Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, and ultimately, bone erosion of the joints. The causes of this disease are multifactorial, including genetic factors, such as the presence of the human leukocyte antigen (HLA)-DRB1*04 variant, alterations in the microbiota, or immune factors including increased cytotoxic T lymphocytes (CTLs), neutrophils, or elevated M1 macrophages which, taken together, produce high levels of pro-inflammatory cytokines. In this review, we focused on the function exerted by osteoclasts on osteoblasts and other osteoclasts by means of the release of exosomal microRNAs (miRNAs). Based on a thorough revision, we classified these molecules into three categories according to their function: osteoclast inhibitors (miR-23a, miR-29b, and miR-214), osteoblast inhibitors (miR-22-3p, miR-26a, miR-27a, miR-29a, miR-125b, and miR-146a), and osteoblast enhancers (miR-20a, miR-34a, miR-96, miR-106a, miR-142, miR-199a, miR-324, and miR-486b). Finally, we analyzed potential therapeutic targets of these exosomal miRNAs, such as the use of antagomiRs, blockmiRs, agomiRs and competitive endogenous RNAs (ceRNAs), which are already being tested in murine and ex vivo models of RA. These strategies might have an important role in reestablishing the regulation of osteoclast and osteoblast differentiation making progress in the development of personalized medicine.This research was supported by the grant CIGE/2021/162 funded by Generalitat Valenciana and by University of Alicante, grant number GRE21-17, both as the Emerging Research Groups Grants

Endoplasmic Reticulum Stress and Oxidative Stress in Cell Fate Decision and Human Disease

Significance: The endoplasmic reticulum (ER) is a specialized organelle for the folding and trafficking of proteins, which is highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Alterations in the protein-folding environment cause accumulation of misfolded proteins in the ER that profoundly affect a variety of cellular signaling processes, including reduction?oxidation (redox) homeostasis, energy production, inflammation, differentiation, and apoptosis. The unfolded protein response (UPR) is a collection of adaptive signaling pathways that evolved to resolve protein misfolding and restore an efficient protein-folding environment. Recent Advances: Production of reactive oxygen species (ROS) has been linked to ER stress and the UPR. ROS play a critical role in many cellular processes and can be produced in the cytosol and several organelles, including the ER and mitochondria. Studies suggest that altered redox homeostasis in the ER is sufficient to cause ER stress, which could, in turn, induce the production of ROS in the ER and mitochondria. Critical Issues: Although ER stress and oxidative stress coexist in many pathologic states, whether and how these stresses interact is unknown. It is also unclear how changes in the protein-folding environment in the ER cause oxidative stress. In addition, how ROS production and protein misfolding commit the cell to an apoptotic death and contribute to various degenerative diseases is unknown. Future Directions: A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases. Antioxid. Redox Signal. 21, 396?413.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140299/1/ars.2014.5851.pd

Adipokines 2.0

Once viewed solely as fat storage cells, adipocytes and their adipokines have now been proven to be central for human health. Understanding that overweight and obesity may increase the risk for various diseases requires detailed characterization of adipokine function. Weight gain, weight regain, and fasting affect adipocyte health and accordingly their secretome. Different adipose tissue deposits exist and they vary in cellular composition and function. The evidence is strong of a role of adipokines in cancer, reproductive function, neurological diseases, cardiovascular diseases ,and rheumatoid arthritis. Adipokines are considered useful biomarkers for adipose tissue and metabolic health, and may be used as diagnostic tools in rheumatoid arthritis, cancer, or sepsis. This book contains 10 original articles and 9 review articles focusing on these bioactive peptides. Several articles deal with chemerin, an adipokine discovered more than 20 years ago. Data so far have resulted in promising insights related to its biological function. We are only beginning to understand the multiple roles of chemerin, the mechanisms regulating its activity, and the signaling pathways used by this chemokine. Adipokine receptor agonists and antagonists may result in the formulation of novel drugs and ultimately may lead to new therapeutic targets to be used in clinical practice

Starting Anti-COVID-19 Drug Discovery with Natural Products

COVID-19 was characterized as a pandemic regarding its rapid international spread and severity on March 2020. The Coronaviridae family receives this name regarding the organization of the spike glycoprotein located in the envelope, which resembles a stellar corona when observed under a microscope. Coronaviruses undergo frequent mutations in their genome due to errors made by RNA-dependent RNA polymerase (RdRp). The SARS-CoV-2 was characterized by high infectivity and person to person transmission, with an incubation period of up to fourteen days. Potent antiviral activities of several natural products such as alkaloids, chalcones, triterpenoids have been reported but with unconfirmed efficacy or safety in the clinic as well as the complete underlying mechanisms. Also, CQ, HCQ and Ivermectin, remdesivir, lopinavir, ritonavir, favipiravir and pegylated interferon with ribavirin have been tested to develop both an effective therapy and a vaccine to treat COVID-19.  This study presents the antiviral effects of the natural products against SARS-CoV, HCoV-NL63, HCoV-229E and HCoV-OC43 showing that Lycorine, Emodin, Promazine, Saikosaponins B2, Silvestrol, Cepharanthine, Fangchinoline, Tetrandrine, Caffeic acid, Chlorogenic acid, Gallic acid and Emetine are a good candidates on treatment of coronaviruses infections.La COVID-19 se caracterizó como una pandemia debido a su rápida propagación y severidad en marzo de 2020. La familia Coronaviridae recibe su nombre de la organización de la glucoproteína 'espigas' ubicada en el sobre, en forma de corona cuando se observa al microscopio. . Los coronavirus sufren mutaciones frecuentes en su genoma debido a errores cometidos por la ARN polimerasa dependiente de ARN (RdRp, RDR). El SARS-CoV-2, el agente causal del COVID-19, es un virus altamente infeccioso y puede transmitirse de persona a persona. Se han informado actividades antivirales potentes de varios productos naturales, como alcaloides, chalcones, triterpenoides, pero sin eficacia ni seguridad clínicamente confirmadas, así como con los mecanismos subyacentes completos. Este artículo de revisión presenta los efectos antivirales de los productos naturales contra el SARS-CoV, HCoV-NL63, HCoV-229E y HCoV-OC43, mostrando que el licorino, emodina, promazina, saikosaponinas B2, silvestrol, la cefarantina, fangchinolina, tetrandrina, el ácido cafeico, el ácido clorogénico, el ácido gálico y la emetina son buenos candidatos para el tratamiento de las infecciones por coranavirus.Le COVID-19 a été caractérisé comme une pandémie en raison de sa propagation internationale rapide et de sa gravité en mars 2020. La famille des Coronaviridae reçoit ce nom concernant l'organisation de la glycoprotéine 'pointes' située dans l'enveloppe, en forme une couronne lorsqu'elle est observée au microscope. Les coronavirus subissent de fréquentes mutations dans leur génome en raison d'erreurs commises par l'ARN polymérase ARN-dépendante (RdRp, RDR). Le SARS-CoV-2 a un pouvoir infectieux élevé et une transmission d'une personne à l'autre. De puissantes activités antivirales de plusieurs produits naturels tels que les alcaloïdes, les chalcones, les triterpénoïdes ont été signalées mais avec une efficacité ou une sécurité non confirmée en clinique ainsi que les mécanismes sous-jacents complets. Cette étude présente les e ets antiviraux des produits naturels contre le SARS-CoV, le HCoV-NL63, le HCoV-229E et le HCoV-OC43 montrant que la lycorine, l'émodine, la promazine, les saikosaponines B2, le silvestrol, la cépharanthine, la fangchinoline, la tétrandrine, l'acide caféique, l'acide chlorogénique , L'acide gallique et l'émétine sont de bons candidats pour le traitement de l'infection par le coranaviruses infections.A COVID-19 foi caracterizada como uma pandemia devido à sua rápida disseminação e severidade em março de 2020. A família Coronaviridae recebe esse nome em relação à organização da glicoproteína 'spikes' localizada no envelope, em forma de uma coroa quando vista sob um microscópio. Os coronavírus sofrem mutações frequentes em seu genoma devido a erros cometidos pela RNA polimerase dependente de RNA (RdRp, RDR). O SARS-CoV-2, agente causador da COVID-19, é um vírus altamente infeccioso e pode ser transmitido de pessoa para pessoa. Foram relatadas atividades antivirais potentes de vários produtos naturais, como alcalóides, chalconas, triterpenóides, mas com eficácia ou segurança não confirmada clinicamente, bem como com os mecanismos subjacentes completos. O presente artigo de revisão apresenta os efeitos antivirais de produtos naturais contra SARS-CoV, HCoV-NL63, HCoV-229E e HCoV-OC43, mostrando que a licorina, emodina, promazina, saikosaponinas B2, silvestrol, la cefarantina, fangchinolina, tetrandrina, ácido cafeico, ácido clorogênico, ácido gálico e emetina são bons candidatos ao tratamento de infecções por coranavírus

High Density Lipoproteins: From Biological Understanding to Clinical Exploitation

Pharmacology/Toxicology; Molecular Medicine; Human Physiology; Immunology; Cell Biolog

Targeting STAT3 and STAT5 in Cancer

Every minute, 34 new patients are diagnosed with cancer globally. Although over the past 50 years treatments have improved and survival rates have increased dramatically for several types of cancers, many remain incurable. Several aggressive types of blood and solid cancers form when mutations occur in a critical cellular signaling pathway, the JAK-STAT pathway; (Janus Kinase-Signal Transducer and Activator of Transcription). Currently, there are no clinically available drugs that target the oncogenic STAT3/5 proteins in particular or their Gain of Function hyperactive mutant products. Here, we summarize targeting approaches on STAT3/5, as the field moves towards clinical applications as well as we illuminate on upstream or downstream JAK-STAT pathway interference with kinase inhibitors, heat shock protein blockers or changing nuclear import/export processes. We cover the design paradigms and medicinal chemistry approaches to illuminate progress and challenges in understanding the pleiotropic role of STAT3 and STAT5 in oncogenesis, the microenvironment, the immune system in particular, all culminating in a complex interplay towards cancer progression

Role Of Interleukin-6 In Cd4 And Cd8 T Cell Effector Functions

IL-6 is an inflammatory cytokine that contributes to the pathogenesis of many immunological diseases including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, allergic asthma, as well as the protection against infections caused by various pathogens. These are linked to its role in regulating CD4 T cell differentiation and effector function. Most of these functions are dependent on the IL-6-mediated signaling through the transcription factor Stat3. In this thesis, we identify a novel molecular mechanism by which IL-6 regulates CD4 T cell effector function. We show that IL-6-dependent signal raises the levels of mitochondrial Ca2+ late during activation of CD4 T cells. This is further used to prolong the expression of effector cytokines IL-4 and IL-21. The modulation of mitochondrial Ca2+ is mediated by the regulation of mitochondrial Stat3 and the formation of respiratory supercomplexes. Thus, in addition to the canonical signaling of IL-6 through Stat3 as a transcription factor, IL-6 also modulates mitochondrial Stat3 to regulate mitochondrial function in CD4 T cells. This could be an alternative pathway by which IL-6 regulates effector function of CD4 T cells and it could contribute to the pathogenesis of inflammatory disease. Little is known about the effects of IL-6 on CD8 T cells. In this thesis, we reveal a paradigm-shifting mechanism by which IL-6 regulates antibody production by converting CD8 T cells into B cell helpers through IL-21. Briefly, IL-6 promotes the differentiation of a subset of naïve CD8 T cells into a unique population of effector CD8 T cells characterized by the production of high levels of IL-21. IL-21-producing CD8 T cells provide help to B cells to induce isotype switching and protective antibody production during infection. In summary, this thesis provides new insights into both mechanistic and functional aspects of IL-6 in regulating T cell function. These findings may shed light on the development of new therapeutic approaches in treating autoimmune disorders and preventing infectious diseases