Wound healing is a complex process, which ultimately leads to fibrosis if not repaired well. Pathologically very similar to fibrosis is the tumor stroma, found in several solid tumors which are ...regarded as wounds that do not heal. Integrins are heterodimeric surface receptors which control various physiological cellular functions. Additionally, integrins also sense ECM-induced extracellular changes during pathological events, leading to cellular responses, which influence ECM remodeling. The purpose and scope of this review is to introduce integrins as key targets for therapeutics and drug delivery within the scope of wound healing, fibrosis and the tumor stroma. This review provides a general introduction to the biology of integrins including their types, ligands, means of signaling and interaction with growth factor receptors. Furthermore, we highlight integrins as key targets for therapeutics and drug delivery, based on their biological role, expression pattern within human tissues and at cellular level. Next, therapeutic approaches targeting integrins, with a focus on clinical studies, and targeted drug delivery strategies based on ligands are described.
Existing integrin drug targeting ligands, applied for the modification of drug molecules, drug carriers and CAR-T cells (CAR-T), in the context of wound healing, fibrosis or tumor stroma and their respective integrin targets. Dashed lines show potential integrin targets for existing ligands (PHSCNK, PR_b, RGD, RKK12, quinolonic, echistatin) that have not yet been used for targeting the respective cell line. In addition to already targeted integrins, integrins that have not yet been targeted but play a role in the pathology of wound healing, fibrosis or tumor stroma are presented. Display omitted
Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident ...hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of ...myofibroblasts in tumor progression, invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor progression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will then discuss the state-of-the art drug targeting technologies to myofibroblasts in context of the above-mentioned organs and tumor microenvironment. The overall objective of this review is therefore to advance our understanding in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for designing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer.
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Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and ...mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.
Tumor‐associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and metastasis while suppressing the tumor immune system. ...These protumoral macrophages display an M2 phenotype induced by IL‐4 and IL‐13 cytokines. In this study, we hypothesized that the inhibition of the signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of IL‐4 and IL‐13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using small interfering RNA or the pharmacologic inhibitor, AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg‐1 (arginase‐1) and Mrc‐1 (mannose receptor 1) expression and arginase activity. In vivo, AS1517499 significantly attenuated tumor growth and early liver metastasis in an orthotopic 4T1 mammary carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic mRNA expression of F4/80 (EGF‐like module‐containing mucin‐like hormone receptor‐like 1; total macrophages) and M2 macrophage markers Ym‐1 (chitinase 3–like protein 3) and Mrc‐1 and metastatic niche markers Mmp‐2 (matrix metalloproteinase‐2), Postn (periostin), and Cd34 in mice with increasing growth of primary tumors. Of interest, these markers were found to be reduced after treatment with AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate tumor growth and metastasis by inhibiting TAM‐induced protumorigenic and prometastatic activities.—Binnemars‐Postma, K., Bansal, R., Storm, G., Prakash, J. Targeting the Stat6 pathway in tumor‐associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J. 32, 969–978 (2018). www.fasebj.org
Glioblastoma‐associated macrophages (GAMs) play a crucial role in the progression and invasiveness of glioblastoma multiforme (GBM); however, the exact crosstalk between GAMs and glioblastoma cells ...is not fully understood. Furthermore, there is a lack of relevant in vitro models to mimic their interactions. Here, novel 3D‐bioprinted mini‐brains consisting of glioblastoma cells and macrophages are presented as tool to study the interactions between these two cell types and to test therapeutics that target this interaction. It is demonstrated that in the mini‐brains, glioblastoma cells actively recruit macrophages and polarize them into a GAM‐specific phenotype, showing clinical relevance to transcriptomic and patient survival data. Furthermore, it is shown that macrophages induce glioblastoma cell progression and invasiveness in the mini‐brains. Finally, it is demonstrated how therapeutics can inhibit the interaction between GAMs and tumor cells resulting in reduced tumor growth and more sensitivity to chemotherapy. It is envisioned that this 3D‐bioprinted tumor model is used to improve the understanding of tumor biology and for evaluating novel cancer therapeutics.
A novel 3D bioprinted model recapitulating the microenvironment of glioblastoma multiforme is presented. The interaction between glioblastoma cells and glioma‐associated macrophages is investigated, demonstrating clinically relevant cell phenotypes, polarization and invasion of cancer cells and macrophages. Moreover, this model is able to mimic the responsiveness to chemotherapy and immunotherapy similar to the clinical situation.
The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism ...using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl4-induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis.
Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing ...to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis.
•Sesame is one of the most health-beneficial seed oil crops.•Sesamin, sesamol, and sesamolin are the main health promoting bioactive components.•Neuroprotective effect of sesame is highly studied ...among others.•Demand for sesame with high lignans, low free fatty acids and anti-nutritional factors.•Recommendations for utilizing sesame and seed oil as food and nutraceutical components.
Sesame is the oldest oilseed crop known to humanity, though it contributes a small share in the global vegetable oil production. Sesame oil contains nutrients, including lignans, tocopherols, phytosterols, natural antioxidants, and bioactive compounds. It provides various health benefits such as anti-lipogenic, hypo-cholesterolemic, anti-degenerative, and neural health-promoting properties. Being an under-utilized minor crop, it has not received enough research attention for its food and nutraceutical potential. The sesame crop is a potential candidate to maintain the diversity of food oils and harness its benefits for improving human health. The present review will provide detailed research on sesame oil contents, health effects, nutraceuticals, oil quality, and value addition strategies. Also, the sesame oil nutritional quality was compared with other vegetable oils, highlighting the potential health and nutrition-related benefits. The way forward for further sesame improvement through value addition traits was also discussed.
Drug diffusion within the skin with a needle-free micro-jet injection (NFI) device was compared with two well-established delivery methods: topical application and solid needle injection. A permanent ...make-up (PMU) machine, normally used for dermal pigmentation, was utilized as a solid needle injection method. For NFIs a continuous wave (CW) laser diode was used to create a bubble inside a microfluidic device containing a light absorbing solution. Each method delivered two different solutions into ex vivo porcine skin. The first solution consisted of a red dye (direct red 81) and rhodamine B in water. The second solution was direct red 81 and rhodamine B in water and glycerol. We measured the diffusion depth, width and surface area of the solutions in all the injected skin samples. The NFI has a higher vertical dispersion velocity of 3 × 10
5
μ
m/s compared to topical (0.1
μ
m/s) and needle injection (53
μ
m/s). The limitations and advantages of each method are discussed, and we conclude that the micro-jet injector represents a fast and minimally invasive injection method, while the solid needle injector causes notable tissue damage. In contrast, the topical method had the slowest diffusion rate but causes no visible damage to the skin.
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