Age-dependent immune responses in COVID-19-mediated liver injury: focus on cytokines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is potentially pathogenic and causes severe symptoms; in addition to respiratory syndromes, patients might experience other severe conditions such as digestive complications and liver complications injury. The abnormality in the liver is manifested by hepatobiliary dysfunction and enzymatic elevation, which is associated with morbidity and mortality. The direct cytopathic effect, immune dysfunction, cytokine storm, and adverse effects of therapeutic regimens have a crucial role in the severity of liver injury. According to aging and immune system alterations, cytokine patterns may also change in the elderly. Moreover, hyperproduction of cytokines in the inflammatory response to SARS-CoV-2 can lead to multi-organ dysfunction. The mortality rate in elderly patients, particularly those with other comorbidities, is also higher than in adults. Although the pathogenic effect of SARS-CoV-2 on the liver has been widely studied, the impact of age and immune-mediated responses at different ages remain unclear. This review discusses the association between immune system responses in coronavirus disease 2019 (COVID-19) patients of different ages and liver injury, focusing on cytokine alterations.

Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

Catalase application in cancer therapy: Simultaneous focusing on hypoxia attenuation and macrophage reprogramming.

The tumor microenvironment (TME), as an immunosuppressive milieu, has a critical role in tumor progression and increases resistance to the conventional treatments. Among the abundant immunosuppressive cells in the TME, tumor-associated macrophages (TAMs) could be a promising target for reprogramming and potentiating the local anti-tumor response. On the other hand, hypoxia is a major barrier in treating solid tumors, which aggravates the situation and alleviates the anti-tumor immune responses. Moreover, catalase and catalase-mimicking compounds can efficiently participate in the TAMs polarization and hypoxia attenuation in the TME. In this review, we will introduce a practical and novel approach which can simultaneously reduce hypoxia and polarize TAMs in the TME. Furthermore, catalase therapeutic effects in combination with cancer therapy methods will be fully discussed. This work aims to inspire readers to explore new avenues for designing and development of next-generation catalase-based formulations for cancer therapy.

The roles of interleukin-1 receptor accessory protein in certain inflammatory conditions.

Interleukin-1 receptor accessory protein (IL-1RAcP) is a member of the immunoglobulin superfamily proteins consisting of soluble and membranous isoforms. IL-1RAcP plays an essential role in the signaling of the IL-1 family cytokines such as IL-1, IL-33 and IL-36, as well as tyrosine kinases FLT3 and C-Kit. IL-1RAcP generally initiates inflammatory signaling pathway through the recruitment of signaling mediators, including MYD88 and IRAK. Chronic inflammation following prolonged signaling of cytokine receptors is a critical process in the pathogenesis of many inflammatory disorders, including autoimmunity, obesity, psoriasis, type 1 diabetes, endometriosis, preeclampsia and Alzheimer's disease. Recently IL-1RAcP aberrant signaling has been considered to play a central role in the pathogenesis of these chronic inflammatory diseases. Targeting IL-1RAcP signaling pathway that was recently considered in clinical trials related to malignancies also indicates its potential as therapeutic target for the inflammatory and autoimmune diseases. This review summarizes the molecular structure, components associated with IL-1RAcP signaling pathways, and their involvement in the pathogenesis of different inflammatory diseases. We will also discuss the effect of IL-1RAcP inhibition for treatment proposes.

Comprehensive Assessment of Skin Disorders in Patients with Common Variable Immunodeficiency (CVID).

BACKGROUND: Common variable immunodeficiency (CVID) is an inborn error of immunity (IEI) characterized by various clinical manifestations such as hypogammaglobulinemia, recurrent infections, and autoimmune diseases. Among different clinical manifestations, skin manifestations have been less reported in these patients. METHODS: In this study, we investigated the prevalence of dermatologic features in 387 CVID patients. Demographic information, clinical manifestations, laboratory data, and genetic findings were collected from medical records. All data were analyzed based on the presence or absence of skin disorders in CVID patients. RESULTS: We observed at least one skin manifestation in about 40% of these patients. Among these complications, skin infection (n = 64, 42.1%) was the most frequent presentation, followed by non-infectious skin lesions (n = 54, 35.6%). Among skin infections, abscesses (n = 34, 22.4%) were the most common complication. Skin infections such as cellulitis, impetigo, measles, and warts were also documented. Eczema (n = 34, 22.4%) was the most common complication in atopic lesions, and vitiligo (n = 13, 8.5%) was prevalent in autoimmune/pigmentation disorders. Among all the patients with genetic mutations, one-quarter had a deleterious mutation in the LRBA gene, relating to the autoimmune and atopic skin lesions. CONCLUSION: This rate of skin disorders in our cohort demonstrating these manifestations could be significant in CVID patients, and they are not rare. Low data of skin complications in CVID patients could be attributed to insufficient attention of physicians and also might alert dermatologists to perform immunological investigations in children with certain skin manifestations.