Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.

Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms.

Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however

Dual kinase/bromodomain inhibitors for rationally designed polypharmacology

Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.

/pdf/harnessing-the-immune-system-to-overcome-cytokine-storm-and-3f26df8wr1.pdf

Harnessing the Immune System to Overcome Cytokine Storm and Reduce Viral Load in COVID-19: A Review of the Phases of Illness and Therapeutic Agents

Effective drug delivery is important in the treatment of various biomedical conditions, ranging from autoimmune disorders to cancer and bacterial infections. Nanostructured systems can help to overcome challenges to efficient drug delivery such as poor drug distribution, inefficient penetration across biological barriers and off-target effects. The bioinspired nanotopography of drug carrier surfaces provides a physical cue to modulate their interaction with biological systems. In this Review, we discuss how naturally occurring nanotopographical systems can inspire the design of biomaterials for drug delivery. We highlight nanoscale surface modifications of drug carriers and fabrication strategies, followed by a discussion about nanotopographical biointerfaces to regulate biological functions. Key bioinspired nanotopographical functionalities include bio-adhesion, barrier remodelling, drug uptake and subcellular trafficking, cellular signalling and modulation, and antimicrobial interfaces. Finally, we provide an outlook on the future of nanotopographical applications in drug delivery, with a focus on key challenges and exciting opportunities from bench to bedside. Three-dimensional nanotopography plays a key role in the interaction of nanoscale drug delivery systems and biological components. This Review discusses bioinspired nanotopographies that can improve muco-adhesion and cyto-adhesion, drug uptake and trafficking, barrier remodelling, cellular modulation and antimicrobial activities of various drug delivery platforms. 

/pdf/bioinspired-nanotopographical-design-of-drug-delivery-2a82fstu.pdf

Bioinspired nanotopographical design of drug delivery systems

BACKGROUND: The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. METHODS: Databases were searched from their inception to 5 September 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. FINDINGS: Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56;95% confidence interval: 0.46-0.69;P < 0.001;I2 = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of Baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. INTERPRETATION: Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of low cost, easy production, and convenient storage. This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.27482

Clinical efficacy and adverse events of baricitinib treatment for coronavirus disease-2019 (COVID-19): A systematic review and meta-analysis

Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling is critical to multiple cellular processes, including survival, differentiation, and proliferation. JAK-STAT signaling dysregulation has been noted in inflammatory disorders, and aberrant JAK2 pathway activation has been implicated in myelofibrosis and polycythemia vera. Moreover, 4 therapeutic JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) have either been approved or are in advanced clinical development for myelofibrosis. Although all inhibit JAK2, reports indicate that they also inhibit other kinases. Profiling based solely on in vitro potencies is insufficient to predict the observed clinical effects. To provide further translational insights into clinical outcomes, we compared phenotypic biomarker profiles of ruxolitinib, fedratinib, momelotinib, and pacritinib in the BioMAP® Diversity PLUS panel of 12 human primary cell systems designed to recapitulate key aspects of tissue and disease states. Biomarker activity profiles that represent mechanistic signatures for each agent were compared with each other and a database of reference benchmark profiles. At clinically relevant concentrations, these agents had distinct biomarker impacts indicating diverse mechanistic signatures, suggesting divergent clinical effects for each agent. They disparately modulated inflammatory cytokine production and immune function. At clinically relevant concentrations, ruxolitinib had the broadest scope of activities across all 12 cellular systems, whereas pacritinib was more specific for the BT system (modelling T cell-dependent B cell activation) and exhibited the strongest inhibition of sIL-17A, sIL-2, and sIL-6. All 4 agents were antiproliferative to B cells, but ruxolitinib and momelotinib were also antiproliferative to T cells. These differential activities likely reflect distinct secondary pharmacology for these agents known primarily as JAK2 inhibitors. The phenotypic analysis reported herein represents key data on distinct modes-of-action that may provide insights on clinical outcomes reported for these agents. Such translational findings may also inform the development of next-generation molecules with improved efficacy and safety.

/pdf/comparative-phenotypic-profiling-of-the-jak2-inhibitors-za1abf1hod.pdf

Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures.

Cells sense and respond to a variety of physical cues from their surrounding microenvironment, and these are interpreted through mechanotransductive processes to inform their behavior. These mechanisms have particular relevance to stem cells, where control of stem cell proliferation, potency, and differentiation is key to their successful application in regenerative medicine. It is increasingly recognized that surface micro- and nanotopographies influence stem cell behavior and may represent a powerful tool with which to direct the morphology and fate of stem cells. Current progress toward this goal has been driven by combined advances in fabrication technologies and cell biology. Here, the capacity to generate precisely defined micro- and nanoscale topographies has facilitated the studies that provide knowledge of the mechanotransducive processes that govern the cellular response as well as knowledge of the specific features that can drive cells toward a defined differentiation outcome. However, the path forward is not fully defined, and the "bumpy road" that lays ahead must be crossed before the full potential of these approaches can be fully exploited. This review focuses on the challenges and opportunities in applying micro- and nanotopographies to dictate stem cell fate for regenerative medicine. Here, key techniques used to produce topographic features are reviewed, such as photolithography, block copolymer lithography, electron beam lithography, nanoimprint lithography, soft lithography, scanning probe lithography, colloidal lithography, electrospinning, and surface roughening, alongside their advantages and disadvantages. The biological impacts of surface topographies are then discussed, including the current understanding of the mechanotransductive mechanisms by which these cues are interpreted by the cells, as well as the specific effects of surface topographies on cell differentiation and fate. Finally, considerations in translating these technologies and their future prospects are evaluated.

The Bumpy Road to Stem Cell Therapies: Rational Design of Surface Topographies to Dictate Stem Cell Mechanotransduction and Fate.

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Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures.

The Bumpy Road to Stem Cell Therapies: Rational Design of Surface Topographies to Dictate Stem Cell Mechanotransduction and Fate.