Buckling forces and the wavy folds between pleural epithelial cells.

Cell shapes in tissues are affected by the biophysical interaction between cells. Tissue forces can influence specific cell features such as cell geometry and cell surface area. Here, we examined the 2-dimensional shape, size, and perimeter of pleural epithelial cells at various lung volumes.

Discovery and Optimization of Novel DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1-pyrazolo[3,4-]pyridine scaffold was identified as an DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1-pyrrolo[2,3-]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (, which was found to be the most promising and drug-like compound with potent inhibitory activity against DHODH (IC = 173.

Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors.

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated.

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival.

Mechanical characterization of human umbilical arteries by thick-walled models: Enhanced vascular compliance by removing an abluminal lining.

The decellularized human umbilical artery (HUA) is considered as a promising option for small-diameter, tissue-engineered vascular grafts (TEVGs). Our previous study showed that the HUA bears a thin, watertight lining on its outermost abluminal surface. Removal of this abluminal lining layer improves efficacy of the perfusion-assisted decellularization of the HUA and increases its compliance.

Discovery of potent human dihydroorotate dehydrogenase inhibitors based on a benzophenone scaffold.

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC value of 10.

A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma.

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated.

Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors.

The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy.

Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment.

Human dihydroorotate dehydrogenase (DHODH), as the fourth and rate-limiting enzyme of the pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as DHODH inhibitors. was the optimal compound with promising enzymatic activity (IC = 16.

Generation, Transmission, and Regulation of Mechanical Forces in Embryonic Morphogenesis.

Embryonic morphogenesis is a biological process which depicts shape forming of tissues and organs during development. Unveiling the roles of mechanical forces generated, transmitted, and regulated in cells and tissues through these processes is key to understanding the biophysical mechanisms governing morphogenesis. To this end, it is imperative to measure, simulate, and predict the regulation and control of these mechanical forces during morphogenesis.

Growth-profile configuration for specific deformations of tubular organs: A study of growth-induced thinning and dilation of the human cervix.

Growth is a significant factor that results in deformations of tubular organs, and particular deformations associated with growth enable tubular organs to perform certain physiological functions. Configuring growth profiles that achieve particular deformation patterns is critical for analyzing potential pathological conditions and for developing corresponding clinical treatments for tubular organ dysfunctions. However, deformation-targeted growth is rarely studied.

Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy.

Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay.

DHODH and cancer: promising prospects to be explored.

Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells.

Stress-Swelling Finite Element Modeling of Cervical Response With Homeostatic Collagen Fiber Distributions.

During pregnancy, the cervix experiences significant mechanical property change due to tissue swelling, and to ongoing changes in the collagen content. In this paper, we model how these two effects contribute to cervical deformation as the pressure load on top of the cervix increases. The cervix and its surrounding supporting ligaments are taken into consideration in the resulting mechanical analysis.

Utilization of the Theory of Small on Large Deformation for Studying Mechanosensitive Cellular Behaviors.

Recent studies suggest that cells routinely probe their mechanical environments and that this mechanosensitive behavior regulates some of their cellular activities. The finite elasticity theory of small-on-large deformation (SoL) has been shown to be effective in interpreting the mechanosensitive behavior of cells on a substrate that has been subjected to a prior large static stretch before the culturing of the cells. Small on large deformation is the superposition of a small deformation onto a prior large deformation that serves as the new reference configuration.

Hyperelastic modeling of the combined effects of tissue swelling and deformation-related collagen renewal in fibrous soft tissue.

A continuum mechanics constitutive model is presented for the interaction between swelling and collagen remodeling in biological soft tissue. The model is inherently two-way: swelling stretches the collagen fibers which affects their rate of degradation-the remodeled fibrous microarchitecture provides selective directional stiffening that causes the swollen tissue to expand more in the unreinforced directions. The constitutive model specifically treats stretch-stabilization wherein the rate of enzymatic-induced degradation of collagen is a decreasing function of fiber stretch.

Computational modeling of tracheal angioedema due to swelling of the submucous tissue layer.

Angioedema is a tissue-swelling pathology due to rapid change in soft tissue fluid content. Its occurrence in the trachea is predominantly localized to the soft mucous tissue that forms the innermost tracheal layer. The biomechanical consequences, such as airway constriction, are dependent upon the ensuing mechanical interactions between all of the various tissues that comprise the tracheal tube.

Hyperelastic modeling of swelling in fibrous soft tissue with application to tracheal angioedema.

Angioedema, the rapid swelling of under-skin tissue, is typically triggered by complex biochemical processes that disrupt an original steady state filtration of liquid through the tissue. Swelling stabilizes once a new steady state is achieved in which the tissue has significantly increased liquid content. These processes are controlled by events at the molecular to the cellular length scale.