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Skin
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Zbigniew W. Wojcinski, Lydia Andrews-Jones, Daher Ibrahim Aibo, Rie Kikkawa, Robert Dunstan
The subcutis (hypodermis) contains abundant fat and loose connective tissue (collagen and elastic fibers) that connect the dermis to the underlying fascia, skeletal muscle, or bone. Fat cells may be arranged in small clusters or large masses (i.e., panniculus adiposus). The prominence of the subcutis varies by anatomic location and nutritional status. Adipose tissue is especially prominent in the footpads where it functions as a “shock absorber” and as an insulating layer (Lafontan 2012). The information and understanding on the role of adipocytes in the subcutis has been expanding during the last decade and now includes regulation of metabolism and energy homeostasis, as well as roles in angiogenesis and immune function (Miner 2004; Lafontan 2012). These cells secrete lipoprotein lipase that hydrolyzes triglycerides into very low-density lipoproteins and chylomicrons, or complement-related proteins including adipsin (or complement factor D). Adipocyte-derived hormones can have proinflammatory (IL-6, tumor necrosis factor alpha [TNF-α], plasminogen activator inhibitor-1, angiotensinogen, resistin, C-reactive protein) or anti-inflammatory (adiponectin and nitric oxide) activities (Miner 2004; Lau et al. 2005).
Chronic Renal Failure
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Over 90 such compounds have been recognized, which include free water-soluble solutes such as guanidines, protein-bound solutes such as phenol, and middle molecules including β2 microglobulin, complement factor D, and multiple cytokines (36). Many other uremic toxins remain unidentified.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
The complement pathway is a complex interplay of serine proteases that requires activation, amplification and lysis. This pathway involves multiple enzymatic processes. The most critical process is the formation of c3 convertase C3bBb. The alternative pathway is regulated by complement factor H which binds to c3b in order to displace Bb and degrade c3 convertase. This critical step is the ideal target for complement pathway inhibition. Complement factor D is important in producing the Bb portion of C3 convertase. While critical and rate limiting, inhibiting mature factor D may not be enough to reduce factor D adequately. Factor D is produced as a pro-enzyme and requires cleavage of 6-amino acid peptide for maturation. This cleavage is under the control of mannose-binding lectin–associated serine protease-3 which is involved in the lectin complement pathway. To inhibit factor D effectively in the majority of patients, inhibition of both factor D and its proenzyme may be necessary. The other possibility is that Factor D may not play such a critical role in the alternative pathway as thought, and may be more critical for the lectin pathway [91].
Retinal findings in glomerulonephritis
Published in Clinical and Experimental Optometry, 2022
Heather G Mack, Deborah J Colville, Phillip Harraka, Judith Anne Savige, Alessandro Invernizzi, Samantha Fraser-Bell
A truncated form of Factor H protein, known as Factor H Like-1, complement factor D and complement 5a all diffuse freely across the blood-retina barrier due to their small size and lack of glycosylation. Complement factor I, complement factor H, complement factor B and complement 3a do not diffuse through Bruch’s membrane, hence remaining at their site of synthesis on either side of Bruch’s membrane, with Factor-H like-1 protein the major complement regulator in Bruch’s membrane. Microglia and the retinal pigment epithelium are the main source of these complement components in the retina. The retina/retinal pigment epithelium/choroid complex also expresses complement regulatory proteins. The main implication from this relates to treating ocular conditions by targeting complement. Several systemically administered treatments have failed to show a beneficial ocular effect, such as eculizumab for dense deposit disease23 and geographic atrophy,24 and liver transplantation for AMD25; however, local administration of these agents may be an interesting research field, further discussed below.
A Novel Full-Length Recombinant Human Complement Factor H (CFH; GEM103) for the Treatment of Age-Related Macular Degeneration Shows Similar In Vitro Functional Activity to Native CFH
Published in Current Eye Research, 2022
Robyn M. Biggs, Elisavet Makou, Scott Lauder, Andrew P. Herbert, Paul N. Barlow, Suresh K. Katti
GEM103 (non-GMP [non-good manufacturing practice] preparation; LakePharma, Inc. [Worcester, MA, USA]) was used for this in vitro study. Native human sdCFH (purified from pooled human serum), purified human C3b, CFB, complement factor D (CFD) and CFI were supplied by Complement Technology, Inc. (Tyler, TX, USA). C3b-binding affinity and decay-accelerating activity (DAA) assays were performed on the BiaCore T200 (GE Healthcare [Chicago, IL, USA]) surface plasmon resonance (SPR) platform. CA was measured using 8-anilinonaphthalene-1-sulfonic acid (ANS) and a SpectraMax M5e (Molecular Devices [San Jose, CA, USA]) plate reader. For hemolysis assays, human CFH-depleted serum and sheep erythrocytes (SEs) were obtained (Complement Technology, Inc.) and measurements performed in a SpectraMax M5e (Molecular Devices) plate reader. See Supplementary Methods for details.