The Role of Autophagy at Nano/Bio Interface - Underlying Mechanisms and Therapeutic Potential in Cancer

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

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Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/1806344 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Yang Zhang ◽

Weifang Liu ◽

Yanqi Zhong ◽

Qi Li ◽

Mengying Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Low Dose ◽

Therapeutic Potential ◽

Metabolic Phenotypes ◽

Pyrin Domain ◽

Underlying Mechanisms ◽

And Oxidative Stress ◽

Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation

Cellular Physiology and Biochemistry ◽

10.1159/000491059 ◽

2018 ◽

Vol 47 (5) ◽

pp. 1769-1784 ◽

Cited By ~ 18

Author(s):

Chuwen Li ◽

Tongkai Chen ◽

Hefeng Zhou ◽

Chao Zhang ◽

Yu Feng ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Therapeutic Potential ◽

Erk Phosphorylation ◽

Nrf2 Activation ◽

Antioxidative Effects ◽

Underlying Mechanisms ◽

Oxidative Effects ◽

Anti Inflammation ◽

Schisantherin A

Background/Aims: In the present study, we investigated whether schisantherin A (StA) had anti-inflammatory effects under neuroinflammatory conditions. Methods: The effects of StA and its underlying mechanisms were examined in lipopolysaccharide (LPS)-activated BV-2 microglial cells by ELISA, qPCR, EMSA, Western blot, and IHC. Results: Firstly, we found that StA inhibited the inflammatory response in LPS-activated BV-2 microglia. Secondly, we found that StA suppressed LPS-induced activation of NF-κB via interfering with degradation of IκB and phosphorylation of IκB, IKK, PI3K/Akt, JNK, and p38 MAPK. Thirdly, StA conferred indirect antioxidative effects via quenching ROS and promoted expression of antioxidant enzymes, including HO-1 and NQO-1, via stimulating activation of Nrf2 pathways. Finally, we demonstrated that anti-neuroinflammatory actions of StA were dependent on ERK phosphorylation-mediated Nrf2 activation. Conclusion: StA induced ERK phosphorylation-mediated Nrf2 activation, which contributed to its anti-inflammation and anti-oxidation. The anti-neuroinflammatory and anti-oxidative effects of StA may show preventive therapeutic potential for various neuroinflammatory disorders.

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Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives

Frontiers in Immunology ◽

10.3389/fimmu.2021.761946 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenyu Wu ◽

Patrick Li ◽

Yuzi Tian ◽

Wenlu Ouyang ◽

Jessie Wai-Yan Ho ◽

...

Keyword(s):

Therapeutic Potential ◽

Host Immunity ◽

Preclinical Research ◽

Post Translational Modifications ◽

Different Types ◽

Arginine Residues ◽

Cell Death Signaling ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.

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Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes

10.21203/rs.2.17327/v1 ◽

2019 ◽

Author(s):

Xiong Zhang ◽

Lan-Bing Zhu ◽

Jia-Hui He ◽

Hong-Qiu Zhang ◽

Shu-Ya Ji ◽

...

Keyword(s):

Inflammatory Responses ◽

Therapeutic Potential ◽

Minor Amount ◽

Innate Immune Responses ◽

Reactive Microglia ◽

Tnf Α ◽

Primary Astrocytes ◽

Underlying Mechanisms ◽

The Impact

Abstract Background Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive of the role of paroxetine in astrocytic responses. Methods Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed. Results Paroxetine had no impact on LPS-stimulated iNOS, TNF-α and IL-1β expression, but inhibited M/Lps-induced TNF-α and IL-1β expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α and/or BDNF in astrocytes were in minor amount compared to those by microglia. Conclusions Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of NF-κB pathway, but has no impact on LPS-stimulated astrocyte activation. While the secondary astrocytic responses are not robust compared to the innate immune responses of microglia, our results support a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson’s disease.

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The Therapeutic Potential of Quercetin in Parkinson’s Disease: Insights into its Molecular and Cellular Regulation

Current Drug Targets ◽

10.2174/1389450120666191112155654 ◽

2020 ◽

Vol 21 (5) ◽

pp. 509-518 ◽

Cited By ~ 2

Author(s):

Omid Reza Tamtaji ◽

Tooba Hadinezhad ◽

Maryam Fallah ◽

Arash Rezaei Shahmirzadi ◽

Mohsen Taghizadeh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Substantia Nigra Pars Compacta ◽

Cellular Regulation ◽

Pathophysiological Role ◽

Underlying Mechanisms ◽

Treatment Procedures

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc). PD is a multifactorial disorder, with several different factors being suggested to play a synergistic pathophysiological role, including oxidative stress, autophagy, underlying pro-inflammatory events and neurotransmitters abnormalities. Overall, PD can be viewed as the product of a complex interaction of environmental factors acting on a given genetic background. The importance of this subject has gained more attention to discover novel therapies to prevent as well as treat PD. According to previous research, drugs used to treat PD have indicated significant limitations. Therefore, the role of flavonoids has been extensively studied in PD treatment. Quercetin, a plant flavonol from the flavonoid group, has been considered as a supplemental therapy for PD. Quercetin has pharmacological functions in PD by controlling different molecular pathways. Although few studies intended to evaluate the basis for the use of quercetin in the context of PD have been conducted so far, at present, there is very little evidence available addressing the underlying mechanisms of action. Various principal aspects of these treatment procedures remain unknown. Here, currently existing knowledge supporting the use of quercetin for the clinical management of PD has been reviewed.

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Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control

Cardiovascular Research ◽

10.1093/cvr/cvaa239 ◽

2020 ◽

Author(s):

Franziska S Rathjens ◽

Alica Blenkle ◽

Lavanya M Iyer ◽

Anke Renger ◽

Fahima Syeda ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Therapeutic Potential ◽

Ventricular Myocardium ◽

Transcriptional Network ◽

Cardiac Conduction ◽

Cytoskeleton Organization ◽

Therapeutic Value ◽

Underlying Mechanisms

Abstract Aims Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias. Methods and results We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced. Conclusions This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.

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A molecular link between diabetes and breast cancer: Therapeutic potential of repurposing incretin-based therapies for breast cancer

Current Cancer Drug Targets ◽

10.2174/1568009621666210901101851 ◽

2021 ◽

Vol 21 ◽

Author(s):

Pooja Jaiswal ◽

Versha Tripathi ◽

Aakruti Nayak ◽

Shreya Kataria ◽

Vladimir Lukashevich ◽

...

Keyword(s):

Breast Cancer ◽

Therapeutic Potential ◽

Female Breast Cancer ◽

Molecular Heterogeneity ◽

Cancer Type ◽

Breast Cancers ◽

Beneficial Effects ◽

Cancer Breast ◽

Underlying Mechanisms

: Female breast cancer recently surpassed lung cancer and became the most commonly diagnosed cancer worldwide. As per the recent data from WHO, breast cancer accounts for one out of every 8 cancer cases diagnosed among an estimated 2.3 million new cancer cases. Breast cancer is the most prevailing cancer type among women causing the highest number of cancer-related mortality. It has been estimated that in 2020, 68,5000 women died due to this disease. Breast cancers have varying degrees of molecular heterogeneity; therefore, they are divided into various molecular clinical sub types. Recent reports suggest that type 2 diabetes (one of the common chronic diseases worldwide) is linked to the higher incidence, accelerated progression, and aggressiveness of different cancers; especially breast cancer. Breast cancer is hormone-dependent in nature and has a cross-talk with metabolism. A number of antidiabetic therapies are known to exert beneficial effects on various types of cancers, including breast cancer. However, only a few reports are available on the role of incretin-based antidiabetic therapies in cancer as a whole and in breast cancer in particular. The present review sheds light on the potential of incretin based therapies on breast cancer and explores the plausible underlying mechanisms. Additionally, we have also discussed the sub types of breast cancer as well as the intricate relationship between diabetes and breast cancer.

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Microglia Polarization in Alzheimer’s Disease: Mechanisms and a Potential Therapeutic Target

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.772717 ◽

2021 ◽

Vol 13 ◽

Author(s):

Qinqin Wang ◽

Hongmei Yao ◽

Wenyan Liu ◽

Bailiu Ya ◽

Hongju Cheng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Amyloid Β ◽

Hyperphosphorylated Tau ◽

M2 Microglia ◽

Microglia Polarization ◽

Underlying Mechanisms ◽

Anti Inflammation

Neuroinflammation regulated by microglia is one of the important factors involved in the pathogenesis of Alzheimer’s disease (AD). Activated microglia exhibited phenotypes termed as M1 and M2 phenotypes separately. M1 microglia contribute to the development of inflammation via upregulating pro-inflammatory cytokines, while M2 microglia exert anti-inflammation effects through enhancing the expression of anti-inflammation factors. Moreover, M1 and M2 microglia could be mutually transformed under various conditions. Both M1 and M2 microglia are implicated in AD. Amyloid-β (Aβ) and hyperphosphorylated tau are two major components of AD pathological hallmarks, neuritic plaques, and neurofibrillary tangles. Both Aβ and hyperphosphorylated tau were involved in microglial activation and subsequent inflammation, which further contribute to neuronal and synaptic loss in AD. In this review, we summarized the roles of M1 and M2 microglia in AD and underlying mechanisms, which will provide an insight into the role of microglia in the pathogenesis of AD and highlight the therapeutic potential of modulating microglia.

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Response Interference as a Mechanism Underlying Implicit Measures

European Journal of Psychological Assessment ◽

10.1027/1015-5759.24.4.218 ◽

2008 ◽

Vol 24 (4) ◽

pp. 218-225 ◽

Cited By ~ 28

Author(s):

Bertram Gawronski ◽

Roland Deutsch ◽

Etienne P. LeBel ◽

Kurt R. Peters

Keyword(s):

Task Performance ◽

Psychological Research ◽

Implicit Measures ◽

Mediation Model ◽

Response Interference ◽

Relevant Evidence ◽

Moderated Mediation Model ◽

Stimulus Features ◽

Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

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