Background DPP-4 inhibitors are increasingly used to accomplish glycemic targets in patients with Type II diabetes (T2DM). Since DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results Male LDLR-/- mice (6 weeks) were fed with a high fat diet (HFD) or normal chow diet (NCD) for 4 weeks and then randomized to vehicle or Alogliptin, a high affinity DPP-4 inhibitor (40 mg/kg/day) for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden and indices of inflammation were obtained in target tissues including the vasculature, adipose and bone marrow with assessment of global and cell specific inflammatory pathways. In-vitro and in-vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE-/- mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (ATMs; CD11b+, CD11c+, Ly6Chi) concomitant with up-regulation of CD163. DPP-4 was highly expressed inbone-marrow derived CD11b+ cells with DPP-4i down-regulating pro-inflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in-vitro assays via Rac dependent mechanisms and prevented in-vivo migration of labeled monocytes to the aorta in response to exogenous TNFα and DPP-4. Conclusion DPP-4i exerts anti-atherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for over 500 thousand deaths in 216 countries across the world and is affecting over 10 million people. The absence of FDA approved drugs against the new SARS-CoV-2 virus has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and the SARS-CoV-2 virus to provide insight into the pathogenetic mechanism of the virus and to support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, rst of all, in its healthy state. We then demonstrate how the entry of the SARS-CoV-2 virus into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. We have completed a comparative analysis of our model and other previously generated cell type models and highlight 48 pathways and over 800 reactions hijacked by the virus for its replication and survival. We designed a new tool which predicts 15 unique reactions as drug targets from our models (the integrated human macrophage, human airway epithelial cells and the SARS-CoV2 virus) and provide a platform for future studies on viral entry inhibition and drug optimisation strategies.

The S100 proteins, a family of calcium-binding cytosolic proteins, have a broad range of intracellular and extracellular functions through regulating calcium balance, cell apoptosis, migration, proliferation, differentiation, energy metabolism, and inflammation. The intracellular functions of S100 proteins involve interaction with intracellular receptors, membrane protein recruitment/transportation, transcriptional regulation and integrating with enzymes or nucleic acids, and DNA repair. The S100 proteins could also be released from the cytoplasm, induced by tissue/cell damage and cellular stress. The extracellular S100 proteins, serving as a danger signal, are crucial in regulating immune homeostasis, post-traumatic injury, and inflammation. Extracellular S100 proteins are also considered biomarkers for some specific diseases. In this review, we will discuss the multi-functional roles of S100 proteins, especially their potential roles associated with cell migration, differentiation, tissue repair, and inflammation.

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Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage–mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

While the role of oxidative stress in the lung has been well demonstrated, the role of oxidative stress in mediating systemic effects especially in inflammation and injury processes needs further work. The role of antioxidant defenses with chronic exposure will also need further exploration. Antioxid. Redox Signal. 28, 797-818.

ObjectiveThe clinical features of rheumatic patients with coronavirus disease 2019 (COVID-19) have not been reported. This study aimed to describe the clinical features of COVID-19 in rheumatic patients and provide information for handling this situation in clinical practice.MethodsThis is a retrospective case series study. Deidentified data, including gender, age, laboratory and radiological results, symptoms, signs, and medication history, were collected from 2326 patients diagnosed with COVID-19, including 21 cases in combination with rheumatic disease, in Tongji Hospital between 13 January and 15 March 2020.ResultsLength of hospital stay and mortality rate were similar between rheumatic and non-rheumatic groups, while the presence of respiratory failure was more common in rheumatic cases (38% vs 10%, p<0.001). Symptoms of fever, fatigue and diarrhoea were seen in 76%, 43% and 23% of patients, respectively. There were four rheumatic patients who experienced a flare of rheumatic disease during hospital stay, with symptoms of muscle aches, back pain, joint pain or rash. While lymphocytopaenia was seen in 57% of rheumatic patients, only one patient (5%) presented with leucopenia in rheumatic cases. Rheumatic patients presented with similar radiological features of ground-glass opacity and consolidation. Patients with pre-existing interstitial lung disease showed massive fibrous stripes and crazy-paving signs at an early stage. Five rheumatic cases used hydroxychloroquine before the diagnosis of COVID-19 and none progressed to critically ill stage.ConclusionsRespiratory failure was more common in rheumatic patients infected with COVID-19. Differential diagnosis between COVID-19 and a flare of rheumatic disease should be considered.Trial registration numberChiCTR2000030795.

Although a critical role of adaptive immune system has been confirmed in driving local and systemic inflammation in type 2 diabetes and promoting insulin resistance, the underlying mechanism is not completely understood. Inflammatory regulation has been focused on innate immunity especially macrophage for a long time, while increasing evidence suggests T cells are crucial for the development of metabolic inflammation and insulin resistance since 2009. There was growing evidence supporting the critical implication of T cells in the pathogenesis of type 2 diabetes. We will discuss the available effect of T cells subsets in adaptive immune system associated with the procession of T2DM, which may unveil several potential strategies that could provide successful therapies in the future.