Volume 4 (2020)
TLR4: the fall guy in sepsis?
Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1
WHOLE GENOME CRISPR SCREEN AND THE IDENTIFICATION OF Treml4 We reasoned that if immune cells undergo apoptosis during sepsis, ablation of the gene responsible for this in a sub-population should
A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome
Valeria Capaci1,2, Fiamma Mantovani1 and Giannino Del Sal1,2,3
– [table id=357/] MUT-p53 AS A DRIVER OF A MALIGNANT SECRETOME p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions, and by modulating the interplay of cancer
Targeting the TGFβ pathway in uterine carcinosarcoma
Shailendra Kumar Dhar Dwivedi1, Geeta Rao2, Anindya Dey1, Megan Buechel1, Yushan Zhang2, Min Zhang3, Da Yang3, Priyabrata Mukherjee2, Resham Bhattacharya1,4
Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. (...)
Endocytosis in the adaptation to cellular stress
Tania López-Hernández1, Volker Haucke1,2 and Tanja Maritzen1
Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic (...)
Exocytotic fusion pore under stress
Helena Haque Chowdhury1,2 and Robert Zorec1,2
Exocytosis is a universal process of eukaryotic cells, consisting of fusion between the vesicle and the plasma membranes, leading to the formation of a fusion pore, a channel through which vesicle cargo exits into the extracellular space. In 1986, Rand and Parsegian proposed several stages to explain the nature of membrane fusion. Following stimulation, it starts with focused stress destabilization of membranes in contact, followed by the coalescence of two membrane surfaces. In the next fraction of a millisecond, restabilization of fused membranes is considered to occur to maintain the cell's integrity. This view predicted that once a fusion pore is formed, it must widen abruptly, irreversibly and fully, whereby the vesicle membrane completely integrates with and collapses into the plasma membrane (full fusion exocytosis). However, recent experimental evidence has revealed that once the fusion pore opens, it may also reversibly close (transient or kiss-and-run exocytosis). Here, we present a historical perspective on understanding the mechanisms that initiate (...)
Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy
Daniel Baumann1,2 and Rienk Offringa1,2
– [table id=351/] IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows. On the one
Hyaluronan goes to great length
Vera Gorbunova1, Masaki Takasugi1 and Andrei Seluanov1
The naked mole rat is the longest-lived rodent with the maximum lifespan of over 35 years. Naked mole rats are protected from a wide range of age-related diseases including cancer,
TLR4: the fall guy in sepsis?
Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1
WHOLE GENOME CRISPR SCREEN AND THE IDENTIFICATION OF Treml4 We reasoned that if immune cells undergo apoptosis during sepsis, ablation of the gene responsible for this in a sub-population should
A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome
Valeria Capaci1,2, Fiamma Mantovani1 and Giannino Del Sal1,2,3
– [table id=357/] MUT-p53 AS A DRIVER OF A MALIGNANT SECRETOME p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions, and by modulating the interplay of cancer
Targeting the TGFβ pathway in uterine carcinosarcoma
Shailendra Kumar Dhar Dwivedi1, Geeta Rao2, Anindya Dey1, Megan Buechel1, Yushan Zhang2, Min Zhang3, Da Yang3, Priyabrata Mukherjee2, Resham Bhattacharya1,4
Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. (...)
Endocytosis in the adaptation to cellular stress
Tania López-Hernández1, Volker Haucke1,2 and Tanja Maritzen1
Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic (...)
High mitochondrial calcium levels precede neuronal death in vivo in Alzheimer’s disease
Maria Calvo-Rodriguez1 and Brian J. Bacskai1
MITOCHONDRIAL CALCIUM OVERLOAD AFTER PLAQUE DEPOSITION Ca2+ is essential for the normal function of mitochondrial activity, and therefore Ca2+ levels are tightly regulated in mitochondria. However, excessive levels of Ca2+
The role of lipids in autophagy and its implication in neurodegeneration
Sergio Hernandez-Diaz1,2 and Sandra-Fausia Soukup1,2
Neurodegenerative diseases are, at present, major socio-economic burdens without effective treatments and their increasing prevalence means that these diseases will be a challenge for future generations. Neurodegenerative diseases may differ in etiology and pathology but are often caused by the accumulation of dysfunctional and aggregation-prone proteins. Autophagy, a conserved cellular mechanism, deals with cellular stress and waste product build-up and has been shown to reduce the accumulation of dysfunctional proteins in animal models of neurodegenerative diseases. Historically, progress in understanding the precise function of lipids has traditionally been far behind other biological molecules (like proteins) but emerging works demonstrate the importance of lipids in the autophagy pathway and how the disturbance of lipid metabolism is connected to neurodegeneration. Here we review how altered autophagy and the disturbance of lipid metabolism, particularly of phosphoinositols and sphingolipids, feature in neurodegenerative diseases and address work from the field that suggests that these potentially offer an opportunity of therapeutic intervention.
Immune system activation by natural products and complex fractions: a network pharmacology approach in cancer treatment
Alejandra Gomez-Cadena1,2,3, Alfonso Barreto3, Susana Fiorentino3 and Camilla Jandus1,2
INTRODUCTION Over the past decade, immunotherapy has become a promising approach to treat cancer and is now being combined with standard chemotherapy and immune response activators to improve the outcome
Towards understanding the role of Receptor Expression Enhancing Protein 5 (REEP5) in cardiac muscle and beyond
Shin-Haw Lee1,2, Sina Hadipour-Lakmehsari1,2 and Anthony O. Gramolini1,2
DISCOVERY OF REEP5 Cardiac membrane proteins play an important role in regulating normal beat-to-beat function of the heart given their importance in coordinating spontaneous contractions of cardiomyocytes in the heart.
Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases
Gina Picchiarelli1 and Luc Dupuis1
A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.
Biomechanical stress regulates mammalian tooth replacement
Xiaoshan Wu1,2 and Songlin Wang1,3
The DT eruption released a biomechanical stress of about 3-20 kPa inside the mandible. By culturing the mandible slice in vitro, the SDL of the PT immediately transitioned into the
Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders
Christian Hiepen1, Jerome Jatzlau1 and Petra Knaus1
BMPR2 MUTATIONS PRIME FOR PAH BUT REQUIRE A SECOND HIT While BMPR2 mutations appear as one of the main genetic drivers for HPAH, low BMPR2 expression is also found in
Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma
James J. Hsieh1 and Emily H. Cheng2,3,4
INTRODUCTION On average a human adult body encompasses fifty trillion cells (~5×1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion
HIF1α or mitophagy: which drives cardiomyocyte differentiation?
Beatriz Villarejo-Zori1,#, Juan Ignacio Jiménez-Loygorri1,# and Patricia Boya1
Cardiomyocytes (CMs) are the main cellular component of the heart's atria and ventricles, and their contractile capacity is the engine that drives blood flow throughout the body. The differentiation of
Copper – a novel stimulator of autophagy
Hans Zischka1,2 and Guido Kroemer3-7
In biomedicine, the transition metal copper has a Janus-faced dual role, as an essential but static cofactor of vital enzymes but also as a highly detrimental poison, if in excess.
Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses
Didier Raoult1, Alimuddin Zumla2,3, Franco Locatelli4, Giuseppe Ippolito5 and Guido Kroemer6-10,*
INTRODUCTION Infections have been limiting quality of life and longevity throughout human history. Endemic infections have been associated to a significant number of avoidable deaths and a significant increase of
ACBP is an appetite stimulator across phylogenetic barriers
Frank Madeo1,2, Nektarios Tavernarakis3,4, José M. Bravo-San Pedro5-7,# and Guido Kroemer5-10,#
Human civilization is unique with respect to the organization of our natural environment, allowing constant supply of nutrients to most individuals in developed countries, contrasting with the natural fluctuation in