Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics Against Mycobacterial Infection

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen causing human tuberculosis, an infectious disease that still remains as a global health problem. Autophagy, a lysosomal degradative process, has emerged as a critical pathway to restrict intracellular Mtb growth through enhancement of phagosomal maturation. Indeed, several autophagy-modulating agents show promise as host-directed therapeutics for Mtb infection. In this Review, we discuss recent progress in our understanding the molecular mechanisms underlying the action of autophagy-modulating agents to overcome the immune escape strategies mediated by Mtb. The factors and pathways that govern such mechanisms include adenosine 5′-monophosphate-activated protein kinase, Akt/mammalian TOR kinase, Wnt signaling, transcription factor EB, cathelicidins, inflammation, endoplasmic reticulum stress, and autophagy-related genes. A further understanding of these mechanisms will facilitate the development of host-directed therapies against tuberculosis as well as infections with other intracellular bacteria targeted by autophagic degradation.

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Anticancer Agents Based on Vulnerable Components in a Signalling Pathway

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200212105417 ◽

2020 ◽

Vol 20 (10) ◽

pp. 886-907 ◽

Cited By ~ 4

Author(s):

Ankur Vaidya ◽

Shweta Jain ◽

Sanjeev Sahu ◽

Pankaj Kumar Jain ◽

Kamla Pathak ◽

...

Keyword(s):

Anticancer Agents ◽

Dna Methyltransferase ◽

Leucine Zipper ◽

Molecular Mechanisms ◽

Resistance Mechanisms ◽

Sphingosine Kinase 2 ◽

Family Protein ◽

Rational Combination ◽

Protein Kinase Akt ◽

Parp 1

Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

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Direct current stimulation enhances neuronal alpha-synuclein degradation in vitro

Scientific Reports ◽

10.1038/s41598-021-81693-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gessica Sala ◽

Tommaso Bocci ◽

Valentina Borzì ◽

Marta Parazzini ◽

Alberto Priori ◽

...

Keyword(s):

Direct Current ◽

Molecular Mechanisms ◽

Neuroblastoma Cell ◽

Alpha Synuclein ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma ◽

Direct Current Stimulation ◽

Gene And Protein Expression ◽

Autophagic Degradation ◽

On Line

AbstractDespite transcranial Direct Current Stimulation (DCS) is currently proposed as a symptomatic treatment in Parkinson’s disease, the intracellular and molecular mechanisms elicited by this technique are still unknown, and its disease-modifying potential unexplored. Aim of this study was to elucidate the on-line and off-line effects of DCS on the expression, aggregation and degradation of alpha-synuclein (asyn) in a human neuroblastoma cell line under basal conditions and in presence of pharmachologically-induced increased asyn levels. Following DCS, gene and protein expression of asyn and its main autophagic catabolic pathways were assessed by real-time PCR and Western blot, extracellular asyn levels by Dot blot. We found that, under standard conditions, DCS increased monomeric and reduced oligomeric asyn forms, with a concomitant down-regulation of both macroautophagy and chaperone-mediated autophagy. Differently, in presence of rotenone-induced increased asyn, DCS efficiently counteracted asyn accumulation, not acting on its gene transcription, but potentiating its degradation. DCS also reduced intracellular and extracellular asyn levels, increased following lysosomal inhibition, independently from autophagic degradation, suggesting that other mechanisms are also involved. Collectively, these findings suggest that DCS exerts on-line and off-line effects on the expression, aggregation and autophagic degradation of asyn, indicating a till unknown neuroprotective role of tDCS.

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RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury

Cell Death and Disease ◽

10.1038/s41419-021-03865-8 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Ruizhao Li ◽

Xingchen Zhao ◽

Shu Zhang ◽

Wei Dong ◽

Li Zhang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Transcription Factor ◽

Nuclear Translocation ◽

Kidney Injury ◽

Septic Acute Kidney Injury ◽

Transcription Factor Eb ◽

Autophagic Degradation ◽

Lps Treatment

AbstractAutophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

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The Function of the PRRSV–Host Interactions and Their Effects on Viral Replication and Propagation in Antiviral Strategies

Vaccines ◽

10.3390/vaccines9040364 ◽

2021 ◽

Vol 9 (4) ◽

pp. 364

Author(s):

Jun Ma ◽

Lulu Ma ◽

Meiting Yang ◽

Wei Wu ◽

Wenhai Feng ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Immune Escape ◽

Rna Virus ◽

Economic Losses ◽

Respiratory Syndrome Virus ◽

Swine Industry ◽

Live Virus ◽

Virus Challenge ◽

Host Interactions

Porcine reproductive and respiratory syndrome virus (PRRSV) affects the global swine industry and causes disastrous economic losses each year. The genome of PRRSV is an enveloped single-stranded positive-sense RNA of approximately 15 kb. The PRRSV replicates primarily in alveolar macrophages of pig lungs and lymphatic organs and causes reproductive problems in sows and respiratory symptoms in piglets. To date, studies on how PRRSV survives in the host, the host immune response against viral infections, and pathogenesis, have been reported. PRRSV vaccines have been developed, including inactive virus, modified live virus, attenuated live vaccine, DNA vaccine, and immune adjuvant vaccines. However, there are certain problems with the durability and effectiveness of the licensed vaccines. Moreover, the high variability and fast-evolving populations of this RNA virus challenge the design of PRRSV vaccines, and thus effective vaccines against PRRSV have not been developed successfully. As is well known, viruses interact with the host to escape the host’s immune response and then replicate and propagate in the host, which is the key to virus survival. Here, we review the complex network and the mechanism of PRRSV–host interactions in the processes of virus infection. It is critical to develop novel antiviral strategies against PRRSV by studying these host–virus interactions and structures to better understand the molecular mechanisms of PRRSV immune escape.

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Long noncoding RNA: a dazzling dancer in tumor immune microenvironment

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01727-3 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Yalu Zhang ◽

Qiaofei Liu ◽

Quan Liao

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Immune Escape ◽

Noncoding Rnas ◽

Pathological Process ◽

Cellular Functions ◽

Immune Microenvironment ◽

Protein Coding ◽

Functional Roles ◽

Tumor Immune Microenvironment

Abstract Long noncoding RNAs (lncRNAs) are a class of endogenous, non-protein coding RNAs that are highly linked to various cellular functions and pathological process. Emerging evidence indicates that lncRNAs participate in crosstalk between tumor and stroma, and reprogramming of tumor immune microenvironment (TIME). TIME possesses distinct populations of myeloid cells and lymphocytes to influence the immune escape of cancer, the response to immunotherapy, and the survival of patients. However, hitherto, a comprehensive review aiming at relationship between lncRNAs and TIME is missing. In this review, we focus on the functional roles and molecular mechanisms of lncRNAs within the TIME. Furthermore, we discussed the potential immunotherapeutic strategies based on lncRNAs and their limitations.

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The Role of Vitamin D and the Vitamin D Receptor in Bone Oncology

Osteologie/Osteology ◽

10.1055/s-0038-1673534 ◽

2018 ◽

Vol 27 (03) ◽

pp. 129-134 ◽

Cited By ~ 1

Author(s):

B. M. Holzapfel ◽

F. Jakob ◽

A. A. Kurth ◽

G. Maier ◽

K. Horas

Keyword(s):

Vitamin D ◽

Cancer Cells ◽

Vitamin D Deficiency ◽

Vitamin D Receptor ◽

Molecular Mechanisms ◽

Full Range ◽

Cancer Cell Growth ◽

The Past ◽

Global Health Problem

SummaryVitamin D deficiency is a global health problem of enormous and increasing dimensions. In the past decades, numerous studies have centered on the role of vitamin D in the pathogenesis and course of many diseases including several types of cancer. Indeed, vitamin D has been widely acknowledged to be involved in the regulation of cell proliferation, differentiation and apoptosis in numerous cancer cells. While the full range of molecular mechanisms involveld in cancer cell growth and progression remains to be elucidated, recent research has deepened our understanding of the processes that may be affected by vitamin D or vitamin D deficiency.In this review, we consider the properties of bone that enable cancer cells to grow and thrive within the skeleton, and the role of vitamin D and the vitamin D receptor in the process of primary and secondary cancer growth in bone.

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Mitofusin 2-Deficiency Suppresses Mycobacterium tuberculosis Survival in Macrophages

Cells ◽

10.3390/cells8111355 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1355 ◽

Cited By ~ 3

Author(s):

Junghwan Lee ◽

Ji-Ae Choi ◽

Soo-Na Cho ◽

Sang-Hun Son ◽

Chang-Hwa Song

Keyword(s):

Mycobacterium Tuberculosis ◽

Molecular Mechanisms ◽

Defense Mechanism ◽

Mitochondrial Fission ◽

Mycobacterial Infection ◽

Mitofusin 2 ◽

Unstimulated Control ◽

Host Defense Mechanism ◽

Important Host

Apoptosis is an important host defense mechanism against mycobacterial infection. However, the molecular mechanisms regulating apoptosis during mycobacterial infection are not well known. Recent reports suggest that bacterial infection regulates mitochondrial fusion and fission in various ways. Here, we investigated the role of mitochondria in Mycobacterium tuberculosis (Mtb)-infected macrophages. Mtb H37Rv (Rv) infection induced mitofusin 2 (MFN2) degradation, leading to mitochondrial fission. Interestingly, Mtb H37Ra (Ra) infection induced significantly greater mitochondrial fragmentation than Rv infection. Mtb-mediated Parkin, an E3 ubiquitin ligase, contributed to the degradation of MFN2. To evaluate the role of endoplasmic reticulum stress in the production of Parkin during Mtb infection, we analyzed Parkin production in 4-phenylbutyric acid (4-PBA)-pretreated macrophages. Pretreatment with 4-PBA reduced Parkin production in Mtb-infected macrophages. In contrast, the level of MFN2 production recovered to a level similar to that of the unstimulated control. In addition, Ra-infected macrophages had reduced mitochondrial membrane potential (MMP) compared to those infected with Rv. Interestingly, intracellular survival of mycobacteria was decreased in siMFN2-transfected macrophages; in contrast, overexpression of MFN2 in macrophages increased Mtb growth compared with the control.

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Rab GTPases in Osteoclastic Bone Resorption and Autophagy

International Journal of Molecular Sciences ◽

10.3390/ijms21207655 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7655

Author(s):

Michèle Roy ◽

Sophie Roux

Keyword(s):

Bone Resorption ◽

Molecular Mechanisms ◽

Bone Diseases ◽

Vesicular Trafficking ◽

Disease Development ◽

Rab Gtpases ◽

Bone Homeostasis ◽

Autophagic Degradation ◽

Ruffled Border ◽

And Function

Small guanosine triphosphate hydrolases (GTPases) of the Rab family are involved in plasma membrane delivery, fusion events, and lysosomal and autophagic degradation pathways, thereby regulating signaling pathways and cell differentiation and function. Osteoclasts are bone-resorbing cells that maintain bone homeostasis. Polarized vesicular trafficking pathways result in the formation of the ruffled border, the osteoclast’s resorptive organelle, which also assists in transcytosis. Here, we reviewed the different roles of Rab GTPases in the endomembrane machinery of osteoclasts and in bone diseases caused by the dysfunction of these proteins, with a particular focus on autophagy and bone resorption. Understanding the molecular mechanisms underlying osteoclast-related bone disease development is critical for developing and improving therapies.

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Molecular Mechanisms of Immune Escape for Foot-and-Mouth Disease Virus

Pathogens ◽

10.3390/pathogens9090729 ◽

2020 ◽

Vol 9 (9) ◽

pp. 729

Author(s):

Bo Yang ◽

Xiaohui Zhang ◽

Dajun Zhang ◽

Jing Hou ◽

GuoWei Xu ◽

...

Keyword(s):

Immune Responses ◽

Disease Virus ◽

Molecular Mechanisms ◽

Immune Escape ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Host Immune Responses ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Vesicular Disease

Foot-and-mouth disease virus (FMDV) causes a highly contagious vesicular disease in cloven-hoofed livestock that results in severe consequences for international trade, posing a great economic threat to agriculture. The FMDV infection antagonizes the host immune responses via different signaling pathways to achieve immune escape. Strategies to escape the cell immune system are key to effective infection and pathogenesis. This review is focused on summarizing the recent advances to understand how the proteins encoded by FMDV antagonize the host innate and adaptive immune responses.

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PPARγExpression and Function in Mycobacterial Infection: Roles in Lipid Metabolism, Immunity, and Bacterial Killing

PPAR Research ◽

10.1155/2012/383829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 52

Author(s):

Patricia E. Almeida ◽

Alan Brito Carneiro ◽

Adriana R. Silva ◽

Patricia T. Bozza

Keyword(s):

Molecular Mechanisms ◽

Critical Role ◽

Mycobacterial Infection ◽

Receptor Activation ◽

Host Cells ◽

Current Evidence ◽

Peroxisome Proliferator ◽

Bacterial Killing ◽

Peroxisome Proliferator Activated Receptor ◽

And Function

Tuberculosis continues to be a global health threat, with drug resistance and HIV coinfection presenting challenges for its control.Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a highly adapted pathogen that has evolved different strategies to subvert the immune and metabolic responses of host cells. Although the significance of peroxisome proliferator-activated receptor gamma (PPARγ) activation by mycobacteria is not fully understood, recent findings are beginning to uncover a critical role for PPARγduring mycobacterial infection. Here, we will review the molecular mechanisms that regulate PPARγexpression and function during mycobacterial infection. Current evidence indicates that mycobacterial infection causes a time-dependent increase in PPARγexpression through mechanisms that involve pattern recognition receptor activation. Mycobacterial triggered increased PPARγexpression and activation lead to increased lipid droplet formation and downmodulation of macrophage response, suggesting that PPARγexpression might aid the mycobacteria in circumventing the host response acting as an escape mechanism. Indeed, inhibition of PPARγenhances mycobacterial killing capacity of macrophages, suggesting a role of PPARγin favoring the establishment of chronic infection. Collectively, PPARγis emerging as a regulator of tuberculosis pathogenesis and an attractive target for the development of adjunctive tuberculosis therapies.

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