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.

Alcohol associated liver disease (ALD) accounts for significant mortality and morbidity in the United States. Prolonged alcohol exposure leads to increased reactive oxygen species and oxidative stress resulting in protein misfolding and/or aggregation. Cellular protein homeostasis network is an adaptive cellular response comprised of machineries that regulate biogenesis or degradation of proteins with chaperones as central coordinators to maintain proteome integrity during stress. Two extensively studied organelle-specific transcriptional proteostasis pathways are the heat shock response (HSR) in the cytosol and unfolded protein response (UPR) in endoplasmic reticulum (ER). Here we review the pathophysiological role of HSR and UPR and their potential as therapeutic targets in ALD. The HSR and UPR are emerging as important pathways in ALD pathogenesis. We reported that acute and chronic alcohol activate the HSR to discretely induce downstream target chaperones, HSPA1A/HSP70 and HSP90, respectively. HSP90 serves as a pro-inflammatory mediator in ALD by stabilizing client kinases and adapters. On the other hand, HSF1 and HSPA1A prevents liver injury due to their anti-inflammatory properties. In vivo pharmacological targeting of HSP90 reduced pro-inflammatory cytokines and NLRP3 inflammasome mediated IL-1β and IL-18. The presence of HSP90 in circulating extracellular vesicles in ALD mouse models suggests its role in pathogenesis. Activation of UPR due to prolonged ER stress is associated with apoptosis, inflammation, and lipogenesis contributing to liver injury. This review highlights the contribution of HSR and UPR, as well as druggable chaperones in pathogenesis of ALD. Binge/moderate or chronic alcohol exposure perturbs proteostasis mediators which fail to maintain proteome integrity and disease ensues. Understanding mechanisms that regulate proteostasis pathways, HSR and UPR, could identify novel disease modulators and guide development of therapeutic targets in ALD.

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 heir 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.

We discuss recent advancements in structural biology methods for investigating sites of protein-protein interactions. We will inform readers outside the field of structural biology about techniques beyond crystallography, and how these different technologies can be utilized for drug development. Advancements in cryo-electron microscopy (cryoEM) and micro-electron diffraction (microED) may change how we view atomic resolution structural biology, such that well-ordered macrocrystals of protein complexes are not required for interface identification. However, some drug discovery applications, such as lead peptide compound generation, may not require atomic resolution; mass spectrometry techniques can provide an expedited path to generation of lead compounds. New crosslinking compounds, more user-friendly data analysis, and novel protocols such as protein painting can advance drug discovery programs, even in the absence of atomic resolution structural data. Finally, artificial intelligence and machine learning methods, while never truly replacing experimental methods, may provide rational ways to stratify potential druggable regions identified with mass spectrometry into higher and lower priority candidates. Electron diffraction of nanocrystals combines the benefits of both x-ray diffraction and cryoEM, and may prove to be the next generation of atomic resolution protein-protein interface identification. However, in situations such as peptide drug discovery, mass spectrometry techniques supported by advancements in computational methods will likely prove sufficient to support drug discovery efforts. In addition, these methods can be significantly faster than any crystallographic or cryoEM methods for identification of interacting regions.

Cardiovascular disease (CVD) involves a broad range of clinical manifestations resulting from a dysfunctional vascular system. Overproduction of reactive oxygen and nitrogen species are causally implicated in the severity of vascular dysfunction and CVD. Antioxidant therapy is an attractive avenue for treatment of CVD associated pathologies. Implementation of targeted nano-antioxidant therapies has the potential to overcome hurdles associated with systemic delivery of antioxidants. This review examines the currently available options for nanotherapeutic targeting CVD, and explores successful studies showcasing targeted nano-antioxidant therapy. Active targeting strategies in the context of CVD heavily focus on immunotargeting to inflammatory markers like cell adhesion molecules, or to exposed extracellular matrix components. Targeted antioxidant nanotherapies have found success in pre-clinical studies. This review underscores the potential of targeted nanocarriers as means of finding success translating antioxidant therapies to the clinic, all with a focus on CVD.

Purpose of ReviewcfDNA is increasingly used for biomonitoring oncological diseases or pregnancy status by different genetic analyses. Uncontrolled pre-analytical variability impacts the quality and quantity and subsequently undermines the utility of this analyte. In this review, we summarize critical pre-analytical factors to be addressed, to avoid irreproducible results.Recent FindingscfDNA quantity and quality can be impacted by the in vivo condition of the donor and the ex vivo biospecimen handling prior to the downstream analysis. In vivo, physical and psychosocial stress, circadian rhythmicity, and age appear to be critical. Ex vivo, the blood collection tubes, pre-centrifugation storage temperature and time, and cfDNA extraction kits are important.SummaryTo address these critical pre-analytical viabilities, in-process quality control material should be applied. Plasma is preferred to serum, as are blood collection tubes with stabilizers. Finally, the donor status and sample processing should be standardized and documented.

Glycogen storage disease type III (GSD III) is an orphan disease that mainly affects the liver, heart, and skeletal muscles. It is caused by the deficiency of glycogen debranching enzyme (GDE), resulting in accumulation of glycogen (limit dextrin) primarily in the cytoplasm. With an increase in life expectancy in patients and advances in research, long-term hepatic manifestations are being recognized. This review examines our understanding of the natural history of the hepatic manifestations of GSD III and the importance of developing definitive therapies. Animal models have shown specific trends in biochemical and histological features such as changes in liver enzymes and progressive hepatic fibrosis, with increasing age. In our clinical experience, patients with GSD III show similar trends. Our review highlights (a) hepatic manifestations in GSD III, (b) the natural history, (c) existing animal models, and (d) current research on therapeutic approaches.