Macrophage-Mediated Inflammation in Skin Wound Healing.

Macrophages are key immune cells that respond to infections, and modulate pathophysiological conditions such as wound healing. By possessing phagocytic activities and through the secretion of cytokines and growth factors, macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. Macrophages orchestrate the process of wound healing through the transitioning from predominantly pro-inflammatory (M1-like phenotypes), which present early post-injury, to anti-inflammatory (M2-like phenotypes), which appear later to modulate skin repair and wound closure. In this review, different cellular and molecular aspects of macrophage-mediated skin wound healing are discussed, alongside important aspects such as macrophage subtypes, metabolism, plasticity, and epigenetics. We also highlight previous studies demonstrating interactions between macrophages and these factors for optimal wound healing. Understanding and harnessing the activity and capability of macrophages may help to advance new approaches for improving healing of the skin.

Pooled Prevalence of NS5A Resistance-Associated Substitutions in Chronic HCV Genotype 3 Infection: A Study Based on Deposited Sequences in GenBank.

Using direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection results in a high treatment response rate. However, several factors can significantly alter this outcome such as resistance-associated substitutions (RASs) in HCV NS5A gene. This study aimed to evaluate the prevalence of naturally occurring RASs of NS5A in HCV genotype 3 (HCV-3) sequences isolated from individuals with chronic HCV-3 infection. All the registered sequences in the GenBank under "NS5A" AND "Hepacivirus C" query were evaluated and screened, those which followed our inclusion criteria were enrolled in our pooled analysis. The retrieved sequences of included studies were evaluated for substitutions, RASs, and RASs conferring >100 resistance fold change (RASs >100 × ) in NS5A amino acid positions 24, 28, 30, 31, 62, 92, and 93. From 7 enrolled studies, a total of 370 HCV-3a isolates were retrieved and investigated. Forty-eight (13.0%, 95% CI = 9.9-16.8%) isolates harbored NS5A RASs. Moreover, Y93H was the only NS5A RAS >100 × observed in 13 (3.5%, 95% CI = 2.0-5.9%) retrieved sequences. The low frequency of naturally occurring NS5A RASs, especially those with clinical relevance (RASs >100 × ), among individuals with HCV-3 infection and the high rate of treatment response to DAAs suggest not to investigate every individual with HCV-3 infection for NS5A RASs before treatment.

Bone marrow sinusoidal endothelium as a facilitator/regulator of cell egress from the bone marrow.

Despite more attention to cell migration from circulation into the bone marrow (BM), particularly homing of haematopoietic stem/progenitor cells, the process and mechanisms of cell mobilisation from the BM into the circulation remain largely underexplored. The process of cell mobilisation or transcellular cell migration from BM into the circulation (cell egress) is a crucial biological process in mammals as it is important to maintain homeostasis of various physiological functions including, but not limited to, the immune system, erythropoiesis, platelet release, and stem cell migration. The BM microvascular system composes of a monolayer of specialized endothelial cells, called sinusoidal endothelial cells (SECs). While it is very well evident that the process of cell egress occurs exclusively through BM SECs, there is a lack of systematic analyses addressing the extent of contribution of BM SECs to the process of cell egress from the BM. Therefore, this review aims to address the potential ability of BM SECs in regulating and/or facilitating the process of cell egress from BM. In this review, we address, firstly, the unique ultra-/structural and molecular features of BM SECs and discuss the possible biological interactions between BM SECs and various egressing cells in physiological conditions. Secondly, we propose the potential role of BM SECs in egress of leukemic cells from BM into the circulation. Finally, we discuss the potential role of BM SECs in homing of haematopoietic stem cells. Collectively, the current review suggests that the BM SECs may not be merely a neutral gatekeeper for cell intravasation and extravasation, but rather is a dynamic trafficking surveillance system, thereby the process of BM cell egress/mobilisation can be regulated.

Opioids and matrix metalloproteinases: the influence of morphine on MMP-9 production and cancer progression.

Opioids are widely administered to alleviate pain, including chronic pain in advanced cancer patients. Among opioids, morphine is one of the most clinically effective drugs for the palliative management of severe pain. In the last few decades, there has been a debate around the possible influence of opioids such as morphine on tumour growth and metastasis. Whilst several in vitro and in vivo studies suggest the possible modulatory effects of morphine on tumour cells, little is known about the impact of this analgesic drug on other mediators such as matrix metalloproteinases (MMPs) that play a key role in the control of cancer cell invasion and metastasis. MMP-9 has been considered as one of the principal mediators in regulation of not only the initial steps of cancer but during the invasion and spreading of cancer cells to distant organs. Herein, current studies regarding the direct and indirect effects of morphine on regulation of MMP-9 production are discussed. In addition, drawing from previous in vivo and in vitro studies on morphine action in regulating MMP-9 production, the potential roles of several underlying factors are summarised, including nuclear factor kappa-B and intracellular molecules such as nitric oxide.

Critical limb ischemia: Current and novel therapeutic strategies.

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell-based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.

Adipose-derived stem cells for wound healing.

Wound healing is a complex but a fine-tuned biological process in which human skin has the ability to regenerate itself following damage. However, in particular conditions such as deep burn or diabetes the process of wound healing is compromised. Despite investigations on the potency of a wide variety of stem cells for wound healing, adipose-derived stem cells (ASCs) seem to possess the least limitations for clinical applications, and literature showed that ASCs can improve the process of wound healing very likely by promoting angiogenesis and/or vascularisation, modulating immune response, and inducing epithelialization in the wound. In the present review, advantages and disadvantages of various stem cells which can be used for promoting wound healing are discussed. In addition, potential mechanisms of action by which ASCs may accelerate wound healing are summarised. Finally, clinical studies applying ASCs for wound healing and the associated limitations are reviewed.

Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy.

It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and also are known as the main cause of damage to the BM microvascular system. However, despite the importance of BM microvasculature in orchestrating various biological functions, less attention has been drawn to address the underlying mechanisms for the damage and to explore cellular and molecular mechanisms by which the recovery/regeneration of chemotherapy- and/or radiotherapy-induced BM microvascular system damage can occur. Therefore, in this review we firstly discuss the ultra-/structure and biological characteristics of BM microvascular system (sinusoids). Secondly, potential contribution of BM sinusoids is discussed in pathophysiological circumstances (bone remodelling, haematopoiesis, cancer bone metastasis, and haematological cancers). Thirdly, we address previous preclinical and clinical studies regarding chemotherapy- and irradiation-induced BM microvasculature damage. Finally, potential cellular and molecular mechanisms are discussed for the recovery/regeneration of damaged BM microvascular system, including the potential roles of endothelial progenitor cells, haematopoietic stem/progenitor cells, and stimulation of VEGF/VEGFR and Ang-1/Tie-2 signalling pathways.