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Mechanical stimuli, such as stretch, shear stress, or compression, activate a range of biomolecular responses through cellular mechanotransduction. In the nervous system, studies on mechanical stress have highlighted key pathophysiological mechanisms underlying traumatic injury and neurodegenerative diseases. However, the biomolecular pathways triggered by mechanical stimuli in the nervous system has not been fully explored, especially compared to other body systems. This gap in knowledge may be due to the wide variety of methods and definitions used in research. Additionally, as mechanical stimulation techniques such as ultrasound and electromagnetic stimulation are increasingly utilized in psychological and neurorehabilitation treatments, it is vital to understand the underlying biological mechanisms in order to develop accurate pathophysiological models and enhance therapeutic interventions. This review aims to summarize the cellular signaling pathways activated by various mechanical and electromagnetic stimuli with a particular focus on the mammalian nervous system. Furthermore, we briefly discuss potential cellular mechanosensors involved in these processes. [ABSTRACT FROM AUTHOR]

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer's Disease (AD) contributes to approximately 60-70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brainresident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics. [ABSTRACT FROM AUTHOR]

The rapid development of the COVID-19 pandemic resulted in a closer analysis of cell functioning during β-coronavirus infection. This review will describe evidence for COVID-19 as a syndrome with a strong, albeit still underestimated, mitochondrial component. Due to the sensitivity of host mitochondria to coronavirus infection, SARS-CoV-2 affects mitochondrial signaling, modulates the immune response, modifies cellular energy metabolism, induces apoptosis and ageing, worsening COVID-19 symptoms which can sometimes be fatal. Various aberrations across human systems and tissues and their relationships with mitochondria were reported. In this review, particular attention is given to characterization of multiple alterations in gene expression pattern and mitochondrial metabolism in COVID-19; the complexity of interactions between SARS-CoV-2 and mitochondrial proteins is presented. The participation of mitogenome fragments in cell signaling and the occurrence of SARS-CoV-2 subgenomic RNA within membranous compartments, including mitochondria is widely discussed. As SARS-CoV-2 severely affects the quality system of mitochondria, the cellular background for aberrations in mitochondrial dynamics in COVID-19 is additionally characterized. Finally, perspectives on the mitigation of COVID-19 symptoms by affecting mitochondrial biogenesis by numerous compounds and therapeutic treatments are briefly outlined. [ABSTRACT FROM AUTHOR]

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer’s Disease (AD) contributes to approximately 60–70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brain-resident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor γ chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics.

The rapid development of the COVID-19 pandemic resulted in a closer analysis of cell functioning during β-coronavirus infection. This review will describe evidence for COVID-19 as a syndrome with a strong, albeit still underestimated, mitochondrial component. Due to the sensitivity of host mitochondria to coronavirus infection, SARS-CoV-2 affects mitochondrial signaling, modulates the immune response, modifies cellular energy metabolism, induces apoptosis and ageing, worsening COVID-19 symptoms which can sometimes be fatal. Various aberrations across human systems and tissues and their relationships with mitochondria were reported. In this review, particular attention is given to characterization of multiple alterations in gene expression pattern and mitochondrial metabolism in COVID-19; the complexity of interactions between SARS-CoV-2 and mitochondrial proteins is presented. The participation of mitogenome fragments in cell signaling and the occurrence of SARS-CoV-2 subgenomic RNA within membranous compartments, including mitochondria is widely discussed. As SARS-CoV-2 severely affects the quality system of mitochondria, the cellular background for aberrations in mitochondrial dynamics in COVID-19 is additionally characterized. Finally, perspectives on the mitigation of COVID-19 symptoms by affecting mitochondrial biogenesis by numerous compounds and therapeutic treatments are briefly outlined.

Macrophages activation and inflammatory response play crucial roles in intracranial aneurysm (IA) formation and progression. The outcome of ruptured IA is considerably poor, and the mechanisms that trigger IA progression and rupture remain to be clarified, thereby developing effective therapy to prevent subarachnoid hemorrhage (SAH) become difficult. Recently, climbing evidences have been expanding our understanding of the macrophages relevant IA pathogenesis, such as immune cells population, inflammatory activation, intra-/inter-cellular signaling transductions and drug administration responses. Crosstalk between macrophages disorder, inflammation and cellular signaling transduction aggravates the devastating consequences of IA. Illustrating the pros and cons mechanisms of macrophages in IA progression are expected to achieve more efficient treatment interventions. In this review, we summarized the current advanced knowledge of macrophages activation, infiltration, polarization and inflammatory responses in IA occurrence and development, as well as the most relevant NF-κB, signal transducer and activator of transcription 1 (STAT1) and Toll-Like Receptor 4 (TLR4) regulatory signaling modulation. The understanding of macrophages regulatory mechanisms is important for IA patients' clinical outcomes. Gaining insight into the macrophages regulation potentially contributes to more precise IA interventions and will also greatly facilitate the development of novel medical therapy. [ABSTRACT FROM AUTHOR]

The development and maturation of cortical GABAergic interneurons has been extensively studied, with much focus on nuclear regulation via transcription factors. While these seminal events are critical for the establishment of interneuron developmental milestones, recent studies on cellular signaling cascades have begun to elucidate some potential contributions of cell signaling during development. Here, we review studies underlying three broad signaling families, mTOR, MAPK, and Wnt/beta-catenin in cortical interneuron development. Notably, each pathway harbors signaling factors that regulate a breadth of interneuron developmental milestones and properties. Together, these events may work in conjunction with transcriptional mechanisms and other events to direct the complex diversity that emerges during cortical interneuron development and maturation. [ABSTRACT FROM AUTHOR]

1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2) There is a cross-talk between vascular and cardiac compliance. Vascular compliance per se is defined by central venous pressure--Blood volume relationship--Global Vascular Compliance (GVC). It is determined by the sum of the vascular compliance of the vessels in every organ in any physiological state, varies with LTHA and thus influences cardiac performance. LTHA improves endothelial function, increases NO (nitric oxide) production, inturn stimulating alterations in ECM (extracellular matrix) via the TGF β1-SMAD pathway. 3) LTHA is associated with transformation from fast to slow myosin, heat acclimation ischemic/hypoxic cross-tolerance and alterations in the extracellular matrix. 4) A human translational study demonstrated improved LV compliance following bypass surgery in LTHA subjects compared to controls. 5) Diastolic dysfunction and the impact of comorbidities with vascular and non-vascular origins are major contributors to the syndrome of heart failure with preserved ejection function (HFPEF). Unfortunately, there is a paucity of treatment modalities that improve diastolic dysfunction. 6) In the current mini-review we suggest that LTHA may be beneficial to HFPEF patients by remodeling cardiac compliance and vascular response. [ABSTRACT FROM AUTHOR]

1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2) There is a cross-talk between vascular and cardiac compliance. Vascular compliance per se is defined by central venous pressure—Blood volume relationship—Global Vascular Compliance (GVC). It is determined by the sum of the vascular compliance of the vessels in every organ in any physiological state, varies with LTHA and thus influences cardiac performance. LTHA improves endothelial function, increases NO (nitric oxide) production, in-turn stimulating alterations in ECM (extracellular matrix) via the TGF β1-SMAD pathway. 3) LTHA is associated with transformation from fast to slow myosin, heat acclimation ischemic/hypoxic cross-tolerance and alterations in the extracellular matrix. 4) A human translational study demonstrated improved LV compliance following bypass surgery in LTHA subjects compared to controls. 5) Diastolic dysfunction and the impact of comorbidities with vascular and non- vascular origins are major contributors to the syndrome of heart failure with preserved ejection function (HFPEF). Unfortunately, there is a paucity of treatment modalities that improve diastolic dysfunction. 6) In the current mini-review we suggest that LTHA may be beneficial to HFPEF patients by remodeling cardiac compliance and vascular response.

Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisensebased inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis. [ABSTRACT FROM AUTHOR]

Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisense-based inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis.

Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field. [ABSTRACT FROM AUTHOR]

The ATP synthase is an essential multifunctional enzyme complex of mitochondria that produces most of cellular ATP, shapes the structure of the inner membrane into cristae and regulates the signals that control cell fate or demise. The ATPase Inhibitory Factor 1 (IF1) functions in vivo as a physiological regulator of the ATP synthase and thereby controls mitochondrial structure and function, and the retrograde signaling pathways that reprogram nuclear gene expression. However, IF1 is not ubiquitously expressed in mammals, showing tissue-restricted expression in humans and mice and large expression differences between the two species in some tissues. Herein, we summarized key regulatory functions of IF1 for tissue homeostasis, with special emphasis on the deleterious effects that its genetic ablation in neurons has in learning. The development and characterization of tissue-specific mouse models with regulated expression of IF1 will be crucial to disentangle the contribution of the ATP synthase/IF1 axis in pathophysiology. [ABSTRACT FROM AUTHOR]

Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans, stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables, spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent years, dietary polyphenols have gained significant interest among researchers due to their potential chemopreventive/protective functions in the maintenance of human health and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS) towards the prevention of OS-related pathological conditions or diseases. Pre-clinical and clinical evidence strongly suggest that long term consumption of diets rich in polyphenols offer protection against the development of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, diabetes, inflammatory disorders and infectious illness. Increased intake of foods containing polyphenols (for example, quercetin, epigallocatechin-3-gallate, resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial infections, and neurodegenerative diseases. It has been suggested that the antioxidant activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human diseases. In this narrative review, the biological/pharmacological significance of dietary polyphenols in the prevention of and/or protection against OS-induced major human diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus, cancer, inflammatory disorders and infectious diseases have been delineated. This review specifically focuses a current understanding on the dietary sources of polyphenols and their protective effects including mechanisms of action against various major human diseases. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field.

The ATP synthase is an essential multifunctional enzyme complex of mitochondria that produces most of cellular ATP, shapes the structure of the inner membrane into cristae and regulates the signals that control cell fate or demise. The ATPase Inhibitory Factor 1 (IF1) functions in vivo as a physiological regulator of the ATP synthase and thereby controls mitochondrial structure and function, and the retrograde signaling pathways that reprogram nuclear gene expression. However, IF1 is not ubiquitously expressed in mammals, showing tissue-restricted expression in humans and mice and large expression differences between the two species in some tissues. Herein, we summarized key regulatory functions of IF1 for tissue homeostasis, with special emphasis on the deleterious effects that its genetic ablation in neurons has in learning. The development and characterization of tissue-specific mouse models with regulated expression of IF1 will be crucial to disentangle the contribution of the ATP synthase/IF1 axis in pathophysiology.

Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans, stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables, spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent years, dietary polyphenols have gained significant interest among researchers due to their potential chemopreventive/protective functions in the maintenance of human health and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS) towards the prevention of OS-related pathological conditions or diseases. Pre-clinical and clinical evidence strongly suggest that long term consumption of diets rich in polyphenols offer protection against the development of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, diabetes, inflammatory disorders and infectious illness. Increased intake of foods containing polyphenols (for example, quercetin, epigallocatechin-3-gallate, resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial infections, and neurodegenerative diseases. It has been suggested that the antioxidant activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human diseases. In this narrative review, the biological/pharmacological significance of dietary polyphenols in the prevention of and/or protection against OS-induced major human diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus, cancer, inflammatory disorders and infectious diseases have been delineated. This review specifically focuses a current understanding on the dietary sources of polyphenols and their protective effects including mechanisms of action against various major human diseases.

The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.

Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases. [ABSTRACT FROM AUTHOR]

Intramembrane proteolysis is more than a mechanism to “clean” the membranes from proteins no longer needed. By non-reversibly modifying transmembrane proteins, intramembrane cleaving proteases hold key roles in multiple signaling pathways and often distinguish physiological from pathological conditions. Signal peptide peptidase (SPP) and signal peptide peptidase-like proteases (SPPLs) recently have been associated with multiple functions in the field of signal transduction. SPP/SPPLs together with presenilins (PSs) are the only two families of intramembrane cleaving aspartyl proteases known in mammals. PS1 or PS2 comprise the catalytic center of the γ-secretase complex, which is well-studied in the context of Alzheimer's disease. The mammalian SPP/SPPL family of intramembrane cleaving proteases consists of five members: SPP and its homologous proteins SPPL2a, SPPL2b, SPPL2c, and SPPL3. Although these proteases were discovered due to their homology to PSs, it became evident in the past two decades that no physiological functions are shared between these two families. Based on studies in cell culture models various substrates of SPP/SPPL proteases have been identified in the past years and recently-developed mouse lines lacking individual members of this protease family, will help to further clarify the physiological functions of these proteases. In this review we concentrate on signaling roles of mammalian intramembrane cleaving aspartyl proteases. In particular, we will highlight the signaling roles of PS via its substrates NOTCH, VEGF, and others, mainly focusing on its involvement in vasculature. Delineating also signaling pathways that are affected and/or controlled by SPP/SPPL proteases. From SPP's participation in tumor progression and survival, to SPPL3's regulation of protein glycosylation and SPPL2c's control over cellular calcium stores, various crossovers between proteolytic activity of intramembrane proteases and cell signaling will be described.

Cell death is a fundamental process in maintaining cellular homeostasis, which can be either accidental or programed. Programed cell death depends on the specific signaling pathways, resulting in either lytic or non-lytic morphology. It exists in two primary forms: apoptosis and autophagic cell death. Apoptosis is a non-lytic and selective cell death program, which is executed by caspases in response to non-self or external stimuli. In contrast, autophagy is crucial for maintaining cellular homeostasis via the degradation and recycling of cellular components. These two mechanisms also function in the defense against pathogen attack. However, picornaviruses have evolved to utilize diverse strategies and target critical components to regulate the apoptotic and autophagic processes for optimal replication and the release from the host cell. Although an increasing number of investigations have shown that the apoptosis and autophagy are altered in picornavirus infection, the mechanism by which viruses take advantage of these two processes remains unknown. In this review, we discuss the mechanisms of picornavirus executes cellular apoptosis and autophagy at the molecular level and the relationship between these interactions and viral pathogenesis.

The cells of the immune system respond to a great variety of different signals that frequently reach them simultaneously. Computational models of signaling pathways and cellular behavior can help us explore the biochemical mechanisms at play during such responses, in particular when those models aim at incorporating molecular details of intracellular reaction networks. Such detailed models can encompass hypotheses about the interactions among molecular binding domains and how these interactions are modulated by, for instance, post-translational modifications, or steric constraints in multi-molecular complexes. In this way, the models become formal representations of mechanistic immunological hypotheses that can be tested through quantitative simulations. Due to the large number of parameters (molecular abundances, association-, dissociation-, and enzymatic transformation rates) the goal of simulating the models can, however, in many cases no longer be the fitting of particular parameter values. Rather, the simulations perform sweeps through parameter space to test whether a model can account for certain experimentally observed features when allowing the parameter values to vary within experimentally determined or physiologically reasonable ranges. We illustrate how this approach can be used to explore possible mechanisms of immunological pathway crosstalk. Probing the input-output behavior of mechanistic pathway models through systematic simulated variations of receptor stimuli will soon allow us to derive cell population behavior from single-cell models, thereby bridging a scale gap that currently still is frequently addressed through heuristic phenomenological multi-scale models.

Epithelial-Mesenchymal Transition (EMT) is a critical process in embryonic development in which epithelial cells undergo a transdifferentiation into mesenchymal cells. This process is essential for tissue patterning and organization, and it has also been implicated in a wide array of pathologies. While the intracellular signaling pathways that regulate EMT are well-understood, there is increasing evidence that the mechanical properties and composition of the extracellular matrix (ECM) also play a key role in regulating EMT. In turn, EMT drives changes in the mechanics and composition of the ECM, creating a feedback loop that is tightly regulated in healthy tissues, but is often dysregulated in disease. Here we present a review that summarizes our understanding of how ECM mechanics and composition regulate EMT, and how in turn EMT alters ECM mechanics and composition.

The cells of the immune system respond to a great variety of different signals that frequently reach them simultaneously. Computational models of signaling pathways and cellular behavior can help us explore the biochemical mechanisms at play during such responses, in particular when those models aim at incorporating molecular details of intracellular reaction networks. Such detailed models can encompass hypotheses about the interactions among molecular binding domains and how these interactions are modulated by, for instance, post-translational modifications, or steric constraints in multi-molecular complexes. In this way, the models become formal representations of mechanistic immunological hypotheses that can be tested through quantitative simulations. Due to the large number of parameters (molecular abundances, association-, dissociation-, and enzymatic transformation rates) the goal of simulating the models can, however, in many cases no longer be the fitting of particular parameter values. Rather, the simulations perform sweeps through parameter space to test whether a model can account for certain experimentally observed features when allowing the parameter values to vary within experimentally determined or physiologically reasonable ranges. We illustrate how this approach can be used to explore possible mechanisms of immunological pathway crosstalk. Probing the input-output behavior of mechanistic pathway models through systematic simulated variations of receptor stimuli will soon allow us to derive cell population behavior from single-cell models, thereby bridging a scale gap that currently still is frequently addressed through heuristic phenomenological multi-scale models. [ABSTRACT FROM AUTHOR]

Cell death is a fundamental process in maintaining cellular homeostasis, which can be either accidental or programed. Programed cell death depends on the specific signaling pathways, resulting in either lytic or non-lytic morphology. It exists in two primary forms: apoptosis and autophagic cell death. Apoptosis is a non-lytic and selective cell death program, which is executed by caspases in response to non-self or external stimuli. In contrast, autophagy is crucial for maintaining cellular homeostasis via the degradation and recycling of cellular components. These two mechanisms also function in the defense against pathogen attack. However, picornaviruses have evolved to utilize diverse strategies and target critical components to regulate the apoptotic and autophagic processes for optimal replication and the release from the host cell. Although an increasing number of investigations have shown that the apoptosis and autophagy are altered in picornavirus infection, the mechanism by which viruses take advantage of these two processes remains unknown. In this review, we discuss the mechanisms of picornavirus executes cellular apoptosis and autophagy at the molecular level and the relationship between these interactions and viral pathogenesis. [ABSTRACT FROM AUTHOR]

Changing the balance between ascorbate, monodehydroascorbate, and dehydroascorbate in plant cells by manipulating the activity of enzymes involved in ascorbate synthesis or recycling of oxidized and reduced forms leads to multiple phenotypes. A systems biology approach including network analysis of the transcriptome, proteome and metabolites of RNAi lines for ascorbate oxidase, monodehydroascorbate reductase and galactonolactone dehydrogenase has been carried out in orange fruit pericarp of tomato (Solanum lycopersicum). The transcriptome of the RNAi ascorbate oxidase lines is inversed compared to the monodehydroascorbate reductase and galactonolactone dehydrogenase lines. Differentially expressed genes are involved in ribosome biogenesis and translation. This transcriptome inversion is also seen in response to different stresses in Arabidopsis. The transcriptome response is not well correlated with the proteome which, with the metabolites, are correlated to the activity of the ascorbate redox enzymes—ascorbate oxidase and monodehydroascorbate reductase. Differentially accumulated proteins include metacaspase, protein disulphide isomerase, chaperone DnaK and carbonic anhydrase and the metabolites chlorogenic acid, dehydroascorbate and alanine. The hub genes identified from the network analysis are involved in signaling, the heat-shock response and ribosome biogenesis. The results from this study therefore reveal one or several putative signals from the ascorbate pool which modify the transcriptional response and elements downstream.

Changing the balance between ascorbate, monodehydroascorbate, and dehydroascorbate in plant cells by manipulating the activity of enzymes involved in ascorbate synthesis or recycling of oxidized and reduced forms leads to multiple phenotypes. A systems biology approach including network analysis of the transcriptome, proteome and metabolites of RNAi lines for ascorbate oxidase, monodehydroascorbate reductase and galactonolactone dehydrogenase has been carried out in orange fruit pericarp of tomato (Solanum lycopersicum). The transcriptome of the RNAi ascorbate oxidase lines is inversed compared to the monodehydroascorbate reductase and galactonolactone dehydrogenase lines. Differentially expressed genes are involved in ribosome biogenesis and translation. This transcriptome inversion is also seen in response to different stresses in Arabidopsis. The transcriptome response is not well correlated with the proteome which, with the metabolites, are correlated to the activity of the ascorbate redox enzymes--ascorbate oxidase and monodehydroascorbate reductase. Differentially accumulated proteins include metacaspase, protein disulphide isomerase, chaperone DnaK and carbonic anhydrase and the metabolites chlorogenic acid, dehydroascorbate and alanine. The hub genes identified from the network analysis are involved in signaling, the heat-shock response and ribosome biogenesis. The results from this study therefore reveal one or several putative signals from the ascorbate pool which modify the transcriptional response and elements downstream. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.

Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2C signaling in an inositol-1,4,5-trisphosphatedependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5- HT2B2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B 's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Our understanding of GPCR signaling in the nervous system remains incomplete and large-scale approaches to understanding GPCR signaling are required. GPCRs, cellular signaling, neuronal pharmacology, drug discovery, proteomics, GPCR dimers Keywords: GPCRs; cellular signaling; neuronal pharmacology; drug discovery; GPCR dimers; proteomics EN GPCRs cellular signaling neuronal pharmacology drug discovery GPCR dimers proteomics 1 2 2 05/05/22 20220503 NES 220503 In this collection in I Frontiers Research Topic i , we have put together an interesting series of articles on multiple aspects of how G protein-coupled receptors (GPCRs) and their associated G proteins signal in the nervous system. [Extracted from the article]

Leishmania spp. and Trypanosoma cruzi are the causative agents of leishmaniasis and Chagas disease, respectively, two neglected tropical diseases that affect about 25 million people worldwide. These parasites belong to the family Trypanosomatidae, and are both obligate intracellular parasites that manipulate host signaling pathways and the innate immune system to establish infection. Mitogen-activated protein kinases (MAPKs) are serine and threonine protein kinases that are highly conserved in eukaryotes, and are involved in signal transduction pathways that modulate physiological and pathophysiological cell responses. This mini-review highlights existing knowledge concerning the mechanisms that Leishmania spp. and T. cruzi have evolved to target the host's MAPK signaling pathways and highjack the immune response, and, in this manner, promote parasite maintenance in the host. [ABSTRACT FROM AUTHOR]

Phosphate plays a chemically unique role in shaping cellular signaling of all current living systems, especially eukaryotes. Protein phosphorylation has been studied at several levels, from the near-site context, both in sequence and structure, to the crowded cellular environment, and ultimately to the systems-level perspective. Despite the tremendous advances in mass spectrometry and efforts dedicated to the development of ad hoc highly sophisticated methods, phosphorylation site inference and associated kinase identification are still unresolved problems in kinome biology. The sequence and structure of the substrate near-site context are not sufficient alone to model the in vivo phosphorylation rules, and they should be integrated with orthogonal information in all possible applications. Here we provide an overview of the different contexts that contribute to protein phosphorylation, discussing their potential impact in phosphorylation site annotation and in predicting kinase-substrate specificity.

Phosphate plays a chemically unique role in shaping cellular signaling of all current living systems, especially eukaryotes. Protein phosphorylation has been studied at several levels, from the near-site context, both in sequence and structure, to the crowded cellular environment, and ultimately to the systems-level perspective. Despite the tremendous advances in mass spectrometry and efforts dedicated to the development of ad hoc highly sophisticated methods, phosphorylation site inference and associated kinase identification are still unresolved problems in kinome biology. The sequence and structure of the substrate near-site context are not sufficient alone to model the in vivo phosphorylation rules, and they should be integrated with orthogonal information in all possible applications. Here we provide an overview of the different contexts that contribute to protein phosphorylation, discussing their potential impact in phosphorylation site annotation and in predicting kinase-substrate specificity. [ABSTRACT FROM AUTHOR]