Mehanizam akutne neurotoksičnosti u Sprague-Dawley štakora izazvane trovanjem endosulfanom

The purpose of this study was to investigate the molecular mechanism underlying oxidative and inflammatory neuronal cell death induced by endosulfan, a pesticide belonging to the chemical family of organochlorines. The cortical and hippocampal tissues derived from Sprague-Dawley (SD) rats treated with endosulfan exhibited increased intracellular accumulation of reactive oxygen species and oxidative damages to cellular macromolecules such as depletion of glutathione, lipid peroxidation, and protein carbonylation. Conversely, the expression of antioxidant enzymes including γ-glutamylcysteine ligase (GCL), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) was markedly reduced in the brain tissues exposed to endosulfan. Moreover, during endosulfan-induced neuronal cell death, mRNA expression of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was elevated, which seemed to be mediated by the activation of nuclear factor-kappa B (NF-κB) by phosphorylation of p65 subunit. These results suggest a new molecular mechanism underlying the endosulfan-induced acute neurotoxicity via induction of oxidative stress and pro-inflammatory responses.Istražen je molekularni mehanizam koji dovodi do smrti neurona potaknute oksidativnim i upalnim procesima uzrokovanim organoklornim pesticidom endosulfanom. U tkivima korteksa i hipokampusa Sprague-Dawley (SD) štakora tretiranih endosulfanom uočena su oksidativna oštećenja staničnih makromolekula, poput smanjene razine glutationa, lipidne peroksidacije i karbonilacije proteina, te povećane unutarstanične akumulacije reaktivnih kisikovih spojeva. Isto tako, u moždanom tkivu nakon izlaganja endosulfanu značajno je smanjena ekspresija enzimskih antioksidansa, uključujući i γ-glutamilcistein ligazu (GCL), superoksidnu dismutazu (SOD) i hem oksigenazu-1 (HO-1). Tijekom endosulfanom izazvane smrti neurona povećala se i ekspresija mRNA pro-upalnih citokina poput čimbenika nekroze tumora-α (TNF-α) i interleukina-1β (IL-1β), što je čini se bilo posredovano aktivacijom nuklearnoga faktora kapa B (NF-κB) putem fosforilacije podjedinice p65. Navedeni rezultati upućuju na novi molekularni mehanizam koji stoji iza akutne neurotoksičnosti izazvane endosulfanom putem indukcije oksidativnoga stresa i pro-upalnih odgovora

Immune-Checkpoint Inhibitors-Induced Type 1 Diabetes Mellitus: From Its Molecular Mechanisms to Clinical Practice

With the increasing use of immune-checkpoint inhibitors (ICIs), such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed cell death-1 (PD-1), for the treatment of malignancies, cases of ICI-induced type 1 diabetes mellitus (ICI-T1DM) have been reported globally. This review focuses on the features and pathogenesis of this disease. T1DM is an immune-related adverse event that occurs following the administration of anti-PD-1 or anti-programmed death ligand-1 (PD-L1) alone or in combination with anti-CTLA-4. More than half of the reported cases presented as abrupt-onset diabetic ketoacidosis. The primary mechanism of ICI-T1DM is T-cell stimulation, which results from the loss of interaction between PD-1 and PD-L1 in pancreatic islet. The similarities and differences between ICI-T1DM and classical T1DM may provide insights into this disease entity. ICI-T1DM is a rare but often life-threatening medical emergency that healthcare professionals and patients need to be aware of. Early detection of and screening for this disease is imperative. At present, the only known treatment for ICI-T1DM is insulin injection. Further research into the mechanisms and risk factors associated with ICI-T1DM development may contribute to a better understanding of this disease entity and the identification of possible preventive strategies

Benign Aspirates on Follow-Up FNA May Be Enough in Patients with Initial Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance

Background. Management of thyroid nodules with benign aspirates following atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is not well established. We reviewed the risk of malignancy and the role of ultrasound (US) features among thyroid nodules with benign results following initial AUS/FLUS diagnoses. Methods. From December 2009 to February 2011, a total of 114 nodules in 114 patients diagnosed as benign on follow-up fine-needle aspiration (FNA) after AUS/FLUS results were included in our study. Eight among 114 nodules were confirmed pathologically and 106 were clinically observed by a follow-up FNA or US. Suspicious US features were defined as markedly hypoechogenicity, irregular or microlobulated margin, presence of microcalcifications, and taller than wide shape. Results. There were 110 (96.5%) benign nodules and 4 (3.5%) malignant nodules. Two (4.8%) among 42 nodules without suspicious US features and 2 (2.8%) out of 72 nodules with suspicious US features were confirmed as malignancy, but there were no significant associations between the malignancy rate and US features (P=0.625). Conclusion. Clinical follow-up instead of surgical excision or continuous repeat FNA may be enough for benign thyroid nodules after AUS/FLUS. The role of US features might be insignificant in the management of these nodules

Renal transplantation in a patient with Bartter syndrome and glomerulosclerosis

Bartter syndrome (BS) is a clinically and genetically heterogeneous inherited renal tube disorder characterized by renal salt wasting, hypokalemic metabolic alkalosis and normotensive hyperreninemic hyperaldosteronism. There have been several case reports of BS complicated by focal segmental glomerulosclerosis (FSGS). Here, we have reported the case of a BS patient who developed FSGS and subsequent end-stage renal disease (ESRD) and provided a brief literature review. The patient presented with classic BS at 3 months of age and developed proteinuria at 7 years. Renal biopsy performed at 11 years of age revealed a FSGS perihilar variant. Hemodialysis was initiated at 11 years of age, and kidney transplantation was performed at 16 years of age. The post-transplantation course has been uneventful for more than 3 years with complete disappearance of BS without the recurrence of FSGS. Genetic study revealed a homozygous p.Trp(TGG)610Stop(TGA) mutation in the CLCNKB gene. In summary, BS may be complicated by secondary FSGS due to the adaptive response to chronic salt-losing nephropathy, and FSGS may progress to ESRD in some patients. Renal transplantation in patients with BS and ESRD results in complete remission of BS

Anoikis Resistance: An Essential Prerequisite for Tumor Metastasis

Metastasis is a multistep process including dissociation of cancer cells from primary sites, survival in the vascular system, and proliferation in distant target organs. As a barrier to metastasis, cells normally undergo an apoptotic process known as “anoikis,” a form of cell death due to loss of contact with the extracellular matrix or neighboring cells. Cancer cells acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to disseminate throughout the body. Because recent technological advances enable us to detect rare circulating tumor cells, which are anoikis resistant, currently, anoikis resistance becomes a hot topic in cancer research. Detailed molecular and functional analyses of anoikis resistant cells may provide insight into the biology of cancer metastasis and identify novel therapeutic targets for prevention of cancer dissemination. This paper comprehensively describes recent investigations of the molecular and cellular mechanisms underlying anoikis and anoikis resistance in relation to intrinsic and extrinsic death signaling, epithelial-mesenchymal transition, growth factor receptors, energy metabolism, reactive oxygen species, membrane microdomains, and lipid rafts