling 3, IL-6, IL-1β, TNF-α, and p50 was observed. Taken together, the current study ultimately demonstrated that Anxa2 may be a novel drug strategy for IR disruption, indicating that Anxa2 gene silencing is capable of alleviating PA or HFD-induced IR and inflammation through its negative regulatory role in the process of p50 nuclear translocation of the NF-κB signaling pathway.

scholarly journals Lipotoxicity-Induced mtDNA Release Promotes Diabetic Cardiomyopathy by Activating the cGAS-STING Pathway in Obesity Related Diabetes

2021 ◽  
Author(s):  
Xiu Mei Ma ◽  
Kang Geng ◽  
Betty Yuen-Kwan Law ◽  
Peng Wang ◽  
Yue Li Pu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Tissue ◽  
H9c2 Cells ◽  
Downstream Targets ◽  
Sting Pathway

Abstract Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissue. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was resulted from PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.

scholarly journals H2S alleviates Parkinson-like phenotypes by modulating lncRNA-CasC7/miR-30c/BNIP3L signaling pathway

2021 ◽  
Author(s):  
Ling Long ◽  
Xiaodong Cai ◽  
Jinchi Liao ◽  
Xiaomeng Ma ◽  
Yingying Liu ◽  
...  
Keyword(s):  
Cell Culture ◽  
Signaling Pathway ◽  
Neuronal Apoptosis ◽  
Cell Model ◽  
Motor Deficits ◽  
Motor Disorder ◽  
Regulatory Relationship ◽  
Interacting Protein ◽  
Protein Levels ◽  
Culture Model

IntroductionThe pathogenesis of Parkinson’s disease (PD) is closely related to mitophagy, a process regulated by miRNAs and long non-coding RNAs (lncRNAs). In this study, we investigated the role of the lncRNA-CasC7/miR-30c/BNIP3L (BCL2 Interacting Protein 3 Like) signaling pathway in PD.Material and methodsA 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD was generated and treated by hydrogen sulfide (H2S) inhalation. The SH-SY5Y cell model of PD was generated by MPP+ and the treatment was NaHS. The open field, rotarod and tail suspension tests were performed to assess motor deficits. TUNEL and immunofluorescence assays were used to evaluate neuronal apoptosis in mice and in SH-SY5Y cell culture. Real-time PCR was performed to measure the expression level of the lncRNA-CasC7, miR-30c and BNIP3L, and western blotting was used to assess the protein levels of CBS, BNIP3L and PINK1. Luciferase assays were conducted to examine the regulatory relationship between miR-30c and lncRNA-CasC7/BNIP3L.ResultsH2S inhalation alleviated the motor disorder and neuronal apoptosis in PD mice, and NaHS treatment inhibited apoptosis in the SH-SY5Y cell culture model of PD. The sulfide compounds also ameliorated the dysregulated expression of CasC7, miR-30c, BNIP3L, and PINK1 in the PD models. Furthermore, miR-30c significantly inhibited the expression of lncRNA-CasC7 and BNIP3L, as assessed with the luciferase assays.ConclusionsOur findings suggest that the lncRNA-CasC7/miR-30c/BNIP3L mitophagy signaling pathway is involved in the pathogenesis of PD.

scholarly journals The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Ji ◽  
Zhihui Zhang ◽  
Songwen Lin ◽  
Chunyang Wang ◽  
Jing Jin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Hedgehog Signaling Pathway ◽  
Orthotopic Mouse Model ◽  
Cycle Arrest ◽  
The Central Nervous System

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

scholarly journals Cryptotanshinone suppresses cell proliferation and glucose metabolism via STAT3/SIRT3 signaling pathway in ovarian cancer cells

2018 ◽  
Vol 7 (9) ◽  
pp. 4610-4618 ◽  
Author(s):  
Yufei Yang ◽  
Yue Cao ◽  
Lihua Chen ◽  
Fei Liu ◽  
Zihao Qi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Ovarian Cancer Cells

scholarly journals BK polyomavirus infection promotes growth and aggressiveness in bladder cancer

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Yigang Zeng ◽  
Jiajia Sun ◽  
Juan Bao ◽  
Tongyu Zhu
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Cell Model ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Urothelial Carcinomas ◽  
Bk Polyomavirus ◽  
And Migration

Abstract Background Recent studies have confirmed the integration of the BK polyomavirus (BKPyV) gene into the cellular genome of urothelial carcinomas in transplant recipients, further confirming the correlation between BKPyV and urothelial carcinomas after transplantation. However, the role BKPyV infections play in the biological function of bladder cancer remains unclear. Methods We developed a BKPyV-infected bladder cancer cell model and a mice tumor model to discuss the role of BKPyV infections. Results Our research proves that BKPyV infections promote the proliferation, invasion and migration of bladder cancer cells, while the activation of β-catenin signaling pathway is one of its mediation mechanisms. Conclusions We first described BKPyV infection promotes the proliferation, invasion and migration of bladder cancer. We verified the role of β-catenin signaling pathway and Epithelial-Mesenchymal Transition effect in BKPyV-infected bladder cancer. These results provide meaningful information towards the diagnosis and treatment of clinical bladder cancer.

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