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Pathophysiology, Volume 32, Issue 3 (September 2025) – 15 articles

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17 pages, 1971 KB  
Review
Current Evidence on the Involvement of RAGE–Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases—An Overview
by Judyta K. Juranek, Bernard Kordas, Piotr Podlasz, Agnieszka Bossowska and Marta Banach
Pathophysiology 2025, 32(3), 43; https://doi.org/10.3390/pathophysiology32030043 - 29 Aug 2025
Viewed by 109
Abstract
Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases. And while [...] Read more.
Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE–Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE–Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases. Full article
(This article belongs to the Section Neurodegenerative Disorders)
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1 pages, 146 KB  
Correction
Correction: Solomon et al. Effects of Platelet-Rich Osteoconductive–Osteoinductive Allograft Compound on Tunnel Widening of ACL Reconstruction: A Randomized Blind Analysis Study. Pathophysiology 2022, 29, 394–404
by Ruth Solomon, Jan Pieter Hommen and Francesco Travascio
Pathophysiology 2025, 32(3), 42; https://doi.org/10.3390/pathophysiology32030042 - 26 Aug 2025
Viewed by 122
Abstract
In the original publication [...] Full article
13 pages, 2840 KB  
Article
Methamphetamine-Induced Loss of Syndecan-1 and Retinal Endothelial Integrity via the TAAR-1/MMP-9 Pathway
by Minsup Lee, Taekyung Ha, Ivan A. Alvarez, Wendy Leskova, Changwon Park and Norman R. Harris
Pathophysiology 2025, 32(3), 41; https://doi.org/10.3390/pathophysiology32030041 - 26 Aug 2025
Viewed by 301
Abstract
Background/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood–brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated [...] Read more.
Background/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood–brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries. Methods: We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors. Results: METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance. Conclusions: Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1–mediated MMP-9 upregulation. Targeting the TAAR-1/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina. Full article
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20 pages, 591 KB  
Article
Limited Transfer of Working Memory Training to Instrumental Activities of Daily Living in Chronic Stroke Survivors: A Randomized Controlled Trial
by Daniel Landínez-Martínez and Andres Grisales-Aguirre
Pathophysiology 2025, 32(3), 40; https://doi.org/10.3390/pathophysiology32030040 - 22 Aug 2025
Viewed by 362
Abstract
Background/Objectives: Post-stroke cognitive impairment significantly impacts long-term functional outcomes, particularly in instrumental activities of daily living (IADLs). Working memory training (WMT) has emerged as a potential cognitive rehabilitation strategy; however, its transfer to real-world functionality remains unclear. This study evaluated whether adaptive computerized [...] Read more.
Background/Objectives: Post-stroke cognitive impairment significantly impacts long-term functional outcomes, particularly in instrumental activities of daily living (IADLs). Working memory training (WMT) has emerged as a potential cognitive rehabilitation strategy; however, its transfer to real-world functionality remains unclear. This study evaluated whether adaptive computerized WMT enhances IADLs performance compared to a non-adaptive control condition in chronic stroke survivors. Methods: A single-blind, randomized controlled trial was conducted with 50 adults aged 50–79 years, ≥12 months post-ischemic stroke, and diagnosed with a mild neurocognitive disorder. Participants were randomized to adaptive WMT or non-adaptive cognitive training, each completing 25 home-based sessions over 12 weeks via a standardized online platform. Primary outcomes included the Lawton and Brody IADL Scale and the Working Memory Questionnaire (WMQ); secondary outcomes included the Working Memory Index (WMI) from the WAIS-IV. Analyses included frequentist and Bayesian methods. Results: Both groups showed significant pre–post improvements in IADL independence and WMI (p < 0.05; BF10 > 10), with no significant between-group differences on overall IADL outcomes. The adaptive WMT group demonstrated specific gains in WMQ—Storing (p = 0.033; BF10 = 3.83), while the control group improved in WMQ—Attention and IADL—Assistance Required (p = 0.004–0.035; BF10 > 6). Bayesian ANOVA indicated that these effects were primarily driven by the interventions, with minimal influence from depressive symptoms or global cognition. Conclusions: Adaptive WMT yielded domain-specific cognitive benefits but did not enhance IADL performance beyond non-adaptive training. These findings highlight the limited far transfer of WMT and the importance of designing ecologically valid, multimodal rehabilitation strategies post-stroke. Full article
(This article belongs to the Section Cardiovascular Pathophysiology)
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17 pages, 972 KB  
Article
SARS-CoV-2 Main Protease Dysregulates Hepatic Insulin Signaling and Glucose Uptake: Implications for Post-COVID-19 Diabetogenesis
by Praise Tatenda Nhau, Mlindeli Gamede, Andile Khathi and Ntethelelo Sibiya
Pathophysiology 2025, 32(3), 39; https://doi.org/10.3390/pathophysiology32030039 - 4 Aug 2025
Viewed by 728
Abstract
Background: There is growing evidence suggesting that SARS-CoV-2 may contribute to metabolic dysfunction. SARS-CoV-2 infection is associated with systemic inflammation, oxidative stress, and metabolic dysregulation, all of which may impair liver function and promote glucose intolerance. This study investigated the role of SARS-CoV-2, [...] Read more.
Background: There is growing evidence suggesting that SARS-CoV-2 may contribute to metabolic dysfunction. SARS-CoV-2 infection is associated with systemic inflammation, oxidative stress, and metabolic dysregulation, all of which may impair liver function and promote glucose intolerance. This study investigated the role of SARS-CoV-2, specifically its Main Protease (Mpro), in accelerating insulin resistance and metabolic dysfunction in HepG2 cells in vitro. Methods: HepG2 cells were treated with varying concentrations of Mpro (2.5, 5, 10, 20, 40, 80, and 160 nmol/mL) for 24 h to assess cytotoxicity and glucose uptake. Based on initial findings, subsequent assays focused on higher concentrations (40, 80, and 160 nmol/mL). The effects of Mpro on cell viability, protein kinase B (AKT) expression, matrix metallopeptidase-1 (MMP1), dipeptidyl peptidase 4 (DPP4), interleukin-6 (IL-6) expression, and lipid peroxidation were investigated. Results: Our findings reveal that the SARS-CoV-2 Mpro treatment led to a concentration-dependent reduction in glucose uptake in HepG2 cells. Additionally, the Mpro treatment was associated with reduced insulin-stimulated AKT activation, particularly at higher concentrations. Inflammatory markers such as IL-6 were elevated in the extracellular medium, while DPP4 expression was decreased. However, extracellular soluble DPP4 (sDPP4) levels did not show a significant change. Despite these changes, cell viability remained relatively unaffected, suggesting that the HepG2 cells were able to maintain overall metabolic functions under Mpro exposure. Conclusions: This study demonstrated the concentration-dependent impairment of hepatic glucose metabolism, insulin signaling, and inflammatory pathways in HepG2 cells acutely exposed to the SARS-CoV-2 Mpro. These findings warrant further investigation to explore the long-term metabolic effects of SARS-CoV-2 and its proteases in the liver and to develop potential therapeutic approaches for post-viral metabolic complications. Full article
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10 pages, 3851 KB  
Case Report
Secondary Prostate Lymphoma Mimicking Prostate Cancer Successfully Managed by Transurethral Resection to Relieve Urinary Retention
by Lorand-Tibor Reman, Ovidiu Malau, Daniel Porav-Hodade, Calin Chibelean, Arpad-Oliver Vida, Ciprian Todea, Veronica Ghirca, Alexandru Laslo, Raul-Dumitru Gherasim, Rares Vascul, Orsolya-Brigitta Katona, Raluca-Diana Hagău and Orsolya Martha
Pathophysiology 2025, 32(3), 38; https://doi.org/10.3390/pathophysiology32030038 - 2 Aug 2025
Viewed by 322
Abstract
Secondary lymphoma of the prostate is described as the involvement of the prostate gland by lymphomatous spread from a primary site. This condition is exceedingly rare and often presents diagnostic and therapeutic challenges. The symptoms often mimic those of benign prostatic hyperplasia or [...] Read more.
Secondary lymphoma of the prostate is described as the involvement of the prostate gland by lymphomatous spread from a primary site. This condition is exceedingly rare and often presents diagnostic and therapeutic challenges. The symptoms often mimic those of benign prostatic hyperplasia or prostate cancer, including LUTS (lower urinary tract symptoms) and even complete urinary retention. Here, we present a rare case of a 62-year-old male patient undergoing chemotherapy for stage IV mantle cell stomach lymphoma and subsequently secondary prostatic involvement. The patient presented with complete urinary retention, accompanied by biochemical (PSA = 11.7 ng/mL) and imaging (Magnetic Resonance Imaging-PIRADS V lesion) suspicion for prostate cancer. Histopathologic analysis of the MRI-targeted prostate fusion biopsy revealed secondary prostatic lymphoma. The chosen treatment was transurethral resection of the prostate (TUR-P) for relief of symptoms, which significantly improved urinary function (postoperative IPSS = 5 and Qmax = 17 mL/s). This case underscores the importance of considering prostatic lymphoma in the differential diagnosis of bladder outlet obstruction, especially in patients with a known lymphoma history. This report also provides a focused review of the literature on secondary prostatic lymphoma, highlighting the diagnostic challenges, treatment options, and clinical outcomes. Full article
(This article belongs to the Collection Feature Papers in Pathophysiology)
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18 pages, 1782 KB  
Review
Nutrition and Micronutrient Interactions in Autoimmune Thyroid Disorders: Implications for Cardiovascular Health
by Michał Mazur, Magdalena Szymańska, Agnieszka Malik, Wojciech Szlasa and Joanna Popiołek-Kalisz
Pathophysiology 2025, 32(3), 37; https://doi.org/10.3390/pathophysiology32030037 - 1 Aug 2025
Viewed by 846
Abstract
Thyroid hormones play a crucial role in regulating metabolism and cardiovascular function, with even mild dysfunction—such as subclinical hypothyroidism—negatively impacting heart health. While previous studies have confirmed the effects of iodine, selenium, and vitamin D on thyroid regulation and inflammation, the combined role [...] Read more.
Thyroid hormones play a crucial role in regulating metabolism and cardiovascular function, with even mild dysfunction—such as subclinical hypothyroidism—negatively impacting heart health. While previous studies have confirmed the effects of iodine, selenium, and vitamin D on thyroid regulation and inflammation, the combined role of these nutrients in reducing cardiovascular disease (CVD) risk in autoimmune thyroid disorders remains insufficiently understood. This review explores the influence of specific micronutrients—including selenium, iodine, and zinc—and dietary patterns, particularly the Mediterranean diet, on the pathophysiology of hypothyroidism and Hashimoto’s thyroiditis. We introduce a novel framework that integrates emerging data on sex-specific micronutrient interactions and nutritional immunomodulation. Unlike the existing literature, this review introduces original hypotheses related to sex-specific nutritional immunomodulation and proposes a novel framework for micronutrient-driven dietary intervention in Hashimoto’s thyroiditis. Full article
(This article belongs to the Section Metabolic Disorders)
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16 pages, 11841 KB  
Article
Post-COVID-19 Femoral Head Osteonecrosis Exhibits Mast Cell Clusters, Fibrosis, and Vascular Thrombosis: Key Pathological Mechanisms in Long COVID-19 Bone Degeneration
by Asya Kuliyeva, Natalia Serejnikova, Gulnara Eshmotova, Yulya Teslya, Anastasia Ivina, Alexey Zarov, Michael Panin, Alexey Prizov, Vera Lyalina, Dmitry Shestakov, Alexey Fayzullin, Peter Timashev and Alexey Volkov
Pathophysiology 2025, 32(3), 36; https://doi.org/10.3390/pathophysiology32030036 - 18 Jul 2025
Viewed by 2556
Abstract
Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a common condition in hip surgery, which is characterized by the death of bone cells due to disruption of the blood supply and ultimately irreversible destruction of the hip joint. As a result of the [...] Read more.
Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a common condition in hip surgery, which is characterized by the death of bone cells due to disruption of the blood supply and ultimately irreversible destruction of the hip joint. As a result of the COVID-19 pandemic, a significant increase in the incidence of ONFH has been identified. To better understand the pathogenesis of ONFH in the context of COVID-19, our research aimed to determine pathomorphological changes in articular tissues specific to post-COVID-19 ONFH. Methods: Using morphological, morphometric, and statistical methods, the femoral heads after hip arthroplasty were retrospectively studied in patients with post-COVID-19 ONFH (n = 41) compared to a non-COVID-19 group of patients (n = 47). Results: Our results revealed that the key morphofunctional biomarkers of post-COVID-19 ONFH were clusters of mast cells, extensive areas of fibrosis, numerous arterial and venous thrombi, and giant cell granulomas. The potential relationship of those morphological features with the action of the SARS-CoV-2 coronavirus was discussed. Conclusions: Mast cells have been proposed as the leading players that may trigger the main molecular and cellular mechanisms in the development of post-COVID-19 ONFH and can be considered a diagnostic sign of the disease. Full article
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7 pages, 444 KB  
Opinion
Prenatal Alcohol Exposure and Congenital Heart Defects: Retinoic Acid Deficiency as a Potential Mechanism in Dextro-Type Transposition of the Great Arteries
by Roberto Paparella, Carolina Putotto, Marco Fiore, Fiorenza Colloridi, Paolo Versacci, Mauro Ceccanti, Bruno Marino and Luigi Tarani
Pathophysiology 2025, 32(3), 35; https://doi.org/10.3390/pathophysiology32030035 - 10 Jul 2025
Viewed by 480
Abstract
Fetal alcohol spectrum disorder (FASD) is a preventable cause of developmental disabilities linked to prenatal alcohol exposure (PAE). Congenital heart defects (CHDs) are frequently observed in FASD, with a notable association between PAE and dextro-type transposition of the great arteries (d-TGA). A potential [...] Read more.
Fetal alcohol spectrum disorder (FASD) is a preventable cause of developmental disabilities linked to prenatal alcohol exposure (PAE). Congenital heart defects (CHDs) are frequently observed in FASD, with a notable association between PAE and dextro-type transposition of the great arteries (d-TGA). A potential pathogenetic mechanism of d-TGA in FASD, involving retinoic acid (RA) deficiency due to the interference of ethanol with RA biosynthesis, is proposed. Further investigation is required to understand the timing and impact of alcohol exposure on congenital anomalies, particularly in the context of CHDs. Full article
(This article belongs to the Section Cardiovascular Pathophysiology)
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26 pages, 1605 KB  
Review
Thiamine Deficiency and Neuroinflammation Are Important Contributors to Alcohol Use Disorder
by Nikhila Kalapatapu, Samantha G. Skinner, Emma G. D’Addezio, Srija Ponna, Enrique Cadenas and Daryl L. Davies
Pathophysiology 2025, 32(3), 34; https://doi.org/10.3390/pathophysiology32030034 - 4 Jul 2025
Viewed by 1580
Abstract
Despite the growing morbidity associated with alcohol use disorder (AUD), current FDA-approved therapeutics fail to adequately address the condition. This is in part due to the complex systemic effects of ethanol (EtOH), which have particularly negative consequences on the gut–liver–brain axis. Importantly, two [...] Read more.
Despite the growing morbidity associated with alcohol use disorder (AUD), current FDA-approved therapeutics fail to adequately address the condition. This is in part due to the complex systemic effects of ethanol (EtOH), which have particularly negative consequences on the gut–liver–brain axis. Importantly, two systemic mechanisms underlying the progression of AUD remain underemphasized in therapeutic development: thiamine deficiency and neuroinflammation. Alcohol-induced thiamine deficiency leads to reduced activity of key metabolic enzymes, thereby resulting in energy deficits, oxidative stress, and severe clinical implications. EtOH also activates TLR4 and NLRP3, both of which play critical roles in the regulation of neuroimmune responses. While research directly investigating the relationship between thiamine deficiency and neuroinflammation is still in its early stages, our review highlights the emerging connections between these two seemingly distinct pathomechanisms. Additionally, potential therapeutic approaches and targets for addressing AUD at a systemic level are discussed. Full article
(This article belongs to the Section Systemic Pathophysiology)
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34 pages, 1227 KB  
Review
Understanding Renal Tubular Function: Key Mechanisms, Clinical Relevance, and Comprehensive Urine Assessment
by Mario Alamilla-Sanchez, Miguel Angel Alcalá Salgado, Victor Manuel Ulloa Galván, Valeria Yanez Salguero, Martín Benjamin Yamá Estrella, Enrique Fleuvier Morales López, Nicte Alaide Ramos García, Martín Omar Carbajal Zárate, Jorge David Salazar Hurtado, Daniel Alberto Delgado Pineda, Leticia López González and Julio Manuel Flores Garnica
Pathophysiology 2025, 32(3), 33; https://doi.org/10.3390/pathophysiology32030033 - 3 Jul 2025
Viewed by 3228
Abstract
Renal function refers to the combined actions of the glomerulus and tubular system to achieve homeostasis in bodily fluids. While the glomerulus is essential in the first step of urine formation through a coordinated filtration mechanism, the tubular system carries out active mechanisms [...] Read more.
Renal function refers to the combined actions of the glomerulus and tubular system to achieve homeostasis in bodily fluids. While the glomerulus is essential in the first step of urine formation through a coordinated filtration mechanism, the tubular system carries out active mechanisms of secretion and reabsorption of solutes and proteins using specific transporters in the epithelial cells. The assessment of renal function usually focuses on glomerular function, so the tubular function is often underestimated as a fundamental part of daily clinical practice. Therefore, it is essential to properly understand the tubular physiological mechanisms and their clinical association with prevalent human pathologies. This review discusses the primary solutes handled by the kidneys, including glucose, amino acids, sodium, potassium, calcium, phosphate, citrate, magnesium and uric acid. Additionally, it emphasizes the significance of physicochemical characteristics of urine, such as pH and osmolarity. The use of a concise methodology for the comprehensive assessment of urine should be strengthened in the basic training of nephrologists when dealing with problems such as water and electrolyte balance disorders, acid-base disorders, and harmful effects of commonly used drugs such as chemotherapy, antibiotics, or diuretics to avoid isolated replacement of the solute without carrying out comprehensive approaches, which can lead to potentially severe complications. Full article
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11 pages, 1959 KB  
Article
Crack Cocaine Smoke Induces Tissue Degeneration in Rat Submandibular Glands by Toll-like Signaling Pathway
by Lorrany da Silva Avanci, Daniel Vitor de Souza, Gabriel Carvalhal de Aguiar, Thiago Guedes Pinto, Barbara dos Anjos Rosario, Milena de Barros Viana, Yasmin Alaby Martins Ferreira, Viviane Carlin Cordaro, Luciana Pellegrini Pisani and Daniel Araki Ribeiro
Pathophysiology 2025, 32(3), 32; https://doi.org/10.3390/pathophysiology32030032 - 2 Jul 2025
Viewed by 352
Abstract
Background: This study investigated the impact of crack cocaine smoke exposure on the submandibular salivary gland of Wistar rats. Methods: The animals were distributed into four groups: control (CTRL); 25 mg exposure (CK25); 50 mg exposure (CK50); and 100 mg exposure (CK100). The [...] Read more.
Background: This study investigated the impact of crack cocaine smoke exposure on the submandibular salivary gland of Wistar rats. Methods: The animals were distributed into four groups: control (CTRL); 25 mg exposure (CK25); 50 mg exposure (CK50); and 100 mg exposure (CK100). The animals were exposed to crack cocaine smoke once a day for five consecutive days. Results: Exposure to crack cocaine smoke-induced histopathological changes in submandibular salivary glands in all groups under exposure. The immunohistochemical analysis demonstrates that exposure to crack cocaine smoke led to an increase in BCL-2 and P16 expression in all groups exposed to crack cocaine (p < 0.05). The analysis of Ki-67 expression revealed a significant increase in immunoreactive cells across all exposure groups (p < 0.05). Although MYD88 expression was observed in all crack cocaine-exposed groups, only the group treated with the highest dose (100 mg) exhibited a statistically significant increase compared to the control group (p < 0.05). Conclusions: In summary, this study demonstrates that exposure to crack cocaine smoke-induced tissue degeneration in the submandibular salivary gland, increasing cellular senescence and promoting compensatory cell proliferation in Wistar rats. Full article
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10 pages, 1531 KB  
Case Report
A Rare Case of Cerebral Amyloidoma Mimicking Thalamic Glioma in a Rheumatoid Arthritis Patient
by Elyaa Saleh, Nour Abdelaziz, Malaak Ramahi, Antonia Loukousia, Theodossios Birbilis and Dimitrios Kanakis
Pathophysiology 2025, 32(3), 31; https://doi.org/10.3390/pathophysiology32030031 - 1 Jul 2025
Viewed by 479
Abstract
Amyloidosis, often referred to as “the great imitator”, is a condition characterized by the abnormal deposition of amyloid proteins in various tissues, potentially leading to organ dysfunction. When these deposits localize in the brain, they can disrupt neurological function and present with diverse [...] Read more.
Amyloidosis, often referred to as “the great imitator”, is a condition characterized by the abnormal deposition of amyloid proteins in various tissues, potentially leading to organ dysfunction. When these deposits localize in the brain, they can disrupt neurological function and present with diverse clinical manifestations, making diagnosis particularly challenging. Cerebral amyloidosis is a rare entity that frequently mimics other neurological disorders, often resulting in significant delays in recognition and management. This case highlights the diagnostic challenge posed by cerebral amyloidosis and underscores its unique presentation. We present the case of a 76-year-old male with a history of rheumatoid arthritis (RA) who developed progressive right-sided weakness over several months. Three years prior, he experienced numbness on the right side of his face and upper limb. Initial imaging identified a small lesion in the left thalamic region, which was originally diagnosed as a glioma. However, due to the worsening of his clinical symptoms, further evaluation was warranted. Subsequent imaging revealed lesion growth, prompting a biopsy that ultimately confirmed the diagnosis of intracerebral amyloidoma. This case underscores the necessity of considering amyloidosis in the differential diagnosis of atypical neurological deficits, particularly in patients with systemic inflammatory conditions such as RA. The initial presentation of hemiparesis resembling a stroke, coupled with non-specific imaging findings and a prior misdiagnosis of glioma, highlights the complexity of cerebral amyloidosis. Only through brain biopsy was the definitive diagnosis established, emphasizing the need for improved diagnostic modalities to facilitate early detection. Further subtyping of amyloidosis, however, requires mass spectrometry-based proteomics or immunohistochemistry to accurately identify the specific amyloid protein involved. Clinicians should maintain a high index of suspicion for cerebral amyloidosis in patients with RA who present with progressive neurological deficits and atypical brain lesions. Early recognition and accurate diagnosis are essential to guiding appropriate management and improving patient outcomes. Full article
(This article belongs to the Section Systemic Pathophysiology)
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9 pages, 8072 KB  
Article
C4d Immunoreactivity in Autoimmune and HBV-Induced Hepatitis: Implications for Complement-Mediated Hepatocellular Injury
by Ye Zheng, Haitao Tong, Wenjuan Guo, Ao Wang, Wenxing Hu, Min Wu and Xiaonan Zhang
Pathophysiology 2025, 32(3), 30; https://doi.org/10.3390/pathophysiology32030030 - 1 Jul 2025
Viewed by 369
Abstract
Background: Although immune complex formation is widely acknowledged as the etiological agent for the development of systemic lupus erythematosus, polyarteritis nodosa, reactive arthritis, etc., its roles in chronic hepatitis are less understood. This study aims to compare the immunohistochemistry profile of immune complex [...] Read more.
Background: Although immune complex formation is widely acknowledged as the etiological agent for the development of systemic lupus erythematosus, polyarteritis nodosa, reactive arthritis, etc., its roles in chronic hepatitis are less understood. This study aims to compare the immunohistochemistry profile of immune complex deposition in patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH). Methods: Immunohistochemistry of C4d, a widely used marker for complement deposition was employed on liver biopsies from 72 and 15 patients with CHB and AIH, respectively. Statistical analysis was performed to analyze its prevalence and its association with a range of clinical and histological parameters. Results: Among the 15 AIH biopsies examined, C4d deposition was observed in 11 cases (73.3%), the majority of which showed a periportal staining pattern (10/11). In CHB, 61 (84.7%) of 72 cases tested positive for C4d, which did not differ significantly with that of AIH. While the periportal pattern was predominantly observed in CHB cases, positive staining in central veins, sinusoids, and hepatic parenchyma were also documented. In particular, C4d deposition is significantly associated with elevated serum ALT and liver inflammation in CHB. Of note, in specimens with a patchy parenchymal C4d staining pattern, a spatially correlated HBsAg IHC signal was observed in adjacent sections from the same tissue. Conclusions: These data suggest an involvement of immune complex-mediated immunopathy in autoimmune hepatitis and HBV-induced hepatitis. The positive intrahepatic C4d signal was associated with heightened liver inflammation. The colocalization of the C4d signal on hepatocytes with HBsAg strongly suggests a causal relationship between viral activity and complement deposition. These observations align with our recent evidence implicating the contribution of capsid–antibody complexes in the pathogenesis of CHB. Full article
(This article belongs to the Section Systemic Pathophysiology)
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18 pages, 1000 KB  
Article
Diabetic Ketoacidosis Is Associated with Lower Serum Sphingolipids but Higher β-Hydroxybutyrate and Lactate: A Pilot Study
by Ibrahim Aslan, Tuğçe Çeker, Tayfun Ustabaş, Vuslat Zorlu, Çağatay Yılmaz and Mutay Aslan
Pathophysiology 2025, 32(3), 29; https://doi.org/10.3390/pathophysiology32030029 - 26 Jun 2025
Viewed by 554
Abstract
Background/Objectives: Diabetic ketoacidosis (DKA) is an acute and severe complication of diabetes mellitus, marked by hyperglycemia, ketosis, and acidosis. It is associated with significant metabolic and inflammatory adjustments that can impact multiple biochemical pathways. This study aimed to determine the serum sphingolipid [...] Read more.
Background/Objectives: Diabetic ketoacidosis (DKA) is an acute and severe complication of diabetes mellitus, marked by hyperglycemia, ketosis, and acidosis. It is associated with significant metabolic and inflammatory adjustments that can impact multiple biochemical pathways. This study aimed to determine the serum sphingolipid profile in DKA and investigate its relationship with neutral sphingomyelinase (N-SMase), pro-inflammatory cytokines, β-hydroxybutyrate (β-OHB), and lactate levels. Methods: Thirty-three participants were divided into three groups: control (BMI ≤ 30, no health issues), obese (BMI > 30), and DKA (BMI ≤ 30). Sphingomyelins (16:0–24:0 SMs) and ceramides (C16–C24 CERs) were measured using ultra-fast liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). N-SMase, interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) levels were assessed by enzyme-linked immunosorbent assay. Evaluations were done in the DKA group before and after standard clinical treatment for DKA (post-DKA group), which included intravenous insulin therapy, fluid resuscitation, and electrolyte replacement, as per established clinical guidelines. Results: β-OHB levels were significantly higher in the DKA group than in the control, obese, and post-DKA groups. Although β-OHB levels decreased in the post-DKA group, they remained elevated compared to the control and obese groups. Lactate levels were also higher in the DKA group, with a significant decrease in the post-DKA group. TNF-α and IL-1β were higher in the obese group compared to control and DKA groups, and TNF-α decreased significantly in the post-DKA group compared to DKA. N-SMase, 16:0–18:0 SMs, and C18-C24 CER levels were lower in the DKA and post-DKA groups compared to obese and control groups. Serum β-OHB and lactate levels were significantly correlated with S1P, total CER, total SM, and N-SMase values. Conclusions: The study reveals significant metabolic and inflammatory differences in DKA and post-DKA states, suggesting a relationship between sphingolipids, N-SMase, and these alterations, which could offer insights into DKA pathophysiology and therapeutic targets. Full article
(This article belongs to the Section Metabolic Disorders)
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