ALBERT

Description: 〈p〉Publication date: Available online 27 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Simona Baroni, Maria Rosaria Ruggiero, Valeria Bitonto, Lionel M. Broche, David J. Lurie, Silvio Aime, Simonetta Geninatti Crich〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tumour-associated macrophages (TAM) are forced by cancer cells to adopt an anti-inflammatory phenotype and secrete factors to promote tumour invasion thus being responsible for poor patient outcome. The aim of this study is to develop a clinically applicable, non-invasive method to obtain a quantitative TAM detection in tumour tissue. The method is based on longitudinal proton relaxation rate (R〈sub〉1〈/sub〉) measurements at low field (0.01–1 MHz) to assess the localization of ferumoxytol (clinical approved iron oxide particles) in TAM present in melanoma tumours, where R〈sub〉1〈/sub〉 = 1/T〈sub〉1〈/sub〉. R〈sub〉1〈/sub〉 at low magnetic fields appears highly dependent on the intra or extra cellular localization of the nanoparticles thus allowing an unambiguous TAM quantification. R〈sub〉1〈/sub〉 profiles were acquired on a Fast Field-Cycling relaxometer equipped with a 40 mm wide bore magnet and an 11 mm solenoid detection coil placed around the anatomical region of interest. The R〈sub〉1〈/sub〉 values measured 3 h and 24 h after the injection were significantly different. At 24 h R〈sub〉1〈/sub〉 exhibited a behavior similar to “in vitro” ferumoxytol-labelled J774A.1 macrophages whereas at 3 h, when the ferumoxytol distribution was extracellular, R〈sub〉1〈/sub〉 exhibited higher values similar to that of free ferumoxytol in solution. This finding clearly indicated the intracellular localization of ferumoxytol at 24 h, as confirmed by histological analysis (Pearls and CD68 assays). This information could be hardly achievable from measurements at a single magnetic field and opens new horizons for cell tracking applications using FFC-MRI.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S014296122030051X-fx1.jpg" width="306" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 27 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Linjie Wang, Yannan Zhao, Feng Yang, Meng Feng, Yazhen Zhao, Xi Chen, Junwei Mi, Yuanjiang Yao, Dongwei Guan, Zhifeng Xiao, Bing Chen, Jianwu Dai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In situ restoration of severely damaged lung remains difficult due to its limited regeneration capacity after injury. Artificial lung scaffolds are emerging as potential substitutes, but it is still a challenge to reconstruct lung regeneration microenvironment in scaffold after lung resection injury. Here, a 3D biomimetic porous collagen scaffold with similar structure characteristics as lung is fabricated, and a novel collagen binding hepatocyte growth factor (CBD-HGF) is tethered on the collagen scaffold for maintaining the biomimetic function of HGF to improve the lung regeneration microenvironment. The biomimetic scaffold was implanted into the operative region of a rat partial lung resection model. The results revealed that vascular endothelial cells and endogenous alveolar stem cells entered the scaffold at the early stage of regeneration. At the later stage, inflammation and fibrosis were attenuated, the microvascular and functional alveolar-like structures were formed, and the general morphology of the injured lung was restored. Taken together, the functional 3D biomimetic collagen scaffold facilitates recovery of the injured lung, alveolar regeneration, and angiogenesis after acute lung injury. Particularly, this is the first study of lung regeneration in vivo guided by biomimetic collagen scaffold materials, which supports the concept that tissue engineering is an effective strategy for alveolar regeneration.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Marc Diederich〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Natural compounds are known to display therapeutic potential against a variety of chronic conditions, including cancer and inflammation. The efficacy of these natural substances can be associated with numerous molecular scaffolds present in extracts of living organisms, both terrestrial and marine. Recently, investigators have identified the ability of natural compounds to trigger immunogenic cell death and subsequent activation of the adaptive immune system. Such findings indicate that the full therapeutic potential of natural products has yet to be defined, and further investigations on such agents will continue to yield novel drug candidates.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 27 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Dianjun Qi, Wen Shi, Adrian R. Black, Mitchell A. Kuss, Xining Pang, Yini He, Bing Liu, Bin Duan〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The small intestine (SI) is difficult to regenerate or reconstruct due to its complex structure and functions. Recent developments in stem cells research, advanced engineering technologies, and regenerative medicine strategies bring new hope of solving clinical problems of the SI. This review will fist summarize the structure, function, development, cell types and matrix components, of the SI. Then, the major cell sources for SI regeneration are introduced, and state-of-the-art biofabrication technologies for generating engineered SI tissues or models are overviewed. Furthermore, 〈em〉in vitro〈/em〉 models and 〈em〉in vivo〈/em〉 transplantation, based on intestinal organoids and tissue engineering, are highlighted. Finally, current challenges and future perspectives are discussed to help direct future applications for SI repair and regeneration.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Fang Liu, Shaohong Fang, Xinxin Liu, Ji Li, Xuedong Wang, Jinjin Cui, Tao Chen, Zhaoying Li, Fan Yang, Jiangtian Tian, Hulun Li, Li Yin, Bo Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉High glucose-induced endothelial dysfunction is a critical initiating factor in the development of diabetic vascular complications. Omentin-1 has been regarded as a novel biomarker of endothelial function in subjects with type-2 diabetes (T2D); however, it is unclear whether omentin-1 has any direct effect in ameliorating high glucose-induced endothelial dysfunction. In the present study, we analyzed the effect of omentin-1 on high glucose-induced endothelial dysfunction in isolated mouse aortas and mouse aortic endothelial cells (MAECs). Vascular reactivity in aortas was measured using wire myography. The expression levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), Akt, endothelial nitric-oxide synthase (eNOS), and endoplasmic reticulum (ER)-stress markers in MAECs were determined by Western blotting. The production of reactive oxygen species (ROS) and nitric oxide (NO) was assessed by diluted fluoroprobe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA), respectively. We found that 〈em〉ex vivo〈/em〉 treatment with omentin-1 reversed impaired endothelial-dependent relaxations (EDR) in mouse aortas after high-glucose insult. Elevated ER-stress markers, oxidative stress, and reduction of NO production induced by high glucose in MAECs were reversed by omentin-1 treatment. Omentin-1 also effectively reversed tunicamycin-induced ER stress responses in MAECs, as well as ameliorated impairment of endothelial-dependent relaxation in mouse aortas. Moreover, omentin-1 increased AMPK phosphorylation with a subsequent increase in PPARδ expression, while also restoring the decreased phosphorylation of Akt and eNOS. The effects of omentin-1 were abolished by cotreatment of compound C (AMPK inhibitor) and GSK0660 (PPARδ antagonist). These data indicate that omentin-1 protects against high glucose-induced vascular-endothelial dysfunction through inhibiting ER stress and oxidative stress and increasing NO production via activation of AMPK/PPARδ pathway.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030040X-ga1.jpg" width="490" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumathy Mathialagan, Yi-an Bi, Chester Costales, Amit S. Kalgutkar, A. David Rodrigues, Manthena V.S. Varma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD〈sup〉+〈/sup〉) – a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7±0.3, and a Michaelis-Menten constant (K〈sub〉m〈/sub〉) of 13.5±3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300393-ga1.jpg" width="489" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Pei Yang, Mingfei Zhang, Xiang Wang, A-Lan Xu, Meiyu Shen, Baoping Jiang, Xueping Zhou, LingLing Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with complicated pathogenesis. IL-17-producing T helper cells (Th17) are important players in the RA process. Despite numerous researches have proven that microRNAs (miRNAs) were crucial regulators of autoimmune diseases including RA, the effect of miRNAs on the development and function of Th17 cells in the RA progress is not clear. Here, our results showed that the expression of miRNA let-7g-5p was substantially lower in RA patients and CIA mice compared with healthy controls. Furthermore, let-7g-5p could notably suppress the differentiation of Th17 cells 〈em〉in vitro〈/em〉. And the disease severity in CIA mice was significantly alleviated after the treatment of let-7g-5p mimics, accompanied by the deficiency of Th17 cells. These findings indicated that the let-7g-5p could markedly block the differentiation of Th17 cells in RA, which provided a promising target for the clinical therapy of RA.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300320-ga1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ryota Yamagata, Wataru Nemoto, Osamu Nakagawasai, Kohei Takahashi, Koichi Tan-No〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient 〈em〉ob/ob〈/em〉 mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in 〈em〉ob/ob〈/em〉 mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in 〈em〉ob/ob〈/em〉 mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in 〈em〉ob/ob〈/em〉 mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in 〈em〉ob/ob〈/em〉 mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in 〈em〉ob/ob〈/em〉 mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in 〈em〉ob/ob〈/em〉 mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300356-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Joanna Wzorek, Radosław Bednarek, Cezary Watala, Magdalena Boncler〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Adenosine analogues have high affinity and selectivity for adenosine receptors (AR), and exhibit anti-platelet activity. Plasma proteins play an important role in the regulation of platelet function and may influence the action of anti-platelet compounds. Little is known about the interactions of AR agonists with plasma proteins. This study investigates the interplay between AR agonists and plasma proteins and the consequences of those interactions.〈/p〉 〈p〉Surface plasmon resonance was employed together with molecular docking study to determine the binding kinetics of four selected AR agonists (PSB 0777, Cl-Ado, MRE 0094, UK 432097) to several carrier proteins and to clarify the nature of these interactions. The influence of a whole plasma and of some plasma components on the effectiveness of AR agonists in the inhibition of platelet function was assessed by flow cytometry (platelet activation) and ELISA (platelet adhesion).〈/p〉 〈p〉Plasma proteins remarkably diminished the effectiveness of AR agonists in inhibiting platelet activation and adhesion 〈em〉in vitro〈/em〉. AR agonists were found to strongly bind to human serum albumin (HSA) and the protein components of lipoproteins - apolipoproteins; HSA was essential for the binding of water-soluble PSB 0777, whereas apolipoproteins were needed for interactions with poorly-water soluble compounds such as UK 432097 and MRE 0094. In addition, HSA was shown to significantly reduce the effectiveness of PSB 0777 in inhibiting ADP-induced platelet activation.〈/p〉 〈p〉In conclusion, HSA and lipoproteins are important carriers for AR agonists, which can affect pharmacodynamics of AR agonists used as platelet inhibitors.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030037X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Balázs Kelemen, Erika Lisztes, Anita Vladár, Martin Hanyicska, János Almássy, Attila Oláh, Attila Gábor Szöllősi, Zsófia Pénzes, János Posta, Thomas Voets, Tamás Bíró, Balázs István Tóth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8. Here, we investigated the effect of VAs on TRPM3, a less characterized member of the thermosensitive TRP channels playing a central role in noxious heat sensation.〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉We investigated the effect of VAs on the activity of recombinant and native TRPM3, by monitoring changes in the intracellular Ca〈sup〉2+〈/sup〉 concentration and measuring TRPM3-mediated transmembrane currents.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉All the investigated VAs (chloroform, halothane, isoflurane, sevoflurane) inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca〈sup〉2+〈/sup〉 signals and transmembrane currents in a concentration dependent way in HEK293T cells overexpressing recombinant TRPM3. Among the tested VAs, halothane was the most potent blocker (IC〈sub〉50〈/sub〉=0.52±0.05 mM). We also investigated the effect of VAs on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While VAs activated certain sensory neurons independently of TRPM3, they strongly and reversibly inhibited the agonist-induced TRPM3 activity.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusions〈/h6〉 〈p〉These data provide a better insight into the molecular mechanism beyond the analgesic effect of VAs and propose novel strategies to attenuate TRPM3 dependent nociception.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300368-ga1.jpg" width="389" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 24 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumit Mukherjee, Juliet N.E. Baidoo, Angela Fried, Probal Banerjee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Curcumin has been at the center of vigorous research and major debate during the past decade. Inspired by its anti-inflammatory properties, many curcumin-based products are being sold now to manage various forms of arthritis. Parallel preclinical studies have established its role in dissolving beta-amyloid plaques, tau-based neurofibrillary tangles, and also alpha-synuclein-linked protein aggregates typically observed in Parkinson’s disease. In cancer research, most cancer cells in culture are eliminated by curcumin at an IC50 of 15-30 µM, whereas the maximum 〈em〉in vivo〈/em〉 curcumin concentration achieved in humans is only about 6 µM. Additionally, a decade ago, no improvement over the placebo groups was observed in clinical studies using free curcumin as an anticancer agent. The lack of anticancer efficacy was attributed to its low bioavailability, which results from the low water-solubility and high metabolic rate 〈em〉in vivo〈/em〉. Newer lipid-complexed or antibody-targeted forms have been used and these studies have revealed an exciting property of curcumin, which involves repolarization of the tumor-promoting, tumor-associated microglia/macrophages (TAMs) into a tumoricidal form and recruitment of natural killer cells from the periphery. This review will cover some efforts to explore the effect of appropriately-delivered curcumin to dramatically alter the tumor microenvironment, thereby launching an indirect attack on the tumor cells and the tumor stem cells. Reviewing some aspects of immunotherapy, this article will argue for the use of the innate immune cells in cancer therapy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300344-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 27 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Jianming Chen, Taojian Fan, Zhongjian Xie, Qiqiao Zeng, Ping Xue, Tingting Zheng, Yun Chen, Xiaoling Luo, Han Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Photodynamic therapy (PDT), as a non-invasive therapeutic modality that is alternative to radiotherapy and chemotherapy, is extensively investigated for cancer treatments. Although conventional organic photosensitizers (PSs) are still widely used and have achieved great progresses in PDT, the disadvantages such as hydrophobicity, poor stability within PDT environment and low cell/tissue specificity largely limit their clinical applications. Consequently, nano-agents with promising physicochemical and optical properties have emerged as an attractive alternative to overcome these drawbacks of traditional PSs. Herein, the up-to-date advances in the fabrication and fascinating applications of various nanomaterials in PDT have been summarized, including various types of nanoparticles, carbon-based nanomaterials, and two-dimensional nanomaterials, etc. In addition, the current challenges for the clinical use of PDT, and the corresponding strategies to address these issues, as well as future perspectives on further improvement of PDT have also been discussed.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Xiaolei Nie, Yon Jin Chuah, Wenzhen Zhu, Pengfei He, Yvonne Peck, Dong-An Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Articular cartilage repair has been a long-standing challenge in orthopaedic medicine due to the limited self-regenerative capability of cartilage tissue. Currently, cartilage lesions are often treated by microfracture or autologous chondrocyte implantation (ACI). However, these treatments are frequently reported to result in a mixture of the desired hyaline cartilage and mechanically inferior fibrocartilage. In this study, by combining the advantages of cartilage tissue engineering and decellularization technology, we developed a decellularized allogeneic hyaline cartilage graft, named dLhCG, which achieved superior efficacy in articular cartilage repair and surpassed living autologous chondrocyte-based cartilaginous engraftment and ACI. By the 6-month time point after implantation in porcine knee joints, the fine morphology, composition, phenotype, microstructure and mechanical properties of the regenerated hyaline-like cartilaginous neo-tissue have been demonstrated via histology, biochemical assays, DNA microarrays and mechanical tests. The articular cartilaginous engraftment with allogeneic dLhCG was indicated to be well consistent, compatible and integrated with the native cartilage of the host. The successful repair of articular chondral defects in large animal models suggests the readiness of allogeneic dLhCG for clinical trials.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Hiroyasu Takemoto, Takanori Inaba, Takahiro Nomoto, Makoto Matsui, Xiaomeng Liu, Masahiro Toyoda, Yuto Honda, Kaori Taniwaki, Naoki Yamada, Junhyun Kim, Keishiro Tomoda, Nobuhiro Nishiyama〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (P-GEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Elisa Zuccarello, Erica Acquarone, Elisa Calcagno, Elentina K. Argyrousi, Shi-Xian Deng, Donald W. Landry, Ottavio Arancio, Jole Fiorito〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer’s disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300289-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 234〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Dewi Safitri, Matthew Harris, Harriet Potter, Ho Yan Yeung, Ian Winfield, Liliya Kopanitsa, Fredrik Svensson, Taufiq Rahman, Matthew T Harper, David Bailey, Graham Ladds〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G〈sub〉2〈/sub〉/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300332-ga1.jpg" width="495" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 27 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Mohamed Elbadawy, Megumi Yamanaka, Yuta Goto, Kimika Hayashi, Ryouichi Tsunedomi, Shoichi Hazama, Hiroaki Nagano, Toshinori Yoshida, Makoto Shibutani, Ryo Ichikawa, Junta Nakahara, Tsutomu Omatsu, Tetsuya Mizutani, Yukie Katayama, Yuta Shinohara, Amira Abugomaa, Masahiro Kaneda, Hideyuki Yamawaki, Tatsuya Usui, Kazuaki Sasaki〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees [defined as mild (NASH A), moderate (NASH B) and severe (NASH C)] of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic satellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Ning Ran, Xianjun Gao, Xue Dong, Junjin Li, Caorui Lin, Mengyuan Geng, HaiFang Yin〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Duchenne muscular dystrophy (DMD) is a devastating disorder caused by loss of functional dystrophin protein, resulting in muscle wasting. Enhancing muscle growth by inhibiting myostatin, a growth factor negatively regulating skeletal muscle mass, is a promising approach to slow disease progression. Direct administration of myostatin propeptide, a natural inhibitor of mature myostatin, has shown limited efficacy probably due to low serum stability. Here, we demonstrate that serum stability, delivery efficiency and efficacy of propeptide can be significantly enhanced by anchoring propeptide to the surface of exosomes by fusing the inhibitory domain of myostatin propeptide into the second extracellular loop of CD63 (EXOpro). Repeated administrations of EXOpro accelerated muscle regeneration and growth, resulting in significantly increased muscle mass and functional rescue without any detectable toxicity in 〈em〉mdx〈/em〉 mice. Importantly, EXOpro partially rehabilitated bone structure and promoted bone regeneration in 〈em〉mdx〈/em〉 mice. Our findings demonstrate that anchoring to exosomes increased delivery and serum stability of propeptide and augmented the inhibitory efficacy of myostatin propeptide and thus provide a delivery platform for propeptide-based intervention in DMD.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 24 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Hui Zhou, Youcong Gong, Yanan Liu, Anlian Huang, Xufeng Zhu, Jiawei Liu, Guanglong Yuan, Li Zhang, Ji-an Wei, Jie Liu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Alzheimer's disease (AD) seriously affects human health and life and lacks effective treatments. The lessons of many clinical trial failures suggest that targeting amyloid beta to treat AD is difficult, and finding new targets is an important direction for AD drug research. The neurofibrillary tangles formed by hyperphosphorylation of tau protein induce the production of cytotoxic reactive oxygen species (ROS) and cause neuronal apoptosis. Therefore, inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD. We herein designed a novel nanocomposite with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium (Ru NPs) as a carrier, loading nerve growth factor (NGF) and sealing with phase change material (PCM). Due to its excellent photothermal effect, under the near-infrared (NIR) irradiation, the nanocomposite could effectively penetrate the blood-brain barrier (BBB) and respond to phase changes in the lesion area, releasing NGF, which inhibited tau hyperphosphorylation, reduced oxidative stress, and more importantly restored nerve damage and maintained neuronal morphology, thereby significantly improving learning and memory in AD mice. Thus, the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Han Wang, Zhaohui Wang, Yuanbiao Tu, Yongkuan Li, Tian Xu, Man Yang, Peng Wang, Yueqing Gu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cancer starvation therapy based on catalytic chemistry of glucose oxidase (GOx) offers great potential for multimodal treatment, benefiting from both nutrition shutting-off and the oxidization product hydrogen peroxide (H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉). Herein, further optimization of such combined therapy was achieved by a cascade Nano-reactor, which was constructed by incorporating GOx into a bio-mimic upconversion nanosystem. The cascade began when GOx was delivered into tumor sites through homotypic targeting, facilitating selective starving of cancer cells and H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉 generation. Then, upon 980 nm laser excitation, the 470 nm light emitted by upconversion nanoparticles (NaYF〈sub〉4〈/sub〉: Yb, Tm) photolyzed H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉 into hydroxyl radical for phototherapy, superior to direct photolysis by blue light with limited tissue penetration depth. Meanwhile, the 800 nm emission of UCNPs was used to track the 〈em〉in vivo〈/em〉 fate and tumor targeting ability of the Nano-reactor. Radionuclide imaging further confirmed the targeting of the Nano-reactor to subcutaneous 4T1 tumor and lung metastasis. Significantly enhanced therapeutic efficacy of this cascade starvation-phototherapy was validated 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉, suggesting the Nano-reactor as a smart, simple and strong system for cancer multimodal therapy.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Huan Xu, Mengying Hu, Mengrui Liu, Sai An, Kaiyun Guan, Menglin Wang, Lei Li, Jing Zhang, Jun Li, Leaf Huang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Tumor associated fibroblasts (TAFs) are key stromal cells mediating the desmoplastic reaction and being partially responsible for the drug-resistance and immunosuppressive microenvironment formation in solid tumors. Delivery of genotoxic drugs off-targetedly to kill TAFs results in production of Wnt16 which renders the neighboring tumor cells drug resistant as shown in our previous study (PMC4623876). Our current approach looks for means to deactivate, rather than kill, TAFs. Reactive oxygen species (ROS) are the central hub of multiple profibrogenic pathways and indispensable for TAFs activation. Herein, puerarin was identified to effectively downregulate ROS production in the activated myofibroblast. In this study, a novel puerarin nanoemulsion (nanoPue) was developed to improve the solubility and bioavailability of puerarin. NanoPue significantly deactivated the stromal microenvironment (e.g., ~6-fold reduction of TAFs in nanoPue treated mice compared with the PBS control, p 〈 0.0001) and facilitated chemotherapy effect of nano-paclitaxel in the desmoplastic triple-negative breast cancer (TNBC) model. Moreover, the removal of the physical barrier increased intra-tumoral infiltration of cytotoxic T cell by 2-fold. This activated immune microenvironment allowed nanoPue to synergize PD-L1 blockade therapy in TNBC model.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 17 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Marietta Landgraf, Christoph A. Lahr, Ishdeep Kaur, Abbas Shafiee, Alvaro Sanchez-Herrero, Phillip W. Janowicz, Akhilandeshwari Ravichandran, Christopher B. Howard, Anna Cifuentes-Rius, Jacqui A. McGovern, Nicolas H. Voelcker, Dietmar W. Hutmacher〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉In advanced breast cancer (BCa) patients, not the primary tumor, but the development of distant metastases, which occur mainly in the organ bone, and their adverse health effects are responsible for high mortality. Targeted delivery of already known drugs which displayed potency, but rather unfavorable pharmacokinetic properties, might be a promising approach to overcome the current limitations of metastatic BCa therapy.〈/p〉 〈p〉Camptothecin (CPT) is a highly cytotoxic chemotherapeutic compound, yet poorly water-soluble and non-specific. Here, CPT was loaded into porous silicon nanoparticles (pSiNP) displaying the epidermal growth factor receptor (EGFR)-targeting antibody (Ab) cetuximab to generate a soluble and targeted nanoscale delivery vehicle for cancer treatment.〈/p〉 〈p〉After confirming the cytotoxic effect of targeted CPT-loaded pSiNP 〈em〉in vitro〈/em〉 on MDA-MB-231BO cells, nanoparticles were studied in a humanized BCa bone metastasis mouse model. Humanized tissue-engineered bone constructs (hTEBCs) provided a humanized microenvironment for BCa bone metastases in female NOD-scid IL2Rg〈sup〉null〈/sup〉 (NSG) mice. Actively targeted CPT-loaded pSiNP led to a reduction of orthotopic primary tumor growth, increased survival rate and significant decrease in hTEBC and murine lung, liver and bone metastases. This study demonstrates that targeted delivery via pSiNP is an effective approach to employ CPT and other potent anti-cancer compounds with poor pharmacokinetic profiles in cancer therapy.〈/p〉 〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961220300375-fx1.jpg" width="485" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhe Pei, Kuo-Chieh Lee, Amber Khan, Gabriell Erisnor, Hoau-Yan Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Brain tumors, particularly high-grade glioblastomas, are a crucial public health issue due to poor prognosis and an extremely low survival rate. The glioblastoma multiforme (GBM) grows rapidly within its unique microenvironment that is characterized by active neural communications. Therefore, diverse neurotransmitters not only maintain normal brain functions but also influence glioma progression. To fully appreciate the relationship between neurotransmitters and glioma progression, we reviewed potential neurotransmitter contributors in human GBM and the much less aggressive Low-grade glioma (LGG) by combining previously published data from gene-mutation/mRNA sequencing databases together with protein–protein interaction (PPI) network analysis results. The summarized results indicate that glutamatergic and calcium signaling may provide positive feedback to promote glioma formation through 1) metabolic reprogramming and genetic switching to accelerate glioma duplication and progression; 2) upregulation of cytoskeleton proteins and elevation of intracellular Ca〈sup〉2+〈/sup〉 levels to increase glutamate release and facilitate formation of synaptic-like connections with surrounding cells in their microenvironment. The upregulated glutamatergic neuronal activities in turn stimulate glioma growth and signaling. Importantly, the enhanced electrical and molecular signals from both neurons and glia propagate out to enable glioma symptoms such as epilepsy and migraine. The elevated intracellular Ca〈sup〉2+〈/sup〉 also activates nitric oxide synthase to produce nitric oxide (NO) that can either promote or inhibit tumorigenesis.〈/p〉 〈p〉By analyzing the network effects for complex interaction among neurotransmitters such as glutamate, Ca〈sup〉2+〈/sup〉 and NO in brain tumor progression, especially GBM, we identified the glutamatergic signaling as the potential therapeutic targets and suggest manipulation of glutamatergic signaling may be an effective treatment strategy for this aggressive brain cancer.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300241-ga1.jpg" width="251" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Chang-Fang Chiu, Jing-Ru Weng, Shou-Lun Lee, Chia-Yung Wu, Po-Chen Chu, Yan-Shen Shan, Horng-Ren Yang, Li-Yuan Bai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of p〈sup〉Tyr105〈/sup〉-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, p〈sup〉Tyr105〈/sup〉-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended 〈em〉in vivo〈/em〉, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear p〈sup〉Tyr105〈/sup〉-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300216-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 172〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Xiaohua Zheng, Lei Wang, Yuyao Guan, Qing Pei, Jian Jiang, Zhigang Xie〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Porphyrin-based porous organic polymers are highly potential candidates for cancer theranostics. However, un-controllable particle size and unclear photoactive mechanisms have been deemed to be “Achilles’ heels” for their biomedical application. Herein, a facile self-template strategy has been applied to integrate two types of porous materials to build the MOF@POP-PEG nanocomposite (named HUC-PEG). As-synthesized HUC-PEG exhibited controllable particle shape and size, good biocompatibility, and better colloidal stability. Importantly, synergy “0 + 1 〉 1” interface effects have been demonstrated to simultaneously enhance both the generation of more singlet oxygen (〈sup〉1〈/sup〉O〈sub〉2〈/sub〉) for photodynamic therapy (PDT) and local hyperthermia for photothermal therapy (PTT), thus to achieve favorable proliferation inhibition of tumor cell both in vitro and in vivo. Moreover, the strong X-ray attenuating ability of Hf element and excellent photothermal conversion efficacy endow this nanocomposite with computed tomography (CT)/photothermal imaging functions. We believe that our ingenious design may open a new horizon for the preparation of nanoscale POP-based therapeutic agents and also realize a paradigm shift in the understanding of photoactive mechanism in porous materials.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Zheyu Shen, Ting Liu, Zhen Yang, Zijian Zhou, Wei Tang, Wenpei Fan, Yijing Liu, Jing Mu, Ling Li, Vladimir I. Bregadze, Swadhin K. Mandal, Anna A. Druzina, Zhenni Wei, Xiaozhong Qiu, Aiguo Wu, Xiaoyuan Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Glioblastoma (GBM) is one of the most malignant tumors with poor prognosis and outcomes. Although smaller particle size can lead to higher blood-brain barrier (BBB)-permeability of the nanomaterials, most of the reported BBB-crossable nanomaterials for targeted GBM therapy are larger than 24 nm. To realize theranostics of GBM, co-loading of therapeutic and diagnostic agents on the same nanomaterials further results in larger particle size. In this study, we developed a kind of novel BBB-transportable nanomaterials smaller than 14 nm for high-efficiency theranostics of GBM (〈em〉i.e.〈/em〉, high contrast magnetic resonance imaging (MRI) and radiosensitization of GBM). Typically, poly(acrylic acid) (PAA) stabilized extremely small gadolinium oxide nanoparticles with modification of reductive bovine serum albumin (ES-GON-rBSA) was synthesized in water phase, resulting in excellent water-dispersibility. RGD dimer (RGD2, Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]}〈sub〉2〈/sub〉) and lactoferrin (LF) were then conjugated to the ES-GON-rBSA to obtain composite nanoparticle ES-GON-rBSA-LF-RGD2 with extraordinary relaxivities (〈em〉r〈/em〉〈sub〉1〈/sub〉 = 60.8 mM〈sup〉−1〈/sup〉 s〈sup〉−1〈/sup〉, 〈em〉r〈/em〉〈sub〉2〈/sub〉/〈em〉r〈/em〉〈sub〉1〈/sub〉 = 1.1). The maximum signal enhancement (ΔSNR) for 〈em〉T〈/em〉〈sub〉1〈/sub〉-weighted MRI of tumors reached up to 423 ± 42% at 12 h post-injection of ES-GON-rBSA-LF-RGD2, which is much higher than commercial Gd-chelates (〈80%). ES-GON-rBSA-LF-RGD2 exhibited high biocompatibility and can transport across the 〈em〉in vitro〈/em〉 BBB model and the 〈em〉in vivo〈/em〉 BBB of mice due to its small particle size (〈em〉d〈/em〉〈sub〉〈em〉h〈/em〉〈/sub〉 = 13.4 nm) and LF receptor mediated transcytosis. Orthotopic GBM studies reinforce that ES-GON-rBSA3-LF-RGD2 can accumulate in the orthotopic GBM and enhance the radiation therapy of GBM as an effective radiosensitizing agent.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Heyong Yin, Franziska Strunz, Zexing Yan, Jiaju Lu, Christoph Brochhausen, Stefanie Kiderlen, Hauke Clausen-Schaumann, Xiumei Wang, Manuela E. Gomes, Volker Alt, Denitsa Docheva〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The poor healing capacity of tendons is known to worsen in the elderly. During tendon aging and degeneration, endogenous human tendon stem/progenitor cells (hTSPCs) experience profound pathological changes. Here, we explored a rejuvenation strategy for hTSPCs derived from aged/degenerated Achilles tendons (A-TSPCs) by a providing three-dimensional (3D) nanofiber hydrogels and comparing them to young/healthy TSPCs (Y-TSPCs). RADA peptide hydrogel has a self-assembling ability, forms a nanofibrous 3D niche and can be further functionalized by adding RGD motifs. Cell survival, apoptosis, and proliferation assays demonstrated that RADA and RADA/RGD hydrogels support A-TSPCs in a comparable manner to Y-TSPCs. Moreover, they rejuvenated A-TSPCs to a phenotype similar to that of Y-TSPCs, as evidenced by restored cell morphology and cytoskeletal architecture. Transmission electron, confocal laser scanning and atomic force microscopies demonstrated comparable ultrastructure, surface roughness and elastic modulus of A- and Y-TSPC-loaded hydrogels. Lastly, quantitative PCR revealed similar expression profiles as well a significant upregulation of genes related to tenogenesis and multipotency. Taken together, the RADA-based hydrogels exert a rejuvenating effect by recapitulating 〈em〉in vitro〈/em〉 specific features of the natural microenvironment of human TSPCs, which strongly indicates their potential to direct cell behaviour and overcome the challenge of cell aging and degeneration in tendon repair.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Vanessa P. Cedron, Andrea M.J. Weiner, Manuel Vera, Laura Sanchez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉In spite of its toxic effects, N-acetyl-p-aminophenol (APAP), also commonly known as acetaminophen or paracetamol, is one of the most widely used analgesic and antipyretic agents. It can be obtained without a medical prescription. To test the effect over the zebrafish embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with acetaminophen to establish the range of concentrations that cause a harmful effect on the zebrafish development. Diminished pigmentation (in embryos treated from 0 h post-fertilization) and blockage of melanin synthesis (in larvae treated from 72 h post-fertilization) were detected, suggesting the involvement of this compound in the development of black pigment cells as described recently for human epidermal melanocytes. Morphological abnormalities such as aberrant craniofacial structures, pericardial edemas, and blood accumulation were also found. All these effects could be due to higher levels of apoptotic cells detected in treated embryos. Therefore, teratogenic effects of acetaminophen cannot be ruled out, and its wide use should be taken with caution.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300265-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Jiefei Wang, Zhongjie Wang, Yong Zhong, Yan Zou, Chong Wang, Haigang Wu, Albert Lee, Weitao Yang, Xiao Wang, Yanjie Liu, Dongya Zhang, Jiliang Yan, Mingcong Hao, Meng Zheng, Roger Chung, Feng Bai, Bingyang Shi〈/p〉

Description: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ashwini Gore, Alex G. Gauthier, Mosi Lin, Vivek Patel, Douglas D. Thomas, Charles R. Ashb, Lin L. Mantell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize 〈em〉Pseudomonas aeruginosa〈/em〉 (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O〈sub〉2〈/sub〉) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O〈sub〉2〈/sub〉) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM - 800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300277-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Young Shin Ko, Hana Jin, Sang Won Park, Hye Jung Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (〈em〉Salvia miltiorrhiza〈/em〉), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-dependently decreased oxLDL- and high Glu–mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu–induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu–induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu–induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300253-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sevda Gheibi, Alan P. Samsonov, Shahsanam Gheibi, Alexandra B. Vazquez, Khosrow Kashfi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide (NO) and hydrogen sulfide (H〈sub〉2〈/sub〉S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H〈sub〉2〈/sub〉S are involved in the pathophysiology of type 2 diabetes and its complications. Restoration of NO levels have favorable metabolic effects in diabetes. The role of H〈sub〉2〈/sub〉S in pathophysiology of diabetes is however controversial; H〈sub〉2〈/sub〉S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H〈sub〉2〈/sub〉S. On the other hand, increased H〈sub〉2〈/sub〉S levels disturb the pancreatic β-cell function and decrease insulin secretion. In addition, there appear to be important interactions between NO and H〈sub〉2〈/sub〉S at the levels of both biosynthesis and signaling pathways, yet clear an insight into this relationship is lacking. H〈sub〉2〈/sub〉S potentiates the effects of NO in the cardiovascular system as well as NO release from its storage pools. Likewise, NO increases the activity and the expression of H〈sub〉2〈/sub〉S-generating enzymes. Inhibition of NO production leads to elimination/attenuation of the cardioprotective effects of H〈sub〉2〈/sub〉S. Regarding the increasing interest in the therapeutic applications of NO or H〈sub〉2〈/sub〉S-releasing molecules in a variety of diseases, particularly in the cardiovascular disorders, much is to be learned about their function in glucose/insulin metabolism, especially in diabetes. The aim of this review is to provide a better understanding of the individual and the interactive roles of NO and H〈sub〉2〈/sub〉S in carbohydrate metabolism.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300290-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Lijuan Wen, Kai Wang, Fengtian Zhang, Yanan Tan, Xuwei Shang, Yun Zhu, Xueqing Zhou, Hong Yuan, Fuqiang Hu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Glioblastoma (GBM) is one of the malignant tumors with high mortality, and the presence of the blood brain barrier (BBB) severely limits the penetration and tissue accumulation of therapeutic agents in the lesion of GBM. Active targeting nanotechnologies can achieve efficient drug delivery in the brain, while still have a very low success rate. Here we revealed a previously unexplored phenomenon that chemotherapy with active targeting nanotechnologies causes pathological BBB functional recovery through VEGF-PI3K-AKT signaling pathway inhibition, accompanied with up-regulated expression of Claudin-5 and Occludin. Seriously, pathological BBB functional recovery induces a significant decrease of intracerebral active targeting nanotechnologies transport during GBM multiple administration, leading to chemotherapy failure in GBM therapeutics. To address this issue, we chose AKT agonist SC79 to transiently re-open functional recovering pathological BBB for continuously intracerebral delivery of brain targeted nanotherapeutics, finally producing an observable anti-GBM effect 〈em〉in vivo〈/em〉, which may offer new sight for other CNS disease treatment.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Songlei Zhou, Yukun Huang, Yu Chen, Shanshan Liu, Minjun Xu, Tianze Jiang, Qingxiang Song, Gan Jiang, Xiao Gu, Xiaoling Gao, Jun Chen〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Efficient delivery of vaccines to dendritic cells (DCs) is critical for inducing sufficient immune response and realizing effective cancer immunotherapy. In the past decade, researchers have spent tremendous effort in delivering vaccines by using nanoparticles. However, most of the present strategies are designed based on receptor-mediated endocytosis to increase nanovaccines uptake by DCs, and underestimate the role of macropinocytosis in taking up exogenous antigen. Here, we proposed that macropinocytosis, an efficient pathway for DCs to internalize extracellular fluid-phase solutes, might be utilized as a highly-effective approach to facilitate nanovaccines uptake in DCs. Accordingly, we designed a biomimetic nanovaccine (R837-αOVA-ApoE3-HNP), composing of a poly-(D, 〈span〉l〈/span〉-lactide-co-glycolide) (PLGA) core to encapsulate adjuvant imiquimod (R837), a phospholipid membrane to load antigen peptide (αOVA), and apolipoprotein E3 (ApoE3), to boost the internalization of antigens into DCs. The nanovaccine exhibited highly efficient cellular uptake into DCs through the macropinocytosis pathway, and significantly promoted DCs maturation and antigen presentation. After subcutaneous injection, the nanovaccine was efficiently drained to lymph nodes. Strong T cell immune responses including the generation of antigen-specific CD8〈sup〉+〈/sup〉 T cells, expansion of IFN-γ〈sup〉+〈/sup〉 CD8〈sup〉+〈/sup〉 T cells and the secretion of IFN-γ〈sup〉+〈/sup〉 were observed after the vaccination of R837-αOVA-ApoE3-HNP. It also efficiently inhibited the formation of tumor metastasis in lung as a prevention vaccine, and exerted superior therapeutic efficiency on B16-OVA tumor-bearing mice when in combination with αPD-1 therapy. Overall, our work demonstrated that by utilizing the macropinocytosis pathway, ApoE3-incorporated biomimetic nanoparticle has great potential to function as a feasible, effective, and safe nanovaccine for cancer immunotherapy.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961220300417-fx1.jpg" width="325" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Christian Bailly, Gérard Vergoten〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300319-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Jun-Wan Shin, Kyung-Soo Chun, Do-Hee Kim, Su-Jung Kim, Seong Hoon Kim, Nam-Chul Cho, Hye-Kyung Na, Young-Joon Surh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and its target protein heme oxygenase-1 (HO-1) in mouse skin 〈em〉in vivo〈/em〉 and in cultured murine epidermal cells. Treatment of mouse epidermal JB-6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it failed to did not alter the steady-state level of the Nrf2 mRNA transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the α,β-unsaturated carbonyl group, failed to induce HO-1 expression as well as Nrf2 nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the α,β-unsaturated carbonyl moiety of curcumin is critical essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300307-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 235〈/p〉 〈p〉Author(s): Helin Xing, Xing Wang, Gao Xiao, Zongmin Zhao, Shiquan Zou, Man Li, Joseph J. Richardson, Blaise L. Tardy, Liangxia Xie, Satoshi Komasa, Joji Okazaki, Qingsong Jiang, Guodong Yang, Junling Guo〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Advancing bone implant engineering offers the opportunity to overcome crucial medical challenges and improve clinical outcomes. Although the establishment of a functional vascular network is crucial for bone development, its regeneration inside bone tissue has only received limited attention to date. Herein, we utilize siRNA-decorated particles to engineer a hierarchical nanostructured coating on clinically used titanium implants for the synergistic regeneration of skeletal and vascular tissues. Specifically, an siRNA was designed to target the regulation of cathepsin K and conjugated on nanoparticles. The functionalized nanoparticles were assembled onto the bone implant to form a hierarchical nanostructured coating. By regulating mRNA transcription, the coating significantly promotes cell viability and growth factor release related to vascularization. Moreover, microchip-based experiments demonstrate that the nanostructured coating facilitates macrophage-induced synergy in up-regulation of at least seven bone and vascular growth factors. Ovariectomized rat and comprehensive beagle dog models highlight that this siRNA-integrated nanostructured coating possesses all the key traits of a clinically promising candidate to address the myriad of challenges associated with bone regeneration.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉siRNA-decorated nanoparticles were assembled to engineer a hierarchical nanostructured coating on clinically used titanium implants for the synergistic regeneration of skeletal and vascular tissues. The release of siRNA targeted the regulation of cathepsin K and enhanced bone-implant interfacial interaction. siRNA-〈em〉CTSK〈/em〉 could be released and internalized by the adjacent macrophages, demonstrating a therapeutic improvement on the osteointegration with synergetic effects on bone regeneration and blood vessel system repair in vitro and 〈em〉in vivo〈/em〉. The use of multi-scaled bio-functional coatings as presented herein may find applications in regenerative medicine for other tissue due to their ability to favor complex stem cell differentiation paths.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961220300302-fx1.jpg" width="500" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 13 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Zejun Wang, Hongjun Li, Jinqiang Wang, Zhaowei Chen, Guojun Chen, Di Wen, Amanda Chan, Zhen Gu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The integration of sampling and instant metabolite readout can fundamentally elevate patient compliance. To circumvent the need for complex in-lab apparatus, here, an all-in-one sampling and display transdermal colorimetric microneedle patch was developed for sensing hyperglycemia in mice. The coloration of 3,3′,5,5′-tetramethylbenzidine (TMB) is triggered by the cascade enzymatic reactions of glucose oxidase (GOx) and horseradish peroxidase (HRP) at abnormally high glucose levels. The HRP in the upper layer is biomineralized with calcium phosphate (CaP) shell to add a pH responsive feature for increased sensitivity as well as protection from nonspecific reactions. This colorimetric sensor achieved minimally invasive extraction of the interstitial fluid from mice and converted glucose level to a visible color change promptly. Quantitative red green and blue (RGB) information could be obtained through a scanned image of the microneedle. This costless, portable colorimetric sensor could potentially detect daily glucose levels without blood drawing procedures.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 233〈/p〉 〈p〉Author(s): Zhenzhen Wang, Kai Dong, Zhen Liu, Yan Zhang, Zhaowei Chen, Hanjun Sun, Jinsong Ren, Xiaogang Qu〈/p〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Amit S. Kalgutkar, James P. Driscoll〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Basic amine substituents provide several pharmacokinetic benefits relative to acidic and neutral functional groups, and have been extensively utilized as substituents of choice in drug design. On occasions, basic amines have been associated with off-target pharmacology via interactions with aminergic G-protein coupled receptors, ion-channels, kinases, etc. Structural features associated with the promiscuous nature of basic amines have been well-studied, and can be mitigated in a preclinical drug discovery environment. In addition to the undesirable secondary pharmacology, α-carbon oxidation of certain secondary or tertiary cycloalkyl amines can generate electrophilic iminium and aldehyde metabolites, potentially capable of covalent adduction to proteins or DNA. Consequently, cycloalkyl amines have been viewed as structural alerts (SAs), analogous to functional groups such as anilines, furans, thiophenes, etc., which are oxidized to reactive metabolites that generate immunogenic haptens by covalently binding to host proteins. Detailed survey of the literature, however, suggests that cases where preclinical or clinical toxicity has been explicitly linked to the metabolic activation of a cycloalkyl amine group are extremely rare. Moreover, there is a distinct possibility for the formation of electrophilic iminium/amino-aldehyde metabolites with numerous cycloalkyl amine-containing marketed drugs, since stable ring cleavage products have been characterized as metabolites in human mass balance studies. In the present work, a critical analysis of the evidence for and against the role of iminium ions/aldehydes as mediators of toxicity is discussed with a special emphasis on often time overlooked detoxication pathways of these reactive species to innocuous metabolites.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030006X-ga1.jpg" width="391" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Tao Yu, Zhibin Wang, Wang Jie, Xiuxiu Fu, Bing Li, Hong Xu, Yan Liu, Min Li, Eunji Kim, Yanyan Yang, Jae Youl Cho〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉BX795, a small molecule with an aminopyrimidine backbone, is a potent ATP-competitive inhibitor of phosphoinositide-dependent kinase 1 (PDK1) and TANK-binding kinase 1 (TBK1). BX795 has significant functions in various immune responses and cancer. Few reports on the anti-inflammatory effect of BX795 are available, and its molecular mechanisms have not been fully elucidated. In this study, lipopolysaccharide (LPS)-treated macrophages (RAW264.7 cells), luciferase reporter gene assay, knock-down and overexpression strategies, kinase assay, protein chip, immunoprecipitation, and immunoblotting analyses were employed to clarify the anti-inflammatory mechanism of BX795. BX795 was found to dose-dependently inhibit the production of pro-inflammatory mediators without exhibiting cytotoxicity. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor 3 (IRF3) are targeted by BX795 rather than nuclear factor (NF)-κB. Moreover, TBK1 and AKT, transforming growth factor activated kinase (TAK)-1/c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase kinase 4 (MKK4) for AP-1 activation, and Janus kinase 2 (JAK2)/STAT1 were inhibited by BX795. Consistent with these findings, BX795 strongly ameliorated inflammatory symptoms in colitis models. These results suggest that BX795 can suppress inflammatory responses triggered by Gram-positive bacteria by suppressing multiple pathways.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300071-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 10 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Rana Gbyli, Yuanbin Song, Stephanie Halene〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Humanized mice have proven to be invaluable for human hematological translational research since they offer essential tools to dissect disease biology and to bridge the gap between pre-clinical testing of novel therapeutics and their clinical applications. Many efforts have been placed to advance and optimize humanized mice to support the engraftment, differentiation, and maintenance of hematopoietic stem cells (HSCs) and the human hematological system in order to broaden the scope of applications of such models. This review covers the background of humanized mice, how they are used as platforms to model myeloid malignancies, and the various current and potential approaches to further enhance their utilization in biomedical research.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300046-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Nadire Özenver, Thomas Efferth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide synthases (NOS) are a family of isoforms, which generate nitric oxide (NO). NO is one of the smallest molecules in nature and acts mainly as a potent vasodilator. It participates in various biological processes ranging from physiological to pathological conditions. Inducible NOS (iNOS, NOS2) is a calcium-independent and inducible isoform. Despite high iNOS expression in many tumors, the role of iNOS is still unclear and complex with both enhancing and prohibiting actions in tumorigenesis. Nature presents a broad variety of natural stimulators and inhibitors, which may either promote or inhibit iNOS response. In the present review, we give an overview of iNOS-modulating agents with a special focus on both natural and synthetic molecules and their effects in related biological processes. The role of iNOS in physiological and pathological conditions is also discussed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300022-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 234〈/p〉 〈p〉Author(s): Junjie Ren, Lei Zhang, Jiayi Zhang, Wei Zhang, Yang Cao, Zhigang Xu, Hongjuan Cui, Yuejun Kang, Peng Xue〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Glucose oxidase (GOx)-mediated starvation circumvents the energy supply for tumor growth, which has been proved as a potent tumor treatment modality. However, tumor hypoxia negatively affects the efficacy of oxygen-involved glucose decomposition reaction. Moreover, curative effect via glucose depletion is not usually satisfactory enough and adjuvant remedies are always required for a promoted tumor ablation. Herein, a multifunctional nanoreactor based on hollow Bi〈sub〉2〈/sub〉Se〈sub〉3〈/sub〉 nanoparticles was developed by loading oxygenated perfluorocarbon (PFC) and surface modification with GOx, which was exploited for an enhanced tumor starvation and highly sensitive photothermal therapy (PTT). GOx-mediated tumor starvation could impede the adenosine triphosphate (ATP) generation and further downregulate the expression of heat shock protein (HSP) to decrease the thermoresistance of cells. Afterwards, near infrared (NIR) laser irradiation was performed not only to trigger sensitized PTT but also to initiate the release of encapsulated oxygen to relieve local hypoxia. Then, such GOx-mediated tumor starvation would be further amplified, accompanying with secondary enhanced suppression of HSP. Both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 investigations demonstrated that such nanoreactor can realize a fascinating therapeutic outcome with minimal adverse effects in virtue of the improved synergistic starvation therapy and PTT. Taken together, the proposed treatment paradigm may inspire the future development of more intelligent nanoplatforms toward high efficient cancer therapy.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 234〈/p〉 〈p〉Author(s): Shi-Bo Wang, Zhao-Xia Chen, Fan Gao, Cheng Zhang, Mei-Zhen Zou, Jing-Jie Ye, Xuan Zeng, Xian-Zheng Zhang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Photodynamic therapy (PDT) is a promising treatment modality for tumor suppression. However, the hypoxic state of most solid tumors might largely hinder the efficacy of PDT. Here, a functional covalent organic framework (COF) is fabricated to enhance PDT efficacy by remodeling the tumor extracellular matrix (ECM). Anti-fibrotic drug pirfenidone (PFD) is loaded in an imine-based COF (COF〈sub〉TTA-DHTA〈/sub〉) and followed by the decoration of poly(lactic-co-glycolic-acid)-poly(ethylene glycol) (PLGA-PEG) to fabricate PFD@COF〈sub〉TTA-DHTA〈/sub〉@PLGA-PEG, or PCPP. After injected intravenously, PCPP can accumulate and release PFD in tumor sites, leading to down-regulation of ECM compenents such as hyaluronic acid (HA) and collagen I. Such depletion of tumor ECM reduces the intratumoral solid stress, a compressive force exerted by the ECM and cells, decompresses tumor blood vessels, and increases the density of effective vascular areas, resulting in significantly improved oxygen supply in tumor. Furthermore, PCPP-mediated tumor ECM depletion also enhances the tumor uptake of subsequently injected Protoporphyrinl IX (PPIX)-conjugated peptide formed nanomicelles (NM-PPIX) due to the improved enhanced permeability and retention (EPR) effect. Both the alleviated tumor hypoxia and improved tumor homing of photosensitizer (PS) molecules after PCPP treatment significantly increase the reactive oxygen species (ROS) generation in tumor and therefore realize greatly enhanced PDT effect of tumor in vivo.〈/p〉〈/div〉 〈/div〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉A covalent organic framework (COF)-based nanosystem PCPP was fabricated to enhance tumor photodynamic therapy (PDT). PCPP can trigger the depletion of tumor extracellular matrix (ECM), leading to improved oxygen supply as well as photosensitizer uptake in tumor to achieve enhanced tumor PDT.〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0142961220300181-fx1.jpg" width="276" alt="Image 1" title="Image 1"〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 233〈/p〉 〈p〉Author(s): Zhengwei Liu, Faming Wang, Jinsong Ren, Xiaogang Qu〈/p〉

Description: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Samir Jana, B. Madhu Krishna, Jyotsana Singhal, David Horne, Sanjay Awasthi, Ravi Salgia, Sharad S. Singhal〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes. Of note, the molecular mechanisms and functional regulation underlying SOX9 upregulation during BC progression are still being uncovered. The focus of this review is to appraise recent advances regarding the involvement of SOX9 in BC pathogenesis. First, we provide a general overview of SOX9 structure and function, as well as its involvement in various kinds of cancer. Next, we discuss pathways of SOX9 regulation, particularly its miRNA-mediated regulation, in BC. Finally, we describe the involvement of SOX9 in BC pathogenesis via its regulation of pathways involved in regulating cancer hallmarks, as well as its clinical and therapeutic importance. In general, this review article aims to serve as an ample source of knowledge on the involvement of SOX9 in BC progression. Targeting SOX9 activity may improve therapeutic strategies to treat BC, but precisely inhibiting SOX9 using drugs and/or small peptides remains a huge challenge for forthcoming cancer research.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295219304885-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 234〈/p〉 〈p〉Author(s): Seep Arora, Shiming Lin, Christine Cheung, Evelyn K.F. Yim, Yi-Chin Toh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The effective deployment of arterial (AECs), venous (VECs) and stem cell-derived endothelial cells (PSC-ECs) in clinical applications requires understanding of their distinctive phenotypic and functional characteristics, including their responses to microenvironmental cues. Efforts to mimic the 〈em〉in-vivo〈/em〉 vascular basement membrane milieu have led to the design and fabrication of nano- and micro-topographical substrates. Although the basement membrane architectures of arteries and veins are different, investigations into the effects of substrate topographies have so far focused on generic EC characteristics. Thus, topographical modulation of arterial- or venous-specific EC phenotype and function remains unknown. Here, we comprehensively evaluated the effects of 16 unique topographies on primary AECs, VECs and human PSC-ECs using a Multi Architectural (MARC) Chip. Gratings and micro-lenses augmented venous-specific phenotypes and depressed arterial functions in VECs; while AECs did not respond consistently to topography. PSC-ECs exhibited phenotypic and functional maturation towards an arterial subtype with increased angiogenic potential, NOTCH1 and Ac-LDL expression on gratings. Specific topographies could elicit different phenotypic and functional changes, despite similar morphological response in different ECs, demonstrating no direct correlation between the two responses.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 233〈/p〉 〈p〉Author(s): Chao Shi, Mingle Li, Zhen Zhang, Qichao Yao, Kun Shao, Feng Xu, Ning Xu, Haidong Li, Jiangli Fan, Wen Sun, Jianjun Du, Saran Long, Jingyun Wang, Xiaojun Peng〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Photodynamic therapy (PDT) and chemotherapy has been applied as a prospective approach in tumor therapeutics. However, suffering from the inherent hypoxia status in tumor microenvironment (TME), the anticancer efficiency is enormously restricted, especially PDT. Herein, we develop a unique liposomal encapsulated catalase (CAT), lyso-targeted NIR photosensitizer (MBDP) and doxorubicin (Dox), forming FA-L@MD@CAT, to increase tumor oxygenation by catalyzing intratumoral high-expressed H〈sub〉2〈/sub〉O〈sub〉2〈/sub〉 for enhancing the combination of chemo-PDT. Moreover, the enhanced tumoral oxygenation not only facilitates singlet oxygen (〈sup〉1〈/sup〉O〈sub〉2〈/sub〉) production but also reverses immunosuppressive TME by modulating immune cytokines to favor antitumor immunities, which significantly induce tumor death. Notably, this system also realizes specific tumor recognition to folate receptor upregulated tumors and improves intratumoral accumulation. This work provides an effective strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: March 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials, Volume 234〈/p〉 〈p〉Author(s): Nayana Tusamda Wakhloo, Sebastian Anders, Florent Badique, Melanie Eichhorn, Isabelle Brigaud, Tatiana Petithory, Maxime Vassaux, Jean-Louis Milan, Jean-Noël Freund, Jürgen Rühe, Patricia M. Davidson, Laurent Pieuchot, Karine Anselme〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cell deformation occurs in many critical biological processes, including cell extravasation during immune response and cancer metastasis. These cells deform the nucleus, their largest and stiffest organelle, while passing through narrow constrictions 〈em〉in vivo〈/em〉 and the underlying mechanisms still remain elusive. It is unclear which biochemical actors are responsible and whether the nucleus is pushed or pulled (or both) during deformation. Herein we use an easily-tunable poly-L-lactic acid micropillar topography, mimicking 〈em〉in vivo〈/em〉 constrictions to determine the mechanisms responsible for nucleus deformation. Using biochemical tools, we determine that actomyosin contractility, vimentin and nucleo-cytoskeletal connections play essential roles in nuclear deformation, but not A-type lamins. We chemically tune the adhesiveness of the micropillars to show that pulling forces are predominantly responsible for the deformation of the nucleus. We confirm these results using an 〈em〉in silico〈/em〉 cell model and propose a comprehensive mechanism for cellular and nuclear deformation during confinement. These results indicate that microstructured biomaterials are extremely versatile tools to understand how forces are exerted in biological systems and can be useful to dissect and mimic complex 〈em〉in vivo〈/em〉 behaviour.〈/p〉〈/div〉 〈/div〉

Description: 〈p〉Publication date: Available online 26 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biomaterials〈/p〉 〈p〉Author(s): Su-Hwan Kim, Kyungmin Kim, Beom Seok Kim, Young-Hyeon An, Uk-Jae Lee, Sang-Hyuk Lee, Seunghyun L. Kim, Byung-Gee Kim, Nathaniel S. Hwang〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhenzhu Sun, Wenqiang Lu, Na Lin, Hui Lin, Jie Zhang, Tingjuan Ni, Liping Meng, Chuanjing Zhang, Hangyuan Guo〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Xunzhen Zheng, Veani Fernando, Vandana Sharma, Yashna Walia, Joshua Letson, Saori Furuta〈/p〉

Description: 〈p〉Publication date: Available online 24 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Dianne Ford〈/p〉