Highly persistent incidence of multidrug resistant (MDR) bacterial pathogens constitutes a global burden for public health. An alternative strategy to alleviate such a crisis is to identify promising compounds to restore antibiotics activity against MDR bacteria. It is reported that the antidiabetic drug metformin exhibits the potentiation effect on tetracycline antibiotics, particularly doxycycline and minocycline, against MDR S. aureus, E. faecalis, E. coli, and S. enteritidis. Mechanistic studies demonstrate that metformin promotes intracellular accumulation of doxycycline in tetracycline‐resistant E. coli. In addition, metformin boosts the immune response and alleviates the inflammatory responses in vitro. Last, metformin fully restores the activity of doxycycline in three animal infection models. Collectively, these results reveal the potential of metformin as a novel tetracyclines adjuvant to circumvent MDR bacterial pathogens and to improve the treatment outcome of recalcitrant infections.

Biological systems can generate microstructured materials that combine organic and inorganic components and possess diverse physical and chemical properties. However, these natural processes in materials fabrication are not readily programmable. Here, we use a synthetic-biology approach to mimic such natural processes to assemble patterned materials.. We demonstrate programmable fabrication of three-dimensional (3D) materials by printing engineered self-patterning bacteria on permeable membranes that serve as a structural scaffold. Application of gold nanoparticles to the colonies creates hybrid organic-inorganic dome structures. The dynamics of the dome structures' response to pressure is determined by their geometry (colony size, dome height and pattern), which is easily modified by varying the properties of the membrane (e.g., pore size and hydrophobicity). We generate resettable pressure sensors that process signals in response to varying pressure intensity and duration.

IntroductionMigration inhibitory factor (MIF) is a pleotropic cytokine which plays a pivotal role in inflammatory and immune-mediated diseases such as rheumatoid arthritis (RA) and atherosclerosis. MIF is secreted by T lymphocytes and macrophages on lipopolysaccharide (LPS) exposure and induces secretion of tumor necrosis factor-␣ (TNF-␣) by mouse macrophages. 1,2 In RA, MIF is highly expressed in macrophages, endothelial cells, synovial tissue (ST) fibroblasts, serum, and synovial fluids. 1,2 MIF stimulates macrophage release of proinflammatory cytokines such as TNF-␣, interleukin 1 ␤ (IL-1␤), 4 MIF up-regulates IL-1␤, matrix metalloproteinases (MMPs) MMP-1, MMP-3, MMP-9, and MMP-13 in RA ST fibroblasts. 5,6 In rodent arthritis models, administration of anti-MIF antibody ameliorates arthritis with profound inhibition of clinical and histologic features of disease. [7][8][9] Anti-MIF treatment ameliorates acute encephalomyelitis and experimental autoimmune myocarditis in mice. 10,11 These studies show a key role of MIF in the pathogenesis of immunologic and inflammatory diseases.We have shown that MIF is a potent angiogenic factor. 12 Anti-MIF inhibits tumor growth and tumor-associated angiogenesis, and MIF is a required factor for tumor-initiated endothelial cell proliferation and tumor neovascularization. 13,14 Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in soluble forms (sVCAM-1 and sICAM-1, respectively) are potent angiogenic mediators, and RA synovial fluid-induced angiogenesis is blocked by anti-VCAM-1. 15,16 MIF is found in human vascular endothelial cells, which have been considered to play a pivotal role in systemic inflammatory and immunologic diseases by producing cytokines and growth factors. 17 Adhesion of inflammatory cells to vascular endothelium is the initial step in leukocyte recruitment and is mediated by a number of cell adhesion molecules such as ICAM-1, VCAM-1, E-, P-, and L-selectin, as well as integrins. MIF up-regulates ICAM-1 on endothelial cells. 18 Rat kidney VCAM-1 and ICAM-1 expression are decreased by anti-MIF treatment, blocking the development of glomerulonephritis. 19 Similarly, anti-MIF prevents VCAM-1 up-regulation on endothelial cells and improves acute encephalomyelitis in mice. 11 Cell adhesion molecules mediate and amplify the inflammatory response by allowing the ingress of leukocytes into diseased tissues. 20-22 VCAM-1 and ICAM-1 may be used as a reliable measure of the extent of atherosclerotic progression, and focal expression of adhesion molecules is consistently found in atherosclerotic plaques in humans. [22][23][24] The most compelling data for the necessity of adhesion molecules in the development of atherosclerotic plaques came from a report indicating that mice deficient in adhesion molecules are protected against atherosclerosis when fed an atherogenic diet. 25 Those studies support the role of adhesion molecules in immune-mediated diseases. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From ...

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