Purposeof the Review Hemostasis plays a central role in maintaining a normal physiological vasculature, especially during and after vascular injury. Low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a transmembrane protein of the LDL family that exhibits multifunctional characteristics that affect endocytosis, signal transduction, and the formation of synthetic cell phenotypes in the vascular wall. Studies have shown that LRP1 is particularly important in various pathways and processes that contribute to the maintenance of vascular homeostasis. Recent Findings LRP1 is pivotal to the pathophysiology of vascular disease that impairs vascular integrity. Recent studies have shown that LRP1 can also act as a coactivator, affecting transcription of other important proteins. Current research uses LRP1-deficient models to specifically study the mechanisms of LRP1 in multiple pathways including vascular cells, helping to guide potential therapeutic targets following vascular injury. Summary This review aims to highlight the broad physiological role that LRP1 plays in vessel integrity, cellular function, and various metabolic and signaling pathways. The review also provides insights into the pathophysiology of vascular diseases, especially those resulting from LRP1 deficiency or dysfunction.
Purpose of the Review This review recapitulates the complex pathophysiology of type 2 diabetes mellitus associated with a prothrombotic and proinflammatory phenotype. It focuses on the roles played by platelets and neutrophils in these pathologies and then focuses on recent advances in therapeutic interventions. Recent Findings Platelets, fundamental to the process of hemostasis (and thrombosis), have been increasingly implicated with inflammatory responses. Similarly, neutrophils, the first line of defense against pathogen invasions, forming a crucial role in body’s inflammatory immune responses, have been progressively associated with coagulation and thrombotic reactions. Interestingly, these two cells also interact with each other in their microenvironment, forming platelet-neutrophil complexes, to achieve full functionality. The incidence of these complexes is found to be higher in patients with diabetes mellitus, promoting associated complications. Summary This review attempts to understand the interplay of these cells in a diabetic, hyperglycemic milieu, concluding with a look back at the available therapeutic interventions to address the complications.
Purpose of Review Signaling pathways serve to communicate information about extracellular conditions into the cell, to both the nucleus and cytoplasmic processes to control cell responses. Genetic mutations in signaling network components are frequently associated with cancer and can result in cells acquiring an ability to divide and grow uncontrollably. Because signaling pathways play such a significant role in cancer initiation and advancement, their constituent proteins are attractive therapeutic targets. In this review, we discuss how signaling pathway modeling can assist with identifying effective drugs for treating diseases, such as cancer. An achievement that would facilitate the use of such models is their ability to identify controlling biochemical parameters in signaling pathways, such as molecular abundances and chemical reaction rates, because this would help determine effective points of attack by therapeutics. Recent Findings We summarize the current state of understanding the sensitivity of phosphorylation cycles with and without sequestration. We also describe some basic properties of regulatory motifs including feedback and feedforward regulation. Summary Although much recent work has focused on understanding the dynamics and particularly the sensitivity of signaling networks in eukaryotic systems, there is still an urgent need to build more scalable models of signaling networks that can appropriately represent their complexity across different cell types and tumors.
Nanotechnology offers enormous opportunities in regulation of the physical, mechanical, electrical, and biological properties of tissue engineering scaffolds. Nanoscale structures have been used as delivery agents that can be incorporated in the scaffolds to deliver the required signaling molecules for tissue regeneration. Purpose of Review Purpose of the present review is to discuss the requirements for a tissue engineering construct and how the nanoscale delivery systems facilitate achieving it. Review also depicts the various types of nanostructures explored for the delivery of growth factors, cell differentiation agents, genes, and antimicrobials so as to enable efficient tissue regeneration. How the dynamic nature of tissue can be extrapolated in the scaffold by the use of nanodelivery systems are also presented. Recent Findings Among various nanostructures, polymer and lipid based have been widely used as delivery systems for tissue engineering due to their easily customizable biodegradability and functionalization. Though the inorganic nano-systems offer advantages in terms of imaging and trigger responsiveness, toxicity issues limit their extensive use. Though there are many literatures available on nanoscale delivery systems for tissue engineering, none of them has reached a level of clinical translation. Summary Nanotechnology-based delivery systems opened wide opportunities to alter the characteristics of tissue engineering scaffolds and cellular behavior, ultimately to achieve a better control over neotissue formation. A thorough examination is crucial to establish product safety, effectiveness, or other attributes before they reach clinics.
Purpose of Review COVID-19 has rapidly evolved into a global pandemic infecting over two hundred and forty-four million individuals to date. In addition to the respiratory sequelae and systemic infection that ensues, an alarming number of micro and macrovascular thrombotic complications have been observed. This review examines the current understanding of COVID-19-associated thrombotic complications, potential mechanisms, and pathobiological basis for thromboses development. Recent Findings The endothelium plays a major role in the process due to direct and indirect injury. The immune system also contributes to a pro-thrombotic environment with immune cell dysregulation leading to excessive formation of cytokines, also called cytokine storm, and an eventual promotion of a hypercoagulable environment, known as immunothrombosis. Additionally, neutrophils play an important role by forming neutrophil extracellular traps, which are shown to be pro-thrombotic and further enhanced in COVID-19 patients. A disruption of the fibrinolysis system has also been observed. Summary Multiple pathways likely contribute synergistically to form a pro-thrombotic milieu. A better understanding of these factors and the complex interplay between them will lead to the improvement of diagnostic and therapeutic interventions.
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 betacoronavirus and has taken over 761,426 American lives as of the date of publication and will likely result in long-term, if not permanent, tissue damage for countless patients. COVID-19 presents with diverse and multisystemic pathologic processes, including a hyperinflammatory response, acute respiratory distress syndrome (ARDS), vascular injury, microangiopathy, tissue fibrosis, angiogenesis, and widespread thrombosis across multiple organs, including the lungs, heart, kidney, liver, and brain. C-X-C chemokines contribute to these pathologies by attracting inflammatory mediators, the disruption of endothelial cell integrity and function, and the initiation and propagation of the cytokine storm. Among these, CXCL10 is recognized as a critical contributor to the hyperinflammatory state and poor prognosis in COVID-19. CXCL10 is also known to regulate growth factor-induced fibrosis, and recent evidence suggests the CXCL10-CXCR3 signaling system may be vital in targeting convergent pro-inflammatory and pro-fibrotic pathways. This review will explore the mechanistic role of CXCL10 and related chemokines in fibrotic complications associated with COVID-19 and the potential of CXCL10-targeted therapeutics for early intervention and long-term treatment of COVID-19-induced fibrosis.
Nanoparticles have revolutionized biomedicine especially in the field of drug delivery due to their intriguing properties such as systemic stability, level of solubility, and target site specificity. It can, however, be both beneficial and damaging depending on the properties in different environments, thus highlighting the importance of nanotoxicology studies before use in humans. Different types of nanoparticles have been used in drug delivery, and this review summarizes the recent toxicity studies of these nanoparticles. The toxicological evaluation of three widely used nanoparticles in drug delivery that are metal, lipid, and protein nanoparticles has been discussed in detail. Studies have recorded several toxic effects of various nanoparticles such as metal-based nanoparticles have been linked to increased oxidative stress and have the potential to infiltrate the cell nucleus and protein-based nanoparticles have been observed to have hepatotoxicity and nephrotoxicity as their adverse effects. Considering the increasing application of nanoparticles in drug delivery and the growing concerns of regulatory authorities regarding the toxicity of nanocarriers in living organisms, it requires urgent attention to identify the gap in toxicity studies. The review highlights the gap in toxicity studies and potential focus areas to overcome the existing challenges.
Cancer is a life-threatening disease and one of the leading causes of death globally. Currently a good number therapeutic modalities including chemotherapy are used to treat cancer. All these treatments have their own advantages and disadvantages, and hence, usually two or more therapies are combined for effective treatment of cancer. However, the inadequacy of treatment is so high that in the past few decades, deaths due to cancer did not change much, even after development of several new treatment modalities and drugs. Early detection and treatment are the most important factors for ensuring success of cancer therapies. So, people are continuously working on an endeavour to develop superior technologies for the early detection and treatment of cancer. Nanotechnology is opening up a window of new possibilities or opportunities to address this menace. Magnetic nanostructures (MNSs) can play an important role in cancer theranostic applications. This review highlights the different applications of MNSs in cancer theranostic applications. Magnetic nanoparticles have been extensively investigated for cancer imaging, drug targeting and hyperthermia applications. This paper reviews the different cancer detection and treatment modalities using magnetic nanostructures, their advantages over the traditional methods, current status, challenges and future prospects with the help of illustrative examples from recent literature.
This review focuses on introducing the role of luminescent gold nanoclusters (AuNCs) as promising combinatorial agents for accurate diagnosis and image guided therapeutics for cancer management. The unique opto-electronic properties as well as high biocompatibilty of luminescent AuNCs enable their use as tracers in optical imaging as well as precise multi-modal tumor imaging with X-ray/CT, PET and MRI. Moreover, the photostability of AuNCs in comparison to conventional fluorescent dyes has allowed their widespread use as sensitizing materials for enhanced photothermal, photodynamic and radiotherapy. Luminescent noble MNCs, especially AuNCs, are rapidly gaining attention as new age nanotheranostic agents for targeted imaging and therapeutics due to their high biocompatibility, good photostability, unique optical properties and favourable pharmacokinetics especially in the field of cancer management. Moreover, the ease of synthesis, tunable photoemission and tumor targeting through biofunctionalization for a rapid and more sensitive diagnosis and efficacious therapeutic applications make them potential candidates for clinical translation.
Docetaxel is an important cancer therapeutic drug that targets microtubules. As a taxane, it has high cytotoxic potential and causes cell death by inducing polymerization of tubulin monomers and inhibiting depolymerization or inducing apoptosis by stimulating the phosphorylation B-cell lymphoma 2 (Bcl-2). As a hydrophobic drug, the clinical application of docetaxel is limited. The nanoparticle-based platforms as drug carriers have opened up the vast potential of docetaxel. The purpose of the review is to introduce the developments in nano-drug carriers in meeting the needs to target individual tumour cellular components. The progress from individual nanoparticles like liposome or cubosome to hybrid nanoparticles capable of carrying multiple drugs, targeting them to the tumour site, and releasing the active molecules in a sustained and prolonged manner has been addressed by researchers in recent times. Newer developments of active targeting systems such as through antibody conjugation to the nanoparticle are observed in this area. From the knowledge that is currently available in public domain, it can be foreseen that extensive in vivo assessment of the formulations that have shown good prospects is required. The in vivo assessment needs to be based on in vitro models coupled with extensive toxicity studies. This is required to take a larger percentage of the methodologies available in the literature to preclinical and clinical trials and thus to the market. Safe, side effect–free, biocompatible and biodegradable nanoparticles as carriers for docetaxel are around the corner.
Despite preclinical success of nanomedicine for anticancer activity, the clinical success of the same has been very limited. This review evaluates and discusses the therapeutic potential and pitfalls of clinically undergoing and successful nanoformulations in treatment of globally prevalent cancers. Cancer is the second leading cause of disease-related deaths all over the world. Alongside the FDA approved indication, chemotherapeutic nanoformulations like Abraxane and Doxil are alternatively evaluated in other cancers providing positive results. The review gives an update on the nanoformulations, which are currently in phase I and phase II clinical trials and approved for the treatment of prevalent cancers. Emphasis on the immediate need for reforming the guidelines for nanoformulations allows significant advances in the field of cancer nano-therapy in the near future.
Purpose of Review Drug and gene deliveries are crucial aspects in biomedical application as they stimulate biological response of the body to elicit a therapeutic effect. It is seen that drugs, their formulations and the route of administrations, play a vital role in enhancing therapeutic effect onto the desired cellular or intracellular target. But, conventional drug forms suffer from poor pharmacodynamics and pharmacokinetics profile. For this purpose, different nanosized dendrimer-based drug and gene delivery systems and the interactions between dendrimers and guest molecules have been reviewed. Recent Findings Dendrimers as drug and gene carriers enhance the systemic blood circulation time, biocompatibility, and reduce toxicity. While, on one hand, non-covalent interactions of dendrimer-drug (physical encapsulation) improves drug solubility, on the other hand, electrostatic interactions with charged molecule encourages endosomal escape. Covalent association through various physiologically labile bonds or cleavable linkers can achieve controlled release and targeted delivery of the therapeutic moiety. Summary Dendrimers can act as versatile tools for delivery of nucleic acids, drugs, vaccines for different diseases via different administration routes.
Purpose of Review Nanoparticles are crucial for developing patient-/target-specific drug delivery systems. In recent days, mathematical modeling and simulation plays an important role in optimization of various parameters like nanoparticle-based drug dose, dissolution of drug particles, and adverse reaction from the nanoparticles. With the help of modeling and simulation, we can determine or optimize the type, shape, and size of the nanoparticles to be utilized as potential drug delivery system and its influence on the targeted cells/tissues. The main purpose of this review article is to discuss the latest modeling and simulation tools available for developing patient-specific nanoparticle-based drug delivery systems. Recent Findings In our current study, we are reporting different mathematical models used for cancer drug delivery systems. It also reports several numerical methods, and simulations models are available for representing nano-drug-bio interactions within the biological systems. Summary This review highlights the applications of mathematical modeling and simulation software for developing a rational nano-carrier design and selecting accurate biomaterials for in vivo model.
Purpose of Review Ulcerative colitis (UC) is a chronic inflammatory bowel disorder that causes inflammation in the colon and rectum and can be lethal to the patients. The dysbiotic intestinal microbiome is considered a major factor of UC, yet it needs more evidences. As there is no cure for UC, anti-inflammatory drugs, potent steroids, immunomodulatory drugs, or even surgery is used to manage the disease. The purpose of this review is to focus on the underlying factors involved in the disease pathogenicity, including host gut microbiome and novel therapies for treatment of UC. Recent Findings Due to disruption of intestinal epithelial layers, the intestinal microflora interacts with immune cells in the lamina propria, which in turn provokes an inflammatory response, which is subsequently exacerbated in the colon. Anti–tumor necrosis factor (anti-TNF), anti-integrin, Janus kinase inhibitors, siRNA, fecal microbiome transfer, synbiotics, and many other small molecules such as ozanimod are emerging as potential therapy for UC. Moreover, a nanoparticle-based drug delivery system enhances localized delivery of the drug to the inflammatory sites. Additionally, herbal-derived nanoparticles are also emerging as a novel drug delivery system in disease management. Summary The homeostasis of gut microbiota is crucial for both prevention and remission of UC. Synbiotics and fecal microbiome transfer is emerging as potential treatment strategies for management of UC. The combination of multiple therapies may have durable therapeutic outcomes against the debilitating condition of UC. The outcome of the ongoing clinical trials of novel drugs will define the new therapeutic approaches in the treatment of UC for long-term remission. Graphical abstract
Alcohol use continues to rise globally. We review the current literature on the effect of alcohol on bone health, homeostasis, and fracture repair to highlight what has been learned in people and animal models of alcohol consumption. Recently, forkhead box O (FoxO) has been found to be upregulated and activated in mesenchymal stem cells (MSC) exposed to alcohol. FoxO has also been found to modulate Wnt/β-catenin signaling, which is necessary for MSC differentiation. Recent evidence suggests alcohol activates FoxO signaling, which may be dysregulating Wnt/β-catenin signaling in MSCs cultured in alcohol. This review highlights the negative health effects learned from people and chronic and episodic binge alcohol consumption animal models. Studies using chronic alcohol exposure or alcohol exposure then bone fracture repair model have explored several different cellular and molecular signaling pathways important for bone homeostasis and fracture repair, and offer potential for future experiments to explore additional signaling pathways that may be dysregulated by alcohol exposure.
Diabetes is a common and prevalent medical condition as it affects many lives around the globe. Specifically, type-2 diabetes (T2D) is characterized by chronic systemic inflammation alongside hyperglycemia and insulin resistance in the body, which can result in atherosclerotic legion formation in the arteries and thus progression of related conditions called diabetic vasculopathies. T2D patients are especially at risk for vascular injury; adjunct in many of these patients, their cholesterol and triglyceride levels reach dangerously high levels and accumulate in the lumen of their vascular system. Microvascular and macrovascular vasculopathies as complications of diabetes can accentuate the onset of organ illnesses; thus, it is imperative that research efforts help identify more effective methods for prevention and diagnosis of early vascular injuries. Current research into vasculopathy identification/treatment will aid in the amelioration of diabetes-related symptoms and thus reduce the large number of deaths that this disease accounts annually. This review aims to showcase the evolution and effects of diabetic vasculopathy from development to clinical disease as macrovascular and microvascular complications with a concerted reference to sex-specific disease progression as well.
Purpose of Review Computational and mathematical modeling have become a critical part of understanding in-host infectious disease dynamics and predicting effective treatments. In this review, we discuss recent findings pertaining to the biological mechanisms underlying infectious diseases, including etiology, pathogenesis, and the cellular interactions with infectious agents. We present advances in modeling techniques that have led to fundamental disease discoveries and impacted clinical translation. Recent Findings Combining mechanistic models and machine learning algorithms has led to improvements in the treatment of Shigella and tuberculosis through the development of novel compounds. Modeling of the epidemic dynamics of malaria at the within-host and between-host level has afforded the development of more effective vaccination and antimalarial therapies. Similarly, in-host and host-host models have supported the development of new HIV treatment modalities and an improved understanding of the immune involvement in influenza. In addition, large-scale transmission models of SARS-CoV-2 have furthered the understanding of coronavirus disease and allowed for rapid policy implementations on travel restrictions and contract tracing apps. Summary Computational modeling is now more than ever at the forefront of infectious disease research due to the COVID-19 pandemic. This review highlights how infectious diseases can be better understood by connecting scientists from medicine and molecular biology with those in computer science and applied mathematics.
Purpose of Review Partial differential equation (PDE) mathematical models of biological systems are widely used to test hypotheses and infer regulatory interactions based on optimization of the PDE model against the observed data. In this review, we discuss the ability of powerful machine learning methods to accelerate the parametric screening of biophysically informed PDE systems. Recent Findings A major shortcoming in more broad adaptation of PDE-based models is the high computational complexity required to solve and optimize the models, and it requires many simulations to traverse the very high-dimensional parameter spaces during model calibration and inference tasks. For instance, when scaling up to tens of millions of simulations for optimization and sensitivity analysis of the PDE models, compute times quickly extend from months to years for sufficient coverage to solve the problems. For many systems, this brute-force approach is simply not feasible. Recently, neural network metamodels have been shown to be an efficient way to accelerate PDE model calibration, and here we look at the benefits and limitations in extending the PDE acceleration methods to improve optimization and sensitivity analysis. Summary We use an example simulation to quantitatively and qualitatively show how neural network metamodels can be accurate and fast and demonstrate their potential for optimization of complex spatiotemporal problems in biology. We expect that these approaches will be broadly applied to speed up scientific research and discovery in biology and other systems that can be described by complex PDE systems.
Purpose of Review Our goal is to show how readily available Pathomics tissue analytics can be used to study tumor immune interactions in cancer. We provide a brief overview of how Pathomics complements traditional histopathologic examination of cancer tissue samples. We highlight a novel Pathomics application, Tumor-TILs, that quantitatively measures and generates maps of tumor infiltrating lymphocytes in breast, pancreatic, and lung cancer by leveraging deep learning computer vision applications to perform automated analyses of whole slide images. Recent Findings Tumor-TIL maps have been generated to analyze WSIs from thousands of cases of breast, pancreatic, and lung cancer. We report the availability of these tools in an effort to promote collaborative research and motivate future development of ensemble Pathomics applications to discover novel biomarkers and perform a wide range of correlative clinicopathologic research in cancer immunopathology and beyond. Summary Tumor immune interactions in cancer are a fascinating aspect of cancer pathobiology with particular significance due to the emergence of immunotherapy. We present simple yet powerful specialized Pathomics methods that serve as powerful clinical research tools and potential standalone clinical screening tests to predict clinical outcomes and treatment responses for precision medicine applications in immunotherapy.
Functional angiogenesis is a critical therapeutic goal in many pathological conditions. Logically, the use of pro-angiogenic growth factors has been the mainstay approach despite obvious limitations and modest success. Recently, macrophages have been identified as key regulators of the host response to implanted materials. Particularly, our understanding of dynamically plastic macrophage phenotypes, their interactions with biomaterials, and varied roles in different stages of angiogenic processes is evolving rapidly. In this review, we discuss changing perspectives on therapeutic angiogenesis, in relation to implantable materials and macrophage-centric strategies therein. Harnessing the different mechanisms through which the macrophage-driven host response is involved in angiogenesis has great potential for improving clinical outcome.
