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Artemisinin, a traditional Chinese medicine with remarkable antimalarial activity. In recent years, studies demonstrated that artemisinin and its derivatives (ARTs) showed anti-inflammatory and immunoregulatory effects. ARTs have been developed and gradually applied to treat autoimmune and inflammatory diseases. However, their role in the treament of patients with autoimmune and inflammatory diseases in particular is less well recognized. This review will briefly describe the history of ARTs use in patients with autoimmune and inflammatory diseases, the theorized mechanisms of action of the agents ARTs, their efficacy in patients with autoinmmune and inflammatory diseases. Overall, ARTs have numerous beneficial effects in patients with autoimmune and inflammatory diseases, and have a good safety profile.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening and progressive interstitial lung disease. Healthy pulmonary tissues were replaced by an altered extracellular matrix (ECM) and destroyed the alveolar architecture, which led to the disruption of gas exchange, decreased lung compliance, and ultimately led to the failure of respiration and death. IPF is associated with dyspnoea and cough, eventually impairing the quality of a large population worldwide, with the incidence rate increasing drastically with age. The IPF involves a complex pathophysiology; thus, it is necessary to understand the precise molecular mechanism for lung fibrosis to develop novel therapeutic options. Different kinases, including p38 mitogen-activated protein kinase, JNK (c-Jun N-terminal kinase), and SAPKs (Stress-activated protein kinases), were ubiquitously expressed in numerous variety of cells and were activated in response to inflammatory stimuli, cellular environmental stress, and stimuli for apoptosis. After many failed drugs for IPF in clinical trials, two drugs, namely nintedanib and pirfenidone, were approved, which helped to slow the disease progression. However, the prognosis of IPF remains poor, which leads to continuing the search for better drugs, targeting to either reduce or halt the disease progression. The current review summarises the pathophysiology, signaling, and role of different kinases, therapeutic interventions, investigational therapies, and biomarkers for IPF. A better understanding of the pathophysiology of IPF will be helpful to understand disease mechanisms, discovering potential biomarkers, and development of effective therapeutics to handle patients.

Summary: Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3+ Treg cells may be a relevant therapeutic target cell type for the treatment of cancer.

Polarization is the process by which a macrophage cell commits to a phenotype based on external signal stimulation. To know how this process is affected by random fluctuations and events within a cell is of utmost importance to better understand the underlying dynamics and predict possible phenotype transitions. For this purpose, we develop a stochastic modeling approach for the macrophage polarization process. We classify phenotype states using the Robust Perron Cluster Analysis and quantify transition pathways and probabilities by applying Transition Path Theory. Depending on the model parameters, we identify four bistable and one tristable phenotype configuration. We find that bistable transitions are fast but their states less robust. In contrast, phenotype transitions in the tristable situation have a comparatively long time duration, which reflects the robustness of the states. The results indicate parallels in the overall transition behavior of macrophage cells with other heterogeneous and plastic cell types, such as cancer cells. Our approach allows for a probabilistic interpretation of macrophage phenotype transitions and biological inference on phenotype robustness. In general, the methodology can easily be adapted to other systems where random state switches are known to occur., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Flame retardants (FRs) are chemical substances used to inhibit the spread of fire in numerous industrial applications, and their abundance in modern manufactured products in the indoor and outdoor environment leads to extensive direct and food chain exposure of humans. Although once considered relatively non-toxic, FRs are demonstrated by recent literature to have disruptive effects on many biological processes, including signaling pathways, genome stability, reproduction, and immune system function. This review provides a summary of research investigating the impact of major groups of FRs, including halogenated and organophosphorus FRs, on animals and humans in vitro and/or in vivo. We put in focus those studies that explained or referenced the modes of FR action at the level of cells, tissues and organs. Since FRs are highly hydrophobic chemicals, their biophysical and biochemical modes of action usually involve lipophilic interactions, e.g. with biological membranes or elements of signaling pathways. We present selected toxicological information about these molecular actions to show how they can lead to damaging membrane integrity, damaging DNA and compromising its repair, changing gene expression, and cell cycle as well as accelerating cell death. Moreover, we indicate how this translates to deleterious bioactivity of FRs at the physiological level, with disruption of hormonal action, dysregulation of metabolism, adverse effects on male and female reproduction as well as alteration of normal pattern of immunity. Concentrating on these subjects, we make clear both the advances in knowledge in recent years and the remaining gaps in our understanding, especially at the mechanistic level., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lukasz Pulaski reports financial support was provided by National Science Centre Poland., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate “classic KD”, as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

Loquat (Eriobotrya japonica) leaves have been used as traditional medicine for chemoprevention and treatment of chronic inflammatory diseases although the evidence supporting their functions is still poor. This study aims to clarify the anti-inflammatory effects and molecular mechanisms of loquat tea extract (LTE), in both cell and animal models. LTE, especially C fraction, inhibited the production of pro-inflammatory factors including inducible nitric oxide synthase (iNOS), nitric oxide (NO), IL-6, RANTES and TNF-α. Cellular signaling data revealed that the downregulation of TGF-β-activated kinase (TAK1)-mediated both mitogen-activated protein kinase (MAPK) and NF-κB pathways were involved in the inhibition of pro-inflammatory factors by C fraction. Mouse paws edema model further confirmed the in vivo anti-inflammatory effects of LTE.

Elastin is a crucial extracellular matrix protein that provides structural integrity to tissues. Crosslinked elastin and associated microfibrils, named elastic fiber, contribute to biomechanics by providing the elasticity required for proper function. During aging and disease, elastic fiber can be progressively degraded and since there is little elastin synthesis in adults, degraded elastic fiber is not regenerated. There is substantial evidence linking loss or damage of elastic fibers to the clinical manifestation and pathogenesis of a variety of diseases. Disruption of elastic fiber networks by hereditary mutations, aging, or pathogenic stimuli results in systemic ailments associated with the production of elastin degradation products, inflammatory responses, and abnormal physiology. Due to its longevity, unique mechanical properties, and widespread distribution in the body, elastic fiber plays a central role in homeostasis of various physiological systems. While pathogenesis related to elastic fiber degradation has been more thoroughly studied in elastic fiber rich tissues such as the vasculature and the lungs, even tissues containing relatively small quantities of elastic fibers such as the eyes or joints may be severely impacted by elastin degradation. Elastic fiber degradation is a common observation in certain hereditary, age, and specific risk factor exposure induced diseases representing a converging point of pathological clinical phenotypes which may also help explain the appearance of co-morbidities. In this review, we will first cover the role of elastic fiber degradation in the manifestation of hereditary diseases then individually explore the structural role and degradation effects of elastic fibers in various tissues and organ systems. Overall, stabilizing elastic fiber structures and repairing lost elastin may be effective strategies to reverse the effects of these diseases., Competing Interests: Declaration of competing interest NRV holds significant equity in Elastrin Therapeutics Inc., Annoviant Inc., and ElastinTech Inc.; however, this review paper is prepared independently based on published papers. We also acknowledge grant funding from National Institutes of Health (R01HL133662, P30 GM131959, R01HL145064)., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

TANK-binding kinase 1 (TBK1) plays a fundamental role in regulating the cellular responses and controlling several signaling cascades. It regulates inflammatory, interferon, NF-κB, autophagy, and Akt pathways. Post-translational modifications (PTM) of TBK1 control its action and subsequent cellular signaling. The dysregulation of the TBK1 pathway is correlated to many pathophysiological conditions, including cancer, that implicates the promising therapeutic advantage for targeting TBK1. The present study summarizes current updates on the molecular mechanisms and cancer-inducing roles of TBK1. Designed inhibitors of TBK1 are considered a potential therapeutic agent for several diseases, including cancer. Data from pre-clinical tumor models recommend that the targeting of TBK1 could be an attractive strategy for anti-tumor therapy. This review further highlighted the therapeutic potential of potent and selective TBK1 inhibitors, including Amlexanox, Compound II, BX795, MRT67307, SR8185 AZ13102909, CYT387, GSK8612, BAY985, and Domainex. These inhibitors may be implicated to facilitate therapeutic management of cancer and TBK1-associated diseases in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Larvae of sea urchins have a population of conspicuous pigmented cells embedded in the outer surface epithelium. Pigment cells are a distinct mesodermal lineage that gives rise to a key component of the larval immune system. During cleavage, signaling from adjacent cells influences a small crescent of cells to initiate a network of genetic interactions that prepare the cells for morphogenesis and specializes them as immunocytes. The cells become active during gastrulation, detach from the epithelium, migrate through the blastocoel, and insert into the ectoderm where they complete their differentiation. Studies of pigment cell development have helped establish how cellular signaling controls networks of genetic interactions that bring about morphogenesis and differentiation. This review summarizes studies of pigment cell development and concludes that pigment cells are an excellent experimental model. Pigment cells provide several opportunities to further test and refine our understanding of the molecular basis of cellular development., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this paper, we present and analyze a mathematical model for polarization of a single macrophage which, despite its simplicity, exhibits complex dynamics in terms of multistability. In particular, we demonstrate that an asymmetry in the regulatory mechanisms and parameter values is important for observing multiple phenotypes. Bifurcation and sensitivity analyses show that external signaling cues are necessary for macrophage commitment and emergence to a phenotype, but that the intrinsic macrophage pathways are equally important. Based on our numerical results, we formulate hypotheses that could be further investigated by laboratory experiments to deepen our understanding of macrophage polarization., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neurodegeneration is the progressive loss of neuronal structures and functions that lead to copious disorders like Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS), and other less recurring diseases. Aging is the prime culprit for most neurodegenerative events. Moreover, the shared pathogenic factors of many neurodegenerative processes are inflammatory responses and oxidative stress (OS). Unfortunately, it is very complicated to treat neurodegeneration and there is no effective remedy. The rapid progression of the neurodegenerative diseases that exacerbate the burden and the concurrent absence of effective treatment strategies force the researchers to investigate more therapeutic approaches that ultimately target the causative factors of the neurodegeneration. Phytochemicals have great potential to exert their neuroprotective effects by targeting various mechanisms, such as OS, neuroinflammation, abnormal protein aggregation, neurotrophic factor deficiency, disruption in mitochondrial function, and apoptosis. Therefore, this review represents the molecular mechanisms of neuroprotection by multifunctional phytochemicals to combat age-linked neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors proclaim no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In recent years, natural products have reemerged as biotherapeutic options, with several dietary carotenoids, viz. astaxanthin, fucoxanthin, siphonaxanthin, β-cryptoxanthin, α-carotene, β-carotene, and lycopene, developing as potential candidates for chemoprevention and chemotherapeutics of breast, colorectal, lung, and prostate cancers. The potent cytotoxic and antiproliferative effects of carotenoids against various cancer cells are mediated by a wide range of molecular mechanisms modulating oxidative stress and redox balance, mitogen-activated protein kinases (MAPK) and other cellular signaling proteins, transcription factors, caspase cascade pathways of apoptosis, cell cycle progression and proliferation, angiogenesis, metastasis, gap junction intercellular communication (GJIC), and multidrug resistance (MDR). This review discusses recent evidence demonstrating the crucial roles of carotenoids in these cellular and molecular events of cancer cell cytotoxicity. In addition, recent case-control and cohort studies are discussed to support the potential role of carotenoids in cancer prevention and therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Burn injury pain is a significant public health problem. Burn injury treatment has improved tremendously in recent decades. However, an unintended consequence is that a larger number of patients now survive more severe injuries, and face intense pain that is very hard to treat. Although many efforts have been made to find alternative treatments, opioids remain the most effective medication available. Burn patients are frequently prescribed opioids in doses and durations that are significantly higher and longer than standard analgesic dosing guidelines. Despite this, many continue to experience unrelieved pain. They are also placed at a higher risk for developing dependence and opioid use disorder. Burn injury profoundly alters the functional state of the immune system. It also alters the expression levels of receptor, effector, and signaling molecules within the spinal cord's dorsal horn. These alterations could explain the reduced potency of opioids. However, recent studies demonstrate that different opioids signal preferentially via differential signaling pathways. This ligand-specific signaling by different opioids implies that burn injury may reduce the antinociceptive potency of opioids to different degrees, in a drug-specific manner. Indeed, recent findings hint at drug-specific differences in the ability of opioids to manage burn pain early after injury, as well as differences in their ability to prevent or treat the development of chronic and neuropathic pain. Here we review the current state of opioid treatment, as well as new findings that could potentially lead to opioid-based pain management strategies that may be significantly more effective than the current solutions., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

β-Arrestins (βarrs) are multifunctional intracellular proteins with an ability to directly interact with a large number of cellular partners including the G protein-coupled receptors (GPCRs). βarrs contribute to multiple aspects of GPCR signaling, trafficking and downregulation. Considering the central involvement of GPCR signaling in the onset and progression of diverse types of cancers, βarrs have also emerged as key players in the context of investigating cancer phenotypes, and as potential therapeutic targets. In this chapter, we first provide a brief account of structure and function of βarrs and then highlight recent discoveries unfolding novel functional attributes of βarrs in breast cancer. We also underscore the recent paradigms of modulating βarr functions in cellular context and potential therapeutic opportunities going forward., (© 2020 Elsevier Inc. All rights reserved.)

There are numerous extra- and intra-cellular processes involved in the production of reactive oxygen species (ROS). Augmented ROS generation can cause the damage of biomolecules such as proteins, nucleic acid and lipids. ROS act as an intracellular signaling component and is associated with various inflammatory responses, chronic arthropathies, including rheumatoid arthritis (RA). It is well documented that ROS can activate different signaling pathways having a vital importance in the patho-physiology of RA. Hence, understanding of the molecular pathways and their interaction might be advantageous in the development of novel therapeutic approaches for RA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G-proteins) mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review, we briefly summarize what is known about the regulation, signaling, and physiological functions of G-proteins. We then focus on a few less explored areas such as the regulation of G-proteins by non-GPCRs and the physiological functions of G-proteins that cannot be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated and of the specificity of G-protein interactions with their regulators., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The coxsackievirus and adenovirus receptor (CAR) belongs to the immunoglobulin superfamily and acts as a receptor for some adenovirus types and group B coxsackieviruses. Its role is best described in epithelia where CAR participates to tight junction integrity and maintenance. Recently, several studies aimed to characterize its potential interaction with intracellular signaling pathways and highlighted several features linking CAR to gene expression. In addition, the molecular mechanisms leading to CAR-specific membrane targeting via the secretory pathway in polarized cells and its internalization are starting to be unraveled. This chapter discusses the interaction between membrane dynamics, intracellular trafficking, and signaling of CAR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Calcium ions (Ca(2+)) play a pivotal role in cellular physiology. Often Ca(2+)-dependent processes are studied in commonly available cell lines. To induce Ca(2+) signals on demand, cells may need to be equipped with additional proteins. A prominent group of membrane proteins evoking Ca(2+) signals are G-protein coupled receptors (GPCRs). These proteins register external signals such as photons, odorants, and neurotransmitters and convey ligand recognition into cellular responses, one of which is Ca(2+) signaling. To avoid receptor cross-talk or cross-activation with introduced proteins, the repertoire of cell-endogenous receptors must be known. Here we examined the presence of histamine receptors in six cell lines frequently used as hosts to study cellular signaling processes. In a concentration-dependent manner, histamine caused a rise in intracellular Ca(2+) in HeLa, HEK 293, and COS-1 cells. The concentration for half-maximal activation (EC50) was in the low micromolar range. In individual cells, transient Ca(2+) signals and Ca(2+) oscillations were uncovered. The results show that (i) HeLa, HEK 293, and COS-1 cells express sufficient amounts of endogenous receptors to study cellular Ca(2+) signaling processes directly and (ii) these cell lines are suitable for calibrating Ca(2+) biosensors in situ based on histamine receptor evoked responses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Higher efficacy and safety of nano gold therapeutics require examination of cellular responses to gold nanoparticles (AuNPs). In this work we compared cellular uptake, cytotoxicity and RNA expression patterns induced in Caco-2 cells exposed to AuNP (5 and 30nm). Cellular internalization was dose and time-dependent for both AuNPs. The toxicity was observed by colony forming efficiency (CFE) and not by Trypan blue assay, and exclusively for 5nm AuNPs, starting at the concentration of 200μM (24 and 72h of exposure). The most pronounced changes in gene expression (Agilent microarrays) were detected at 72h (300μM) of exposure to AuNPs (5nm). The biological processes affected by smaller AuNPs were: RNA/zinc ion/transition metal ion binding (decreased), cadmium/copper ion binding and glutathione metabolism (increased). Some Nrf2 responsive genes (several metallothioneins, HMOX, G6PD, OSGIN1 and GPX2) were highly up regulated. Members of the selenoproteins were also differentially expressed. Our findings indicate that exposure to high concentration of AuNPs (5nm) induces metal exposure, oxidative stress signaling pathways, and might influence selenium homeostasis. Some of detected cellular responses might be explored as potential enhancers of anti-cancer properties of AuNPs based nanomedicines., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases., (© 2015 American Society for Nutrition.)

The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)