Molecular and cellular pediatrics最新文献

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with anti-inflammatory effects. However, few studies have investigated their molecular effects in the kidney. We have previously shown that intrauterine growth restriction (IUGR) can lead to aggravation of mesangioproliferative glomerulonephritis and that n-3 PUFAs can attenuate long-term effects of IUGR by reversing pro-inflammatory molecular signatures in kidney cortex.

Results: The original aim of the study was to investigate the potential protective mechanisms of docosahexaenoic acid (DHA) on murine mesangial cells. However, stimulation with DHA alone led to reduced cell viability and ultimately cell death. Proteome analysis revealed significant regulation of ferroptosis-associated proteins. Increased expression of the pro-ferroptotic protein HMOX1 and decreased expression of the pro-ferroptotic proteins TFRC and ACSL4 could indicate the onset of self-protection mechanisms in ferroptosis that is already underway. Interestingly, treatment with the ferroptosis inhibitor ferrostatin-1 maintained cellular metabolic activity and prevented cell death, further supporting a role of ferroptosis in DHA-induced cytotoxicity. Consistently, DHA-treated cells exhibited pronounced lipid peroxidation while showing no relevant activation of apoptosis. Simultaneous treatment with DHA and an antioxidant cocktail significantly attenuated cell death and induced upregulation of several key anti-ferroptotic proteins, including TXNRD1 and GPX4, while pro-ferroptotic proteins such as TFRC and ASCL4 were further reduced.

Conclusion: Our results provide evidence that DHA-treatment alone may have detrimental effects in susceptible cells, which could partially explain inconsistent results of clinical studies. This emphasizes the importance of a balance between pro- and anti-ferroptotic mechanisms in therapeutic strategies using n-3 PUFAs to promote kidney health.

Background: Melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity, yet remains underdiagnosed. Patients with monogenic obesity often undergo a frustrating diagnostic and therapeutic odyssey of years of ineffective lifestyle interventions before a causal diagnosis is made. We report a four-generation family where genetic testing in a child identified a likely pathogenic MC4R variant also carried by three ancestors.

Methods: The studied family included a 7-year-old index patient, her mother, grandmother, and great-grandmother with a history of early-onset obesity. Panel sequencing of monogenic obesity genes was performed in the index patient whereas in the relatives targeted analysis of the familial MC4R variant was performed by Sanger sequencing.

Results: The index patient developed severe obesity by age 2 years, with hyperphagia, tall stature, and dyslipidemia. Despite lifestyle interventions, her body mass index (BMI) continued to increase. At the age of 7 years, genetic panel testing identified a rare monoallelic variant in the MC4R gene c.913C > T; p.Arg305Trp, previously shown to impair receptor function. Treatment with liraglutide (3.0 mg/day) was initiated at age 8 years, resulting in marked reduction in BMI during the first year of treatment. Subsequent genetic testing of family members identified the same variant in her mother, grandmother, and great-grandmother, all of whom had a history of early-onset obesity and related comorbidities, consistent with segregation of the variant within the family.

Conclusions: This case underscores the importance of early genetic testing in severe childhood obesity to avoid ineffective treatments and enable targeted therapies (e.g., GLP-1 analogues). Diagnosing (likely) pathogenic MC4R variants can also identify at-risk relatives, providing psychological and clinical benefits across generations.

ILC2s are innate lymphoid cells that become activated by alarmins and are major producers of type 2 signature cytokines. In mice and human, ILC2s have been identified and characterized in several pre-clinical disease models and patients with a spectrum of diseases. Interest in the regulation and function of ILC2s has grown substantially in recent years due to their capability to act as first responders to external and internal stimuli and their contribution to tissue immunity in health and disease. Importantly, ILC2s are present early on during ontogeny, long lived and can orchestrate immune and non-immune cell populations highlighting their potential impact early and late in life. However, the impact of ILC2s is only starting to be appreciated in early life immune responses. Here, we provide an overview of ILC2s in childhood and adolescence in health and disease. We further discuss the (potential) modulation of early life ILC2s and their clinical implications for therapeutic treatments.