Karl Martin Frøseth Forbord

• Geiseler, Samuel Jakob; Hadzic, Alena; Lambertus, Marvin; Forbord, Karl Martin; Sajedi, Ghazal & Liesz, Arthur [Show all 7 contributors for this article] (2024). L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA<inf>1</inf>. International Journal of Molecular Sciences. ISSN 1661-6596. 25(2). doi: 10.3390/ijms25021232.
• Forbord, Karl Martin; Okla, Meshail; Lunde, Ngoc Nguyen; Bosnjak, Tatjana; Arnekleiv, Guro Lorvik & Hesselson, Daniel [Show all 11 contributors for this article] (2023). The Cysteine Protease Legumain Is Upregulated by Vitamin D and Is a Regulator of Vitamin D Metabolism in Mice. Cells. ISSN 2073-4409. 13(1). doi: 10.3390/cells13010036. Full text in Research Archive Show summary

  Legumain is a lysosomal cysteine protease that has been implicated in an increasing amount of physiological and pathophysiological processes. However, the upstream mechanisms regulating the expression and function of legumain are not well understood. Here, we provide in vitro and in vivo data showing that vitamin D3 (VD3) enhances legumain expression and function. In turn, legumain alters VD3 bioavailability, possibly through proteolytic cleavage of vitamin D binding protein (VDBP). Active VD3 (1,25(OH)2D3) increased legumain expression, activity, and secretion in osteogenic cultures of human bone marrow stromal cells. Upregulation of legumain was also observed in vivo, evidenced by increased legumain mRNA in the liver and spleen, as well as increased legumain activity in kidneys from wild-type mice treated with 25(OH)D3 (50 µg/kg, subcutaneously) for 8 days compared to a control. In addition, the serum level of legumain was also increased. We further showed that active legumain cleaved purified VDBP (55 kDa) in vitro, forming a 45 kDa fragment. In vivo, no VDBP cleavage was found in kidneys or liver from legumain-deficient mice (Lgmn−/−), whereas VDBP was cleaved in wild-type control mice (Lgmn+/+). Finally, legumain deficiency resulted in increased plasma levels of 25(OH)D3 and total VD3 and altered expression of key renal enzymes involved in VD3 metabolism (CYP24A1 and CYP27B1). In conclusion, a regulatory interplay between VD3 and legumain is suggested.

• Solberg, Rigmor; Lunde, Ngoc Nguyen; Forbord, Karl Martin Frøseth; Okla, Meshail; Kassem, Moustapha & Jafari, Abbas (2022). The Mammalian Cysteine Protease Legumain in Health and Disease. International Journal of Medical Sciences. ISSN 1449-1907. 23(24). doi: 10.3390/ijms232415983. Full text in Research Archive Show summary

  The cysteine protease legumain (also known as asparaginyl endopeptidase or δ-secretase) is the only known mammalian asparaginyl endopeptidase and is primarily localized to the endolysosomal system, although it is also found extracellularly as a secreted protein. Legumain is involved in the regulation of diverse biological processes and tissue homeostasis, and in the pathogenesis of various malignant and nonmalignant diseases. In addition to its proteolytic activity that leads to the degradation or activation of different substrates, legumain has also been shown to have a nonproteolytic ligase function. This review summarizes the current knowledge about legumain functions in health and disease, including kidney homeostasis, hematopoietic homeostasis, bone remodeling, cardiovascular and cerebrovascular diseases, fibrosis, aging and senescence, neurodegenerative diseases and cancer. In addition, this review addresses the effects of some marketed drugs on legumain. Expanding our knowledge on legumain will delineate the importance of this enzyme in regulating physiological processes and disease conditions.

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• Geiseler, Samuel; Hadzic, Alena; Sajedi, Ghazal; Forbord, Karl Martin Frøseth & Morland, Cecilie (2020). Lactate injections are neuroprotective in stroke via HCAR1 .

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