The Cellular Stress and Cutaneous Manifestations in Renal Cell Carcinomas-A Narrative Review.

The carcinomas originating from the renal cortex are the most aggressive renal malignancies, with a high tendency for metastasis. Understanding the incidence of cutaneous manifestations caused by renal carcinomas is a challenge. In the first part, this article summarizes a series of factors that promote oncogenesis, invasiveness, and the ability of renal cell carcinoma (RCC) to develop secondary cutaneous manifestations. It is postulated that the cellular stress response is one of the leading causes of developing dermatological events induced by cancers located at distant sites. Furthermore, the paper provides an overview of cutaneous complications associated with renal cancer, categorized as malignant manifestations (metastases, synchronous or metachronous cutaneous malignancies associated with renal cancer), non-malignant indirect cutaneous manifestations associated with renal cancer, and treatment consequences. The data presented in this article suggest that recognizing certain cutaneous disorders could assist the physician in the early identification of renal neoplasms and could lead to a better prognosis.

The Interplay between Nitrosative Stress, Inflammation, and Antioxidant Defense in Patients with Lichen Planus.

BACKGROUND: Lichen planus (LP) is a chronic inflammatory skin disease of unelucidated etiology. LP immunopathogenesis is mainly governed by cytotoxic T lymphocytes that mediate an immune response in basal keratinocytes, which may transform into a reservoir of antigens able to initiate an autoimmune reaction. However, other pathogenic pathways complement these mechanisms. Recent studies highlight the involvement of nitrosative stress in the pathogenesis of chronic inflammatory skin diseases. Current data on its role in the pathogenesis of LP are scarce. METHODS: In this article, we investigated nitrosative stress in 40 cutaneous LP (CLP) patients compared to 40 healthy subjects using serum markers including nitrosative stress markers-direct nitrite, total nitrite, nitrate and symmetric dimethylarginine (SDMA), total antioxidant status (TAS), and hsCRP, a marker of inflammation, and analyzed the relationship between nitrosative stress, antioxidant defense, and inflammation to offer new insights into the role of the NO pathway in LP pathogenesis. RESULTS: We identified significantly higher serum levels of direct nitrite, total nitrite, nitrate, SDMA and hsCRP, and significantly lower levels of TAS in CLP patients versus controls. There were significant negative correlations between the serum levels of TAS and significantl positive correlations between the serum levels of hsCRP and the analyzed nitrosative stress markers in patients with CLP. CONCLUSION: Our results indicate an increased level of nitrosative stress in LP patients that correlates with a pro-inflammatory status and altered antioxidant defense.

Changes in Serum IL-12 Levels following the Administration of H1-Antihistamines in Patients with Chronic Spontaneous Urticaria.

INTRODUCTION: Research regarding the role of the IL-12 cytokine family in modulating immune and inflammatory responses is continuously evolving. In this study, the contribution of the p35 and p40 subunits as monomers (noted as IL-12p35 and IL-12p40) and heterodimers (noted as IL-12p70 or IL-12p35/p40) was analysed in the pathophysiology and progression of chronic spontaneous urticaria (CSU). MATERIALS AND METHODS: We conducted a longitudinal, case-control study involving 42 CSU cases and 40 control cases comprising adults without associated conditions. Serial measurements were performed to assess the serum levels of IL-12p70, IL-12p35, and IL-12p40 at the onset of the disease (pre-therapy phase) and 6 weeks after the initiation of the treatment (post-therapy phase). RESULTS: During the pre-therapeutic phase of CSU, elevated serum levels of IL-12 cytokine subtypes were detected compared to the control group. The relationship between IL-12 profiles and the course of CSU highlighted the pro-inflammatory role of IL-12p70 and the anti-inflammatory role of IL-12p35. Significant correlations were observed between IL-12p70 levels and the duration of the disease, as well as between IL-12 and the effectiveness of H1-antihistamines. CONCLUSIONS: The molecular background for the pleiotropic activities mediated by IL-12-derived cytokines in patients with CSU lies in the strict regulation of the production, signalling pathways, and cytokine-specific influences on the same pathophysiological events. The results of the present study suggest that the superficial layers of the skin serve as a cellular source of IL-12, a cytokine produced through antigenic stimulation. In patients with CSU, we identified independent, additive, or divergent functions of IL-12p70, IL-12p35, and IL-12p40, all relevant to systemic inflammation. These findings prove that the prototype programming of IL-12 is abnormal in CSU.

The Role of the L-Arginine-Nitric Oxide Molecular Pathway in Autosomal Dominant Polycystic Kidney Disease.

Recently, arginine has been proven to play an important role in ADPKD physiopathology. Arginine auxotrophy in ADPKD induces cell hyperproliferation, blocking the normal differentiation of renal tube cells and causing cyst formation. We explored the L-arginine (Arg)-nitric oxide (NO) molecular pathway in ADPKD, a multisystemic arginine auxotrophe disease. We developed a prospective case-control study that included a group of 62 ADPKD subjects with an estimated filtration rate over 60 mL/min/1.73 mp, 26 subjects with chronic kidney disease with an eGFR > 60 mL/min/1.73 mp, and a group of 37 healthy subjects. The laboratory determinations were the serum level of arginine, the enzymatic activity of arginase 2 and inducible nitric oxide synthase, the serum levels of the stable metabolites of nitric oxide (nitrate, direct nitrite, and total nitrite), and the endogenous inhibitors of nitric oxide synthesis (asymmetric dimethylarginine and symmetric dimethylarginine). In the ADPKD group, the levels of the arginine and nitric oxide metabolites were low, while the levels of the metabolization enzymes were higher compared to the control group. Statistical analysis of the correlations showed a positive association between the serum levels of Arg and the eGFR and a negative association between Arg and albuminuria. ADPKD is a metabolic kidney disease that is auxotrophic for arginine. Exploring arginine reprogramming and L-Arg-NO pathways could be an important element in the understanding of the pathogenesis and progression of ADPKD.

A Panel of Potential Serum Markers Related to Angiogenesis, Antioxidant Defense and Hypoxia for Differentiating Cutaneous Squamous Cell Carcinomas from Actinic Keratoses.

Cutaneous squamous cell carcinoma (cSCC) arising from the malignant proliferation of epidermal keratinocytes is the second most common skin cancer. Actinic keratosis (AK), which is considered cSCC in situ, may progress into invasive tumors. Currently, there are no serum markers that can differentiate cSCC from AK. The aim of our study was to assess angiogenesis and oxidative stress in patients with cSCC and patients with AK and find reliable serum markers useful in the diagnosis of cSCC. We have determined the serum levels of a group of proangiogenic factors (MMP-2, MMP-9, VEGF, FGF2), the total antioxidative status/capacity (TAS/TAC), ImAnOx, a marker of oxidative stress, and HIF-1 alpha, an indicator of hypoxia. We have identified higher serum levels of MMP-2. MMP-9, VEGF, FGF2 and HIF-1 alpha and lower levels of ImAnOx in cSCC patients compared to AK patients and controls. There were no statistically significant differences between AK patients and controls. We have found positive correlations between proangiogenic markers and HIF-1 alpha and negative correlations between proangiogenic markers and ImAnOx. Our results suggest that MMP-2, MMP-9, VEGF, FGF2, ImAnOx and HIF-1 may be promising markers for differentiating AK from cSCC, and there is a link between angiogenesis, oxidative stress and hypoxia.

Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma.

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition.

New Insights into Lynch Syndrome: A Narrative Review.

Lynch syndrome, characterized by DNA mismatch repair deficiency, represents a significant paradigm among cancer predisposition syndromes and is notably associated with heightened susceptibility to various cancers, particularly colorectal and endometrial malignancies. The primary aim of this research paper is to scrutinize specific associations and delve into the underlying molecular mechanisms of Lynch syndrome. Genetic alterations in MMR genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM, compromise DNA repair mechanisms, predisposing affected individuals to a spectrum of malignancies. This paper comprehensively investigates current screening methodologies and preventive measures tailored for individuals identified or at risk of Lynch syndrome. The integration of advanced sequencing technologies and refined bioinformatics tools has significantly improved mutation detection accuracy, facilitating precise identification of mutation carriers and their at-risk relatives. Moreover, this review emphasizes the evolving diagnostic landscape, which have revolutionized the identification of potential mutation carriers. The structured diagnostic algorithm, incorporating clinical criteria, tumor testing, and genetic analysis, plays a pivotal role in systematically identifying and managing individuals with Lynch syndrome. While the well-established association of Lynch syndrome with colorectal and endometrial cancers is recognized, emerging evidence suggests an increased risk for other types of malignancies. A crucial aspect of this literature review is to extensively analyze the less commonly acknowledged correlation between Lynch syndrome and prostate or testicular malignancies. Understanding these correlations holds significant importance in guiding tailored screening protocols and preventive strategies for individuals carrying Lynch syndrome-associated genetic mutations. The comprehensive assessment of this diverse spectrum of cancers underscores the necessity for tailored surveillance strategies and multidisciplinary approaches to effectively manage and mitigate risks in individuals harboring Lynch syndrome-associated genetic alterations.