Chronic inflammation and hyperglycemia in diabetic patients increase the risk of implant failure and impaired fracture healing. We previously developed and characterized a titanium (Ti) coating strategy using an imidazolium-based ionic liquid (IonL) with a fully reduced, non-oxidizable High Mobility Group Box 1 (HMGB1) isoform (Ti-IonL-HMGB1) to immunomodulate tissue healing. In this study, we used an open reduction fracture fixation (ORIF) model in non-diabetic (ND) and diabetic (D) rats to further investigate the effectiveness of this Ti-IonL-HMGB1 coating on orthopedic applications. Ninety male Lewis rats (12-15 weeks) were divided into D (n = 45) and ND (n = 45) groups that were distributed into three subgroups based on the type of local treatment received: Ti (uncoated Ti), Ti-IonL, and Ti-IonL-HMGB1 implants. Fracture healing and osseointegration were evaluated using microtomographic, histological, and immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), Runt-related transcription factor 2 (RUNX2), and HMGB1 markers at 2, 10, and 21 days post-ORIF. Scanning Electron Microscopy verified the coating stability after placement. Microtomographic and histological analysis demonstrated increased fracture healing and osseointegration for ND rats in all treatment groups at 10 days, with impaired healing for D rats. Immunohistochemical analysis exhibited elevated PCNA+ and RUNX2+ cells for D animals treated with Ti-IonL-HMGB1 at 21 days compared to all other groups. The immunohistochemical marker HMGB1 was elevated at all time points for D animals in comparison to ND animals, yet was lowered for D tissues near the Ti-IonL-HMGB1 treated implant. Improved osseous healing was demonstrated in D animals with Ti-IonL-HMGB1 treatment by 21 days, compared to D animals with other treatments. To the best of our knowledge, this is the first study analyzing Ti-IonL-HMGB1 implantation in an injury site through ORIF procedures in ND and D rats. This surface approach has potential for improving implanted biomaterials in diabetic environments.

01 Nov 2022·Journal of Cystic Fibrosis

Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

Article

Author: Kirk Harris, J ; Wagner, Brandie D ; Rowe, Steven M ; Heltshe, Sonya L ; Hoppe, Jordana E ; DeBoer, Emily M ; Sagel, Scott D

BACKGROUNDIvacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment.METHODSBlood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed.MEASUREMENTS AND MAIN RESULTSSignificant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight.CONCLUSIONSIvacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.

01 Dec 2020·BMC Pharmacology and ToxicologyQ4 · MEDICINE

Cyclosporine-a attenuates retinal inflammation by inhibiting HMGB-1 formation in rats with type 2 diabetes mellitus

Q4 · MEDICINE

ArticleOA

Author: Chen, Fei ; Zhang, Xuedong ; Wang, Peng

AbstractBackgroundCyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy.MethodsMale Sprague-Dawley rats were established to type 2 diabetic model. After 6 weeks, diabetic rats and normal controls were intravitreally injected with. Cs-A (42 ng/2 μL) to the left eye, and 2 μL DMSO to the right eye for the control.. Another group of normal wild-type rats was subjected to intravitreal injections into. The left eyes with 5 μL PBS or HMGB-1 (5 ng/5 μL) or HMGB-1(5 ng/5 μL) plus. Cs-A (42 ng/2 μL), respectively. Retinal morphological changes were observed with. Hematoxylin–eosin staining. Expressions of HMGB-1, IL-1β and TNF-α were. Detected by immunohistochemistry, ELISA or Western blot or RT-PCR.ResultsRetinal expression levels of IL-1β and TNF-α were upregulated in type 2. diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were. Attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in. diabetic retina and relieved the retinopathy in type 2 diabetic rats.ConclusionsIntravitreal administration of Cs-A showed a protective effect on retina. of diabetic rats, possibly by downregulating retinal expressions of IL-1β and TNF-α. via the suppression of HMGB-1.

100 Deals associated with HMGB-1 (180 Life Sciences)

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis, Liver	Preclinical	GB	180 Life Sciences Corp.	15 Dec 2021
Liver Diseases	Preclinical	GB	University of Oxford	15 Dec 2021

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