Biomolecules

14 pages, 3401 KB

Open AccessArticle

Selective Complement Inhibition in Anti-p200 Pemphigoid: Immune Infiltrate Profiles and Therapeutic Implications Compared to Bullous Pemphigoid

by Shirin Emtenani, Tina Rastegar Lari, Charlotte Kiehne, Nina van Beek, Maike M. Holtsche and Enno Schmidt

Biomolecules 2026, 16(2), 182; https://doi.org/10.3390/biom16020182 - 23 Jan 2026

Abstract

Anti-p200 pemphigoid is an autoimmune blistering disease (AIBD) caused by autoantibodies against laminin β4 and/or γ1, and clinically resembles bullous pemphigoid (BP) as well as the inflammatory variant of epidermolysis bullosa acquisita (EBA). All three diseases show IgG and/or C3 deposition along the cutaneous basement membrane zone (BMZ). Although complement activation is central to BP and EBA pathogenesis, its role in anti-p200 pemphigoid remains unclear. To investigate this, we analyzed inflammatory infiltrates in lesional and perilesional skin from anti-p200 pemphigoid patients (n = 11), revealing a neutrophil-predominant pattern, with mixed neutrophil–eosinophil infiltrates in 81% of cases, which contrasted with the eosinophil-rich infiltrates typical of BP. Infiltrating neutrophils expressed C5aR1 and C5aR2. Complement fixation test (CFT) of patient sera demonstrated C3c deposition at the BMZ in 40% (20/50) of anti-p200 pemphigoid cases and 87% (13/15) of BP cases. Patients in both cohorts could be stratified into high, mild, and non-complement-fixating groups. Pharmacological inhibition of C1s (sutimlimab), C3 (compstatin), C5 (tesidolumab), or C5aR1 (avacopan) significantly blocked C3c or C5 deposition in vitro. These findings indicate that selective blockade of the classical, alternative, or terminal complement pathways effectively prevents BMZ complement deposition, highlighting pathway-specific complement inhibition as a potential therapeutic strategy for anti-p200 pemphigoid. Full article

(This article belongs to the Special Issue Molecular Insights into Treatment and Prognosis of Autoimmune Bullous Diseases)

19 pages, 4121 KB

Open AccessArticle

TRIC-A Loss Sensitizes the Heart to β-Adrenergic Stress and Drives Cardiomyocyte Death and Fibrosis

by Ki Ho Park, Daiju Yamazaki, Xinyu Zhou, Shinji Komazaki, Chengzhu Zhao, Miyuki Nishi, Jingsong Zhou, Hiroshi Takeshima and Jianjie Ma

Biomolecules 2026, 16(2), 181; https://doi.org/10.3390/biom16020181 - 23 Jan 2026

Abstract

Trimeric intracellular cation channel A (TRIC-A) provides counter-ion support for sarcoplasmic reticulum (SR) Ca²⁺ release, yet its physiological role in the intact heart under stress remains poorly defined. Here, we demonstrate that TRIC-A is essential for maintaining balanced SR Ca²⁺ release, mitochondrial integrity, and cardiac resilience during β-adrenergic stimulation. Tric-a^−/− cardiomyocytes exhibited Ca²⁺ transients evoked by electrical stimuli and exaggerated isoproterenol (ISO)-evoked Ca²⁺ release, consistent with SR Ca²⁺ overload. These defects were accompanied by selective upregulation of protein kinase A (PKA)-dependent phosphorylation of ryanodine receptor 2 (RyR2) (S2808) and phospholamban (PLB) (S16). Acute ISO challenge induced mitochondrial swelling, cristae disruption, and Evans Blue Dye uptake, and elevated circulating troponin T in Tric-a^−/− hearts, hallmarks of necrosis-like cell death. Mitochondrial Ca²⁺ uptake inhibition with Ru360 markedly reduced membrane injury, establishing mitochondrial Ca²⁺ overload as the proximal trigger of cardiac cell death. With sustained β-adrenergic stimulation by ISO, Tric-a^−/− hearts developed extensive interstitial and perivascular fibrosis without exaggerated hypertrophy. Cardiac fibroblasts lacked TRIC-A expression and displayed normal Ca²⁺ signaling and activation, indicating that fibrosis arises secondarily from cardiomyocyte injury rather than fibroblast-intrinsic abnormalities. These findings identify TRIC-A as a critical regulator of SR-mitochondrial Ca²⁺ coupling and a key molecular safeguard that protects the heart from catecholamine-induced injury and maladaptive remodeling. Full article

(This article belongs to the Special Issue Mitochondrial Calcium Signaling in Cardiac Health and Disease)

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17 pages, 1352 KB

Open AccessArticle

TrkB Agonist Treatment Decreases Hippocampal Testosterone Contents in a Sex-Dependent Manner Following Neonatal Hypoxia and Ischemia

by Nur Aycan, Irem Isik, Nur Sena Cagatay, Feyza Cetin, Teresita J. Valdes-Arciniega, Burak Ozaydin, Sefer Yapici, Robinson W. Goy, Luc Collo, Qianqian Zhao, Jens Eickhoff, Peter Ferrazzano, Jon E. Levine, Amita Kapoor and Pelin Cengiz

Biomolecules 2026, 16(2), 180; https://doi.org/10.3390/biom16020180 - 23 Jan 2026

Abstract

Hypoxia–ischemia (HI)-related brain injury impacts millions of neonates worldwide. Male neonates are two times more susceptible to developing HI. We have previously reported that the administration of the neurotrophin receptor tyrosine kinase B (TrkB) agonist 7,8-dihydroxyflavone (DHF) following neonatal HI increases hippocampal TrkB phosphorylation and improves hippocampal-dependent learning and memory in early adult life only in females. We hypothesize that sex differences in HI outcomes are due to alterations in neonatal hippocampal steroid content, mainly the neural testosterone. At postnatal day 9, C57BL/6J mice underwent sham and Vannucci’s HI surgeries and were treated either with DHF or vehicle control. Hippocampi and plasma were collected on days 1 and 3 post-HI and liquid chromatography tandem mass spectrometry was used to determine the testosterone (T), estradiol (E₂), progesterone (P₄), and corticosterone (CORT) contents in these samples. All hippocampal steroid contents were at least 10-fold higher than in plasma, suggesting neural synthesis. Males had higher hippocampal T content than females at 3 days post-HI. Treatment with DHF reduced T in the female hippocampi at 3 days post-HI, but not in males. These findings suggest that the neuroprotective effect of DHF in females may be mediated, at least in part, through the reduction in hippocampal T following HI. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)

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Biomolecules, Volume 16, Issue 2 (February 2026) – 3 articles

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