Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex

Abstract Albumin re-uptake is a receptor-mediated pathway located in renal proximal tubuli. There is increasing evidence of glomerular protein handling by podocytes, but little is known about the mechanism behind this process. In this study, we found that human podocytes in vitro are committed to internalizing albumin through a receptor-mediated mechanism even after exposure to low doses of albumin. We show that these cells express cubilin, megalin, ClC-5, amnionless and Dab2, which are partners in the tubular machinery. Exposing human podocytes to albumin overload prompted an increase in CUBILIN, AMNIONLESS and CLCN5 gene expression. Inhibiting cubilin led to a reduction in albumin uptake, highlighting its importance in this mechanism. We demonstrated that human podocytes are committed to performing endocytosis via a receptor-mediated mechanism even in the presence of low doses of albumin. We also disclosed that protein overload first acts on the expression of the cubilin-amnionless (CUBAM) complex in these cells, then involves the ClC-5 channel, providing the first evidence for a possible role of the CUBAM complex in albumin endocytosis in human podocytes

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC

Performance Improvement of Low-Cost Iterative Learning-Based Fuzzy Control Systems for Tower Crane Systems

This paper is dedicated to the memory of Prof. Ioan Dzitac, one of the fathers of this journal and its founding Editor-in-Chief till 2021. The paper addresses the performance improvement of three Single Input-Single Output (SISO) fuzzy control systems that control separately the positions of interest of tower crane systems, namely the cart position, the arm angular position and the payload position. Three separate low-cost SISO fuzzy controllers are employed in terms of first order discrete-time intelligent Proportional-Integral (PI) controllers with Takagi-Sugeno-Kang Proportional-Derivative (PD) fuzzy terms. Iterative Learning Control (ILC) system structures with PD learning functions are involved in the current iteration SISO ILC structures. Optimization problems are defined in order to tune the parameters of the learning functions. The objective functions are defined as the sums of squared control errors, and they are solved in the iteration domain using the recent metaheuristic Slime Mould Algorithm (SMA). The experimental results prove the performance improvement of the SISO control systems after ten iterations of SMA

Circulating levels and characterization of microparticles in patients with different degrees of glucose tolerance

Abstract Background Microparticles (MPs) are vesicular structures shed from endothelial or circulating blood cells, after activation or apoptosis, and can be considered markers of vascular damage. We aimed to determine the levels of circulating MPs, their content of miRNA-126-3p and 5p, and their relationship with early endothelial activation/damage, in patients with different degree of glucose tolerance. Methods CD62E+, CD62P+, CD142+, CD45+ circulating MPs, their apoptotic (AnnexinV+) fractions, and miRNA-126 expression were determined in 39 prediabetic (PreDM), 68 type 2 diabetic (T2DM), and 53 control (NGT) subjects, along with main anthropometric and biochemical measurements. MPs were analysed by flow cytometry. miRNA-126 was measured by quantitative real-time PCR. Plasma antioxidant capacity was determined by electronic spin resonance; ICAM-1, and VCAM-1 by ELISA. Results Activated endothelial cell-derived MPs (CD62E+) were significantly increased in PreDM and T2DM in comparison to NGT (p < 0.0001). AnnexinV+/CD62E+ MPs and Annexin V+ MPs were significantly increased in T2DM compared to PreDM and NGT (p < 0.001); other MPs were not significantly different among groups. Plasma antioxidant capacity was significantly decreased in PreDM and T2DM compared to NGT (p = 0.001); VCAM-1 significantly increased in PreDM and T2DM in comparison to NGT (p = 0.001). miR-126-3p expression, but not miR-126-5p, in MPs, decreased significantly and progressively from NGT, to PreDM, and T2DM (p < 0.001). In PreDM and T2DM, CD62E+ MPs level was significantly and negatively associated with plasma glucose (p = 0.004). Conclusion We show for the first time that circulating CD62E+ MPs level and miR-126-3p content in MPs are abnormal in subjects with pre-diabetes; the content of miR-126-3p correlates with markers of endothelial inflammation, such as VCAM-1, plasma antioxidant capacity, and microparticles, well-accepted markers of endothelial dysfunction

Insights into the pathogenesis of nicotine addiction. Could a salivary biosensor be useful in Nicotine Replacement Therapy (NRT)?

Nicotine has gained the attention of the medical community due to its insidious addictive mechanisms which lead to chronic consumption. The multitude of compounds derived from tobacco smoke have local and systemic negative impacts, resulting in a large number of smoking-related pathologies. The present review offers insights into nicotine addiction physiopathology, as well as social and medical implications, with emphasis on its correlation with Advanced Glycation End Products (AGEs). Therapeutic strategies and new approaches to nicotine assessment and cessation treatment are discussed, noting that such strategies could take into account the possibility of slow and gradual nicotine release from a device attached to a prosthetic piece, based on salivary nicotine-concentration feedback. This approach could offer real-time and home-based self-therapy monitoring by the physician and the patient for follow-up and improve long-term cessation treatment success- Graphical abstract

Proportional-Integral-Derivative Gain-Scheduling Control of a Magnetic Levitation System

The paper presents a gain-scheduling control design procedure for classical Proportional-Integral-Derivative controllers (PID-GS-C) for positioning system. The method is applied to a Magnetic Levitation System with Two Electromagnets (MLS2EM) laboratory equipment, which allows several experimental verifications of the proposed solution. The nonlinear model of MLS2EM is linearized at seven operating points. A state feedback control structure is first designed to stabilize the process. PID control and PID-GS-C structures are next designed to ensure zero steady-state control error and bumpless switching between PID controllers for the linearized models. Real-time experimental results are presented for validation.

Anesthetic challenges in patients with ankylosing spondylitis requiring lower limb surgery – A case report and literature review

Ankylosing spondylitis is one of the global top health burdens and patients affected by it frequently require surgery related to disease progression, such as orthopedic surgery. These patients may prove difficult to manage from an anesthetic standpoint, regardless of the anesthetic technique employed, mainly given the potential for difficult airway access and related comorbidities. We present the case of a 52-year-old male posted for urgent cemented total hip arthroplasty with associated bilateral pulmonary fibrosis and an anticipated difficult airway in whom regional anesthesia was performed with satisfactory results, with a favorable intraoperative and postoperative course. The literature review explores the anesthetic techniques employed when a tailored approach is required in managing patients with ankylosing spondylitis

Insights into the pathogenesis of nicotine addiction. Could a salivary biosensor be useful in Nicotine Replacement Therapy (NRT)?

Nicotine has gained the attention of the medical community due to its insidious addictive mechanisms which lead to chronic consumption. The multitude of compounds derived from tobacco smoke have local and systemic negative impacts, resulting in a large number of smoking-related pathologies. The present review offers insights into nicotine addiction physiopathology, as well as social and medical implications, with emphasis on its correlation with Advanced Glycation End Products (AGEs). Therapeutic strategies and new approaches to nicotine assessment and cessation treatment are discussed, noting that such strategies could take into account the possibility of slow and gradual nicotine release from a device attached to a prosthetic piece, based on salivary nicotine-concentration feedback. This approach could offer real-time and home-based self-therapy monitoring by the physician and the patient for follow-up and improve long-term cessation treatment success- Graphical abstract

Pheochromocytoma Is characterized by catecholamine-mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dysfunction

AbstractBackgroundPheochromocytoma is associated with catecholamine-induced cardiac toxicity, but the extent and nature of cardiac involvement in clinical cohorts is not well-characterized.ObjectivesThis study characterized the cardiac phenotype in patients with pheochromocytoma using cardiac magnetic resonance (CMR).MethodsA total of 125 subjects were studied, including patients with newly diagnosed pheochromocytoma (n = 29), patients with previously surgically cured pheochromocytoma (n = 31), healthy control subjects (n = 51), and hypertensive control subjects (HTN) (n = 14), using CMR (1.5-T) cine, strain imaging by myocardial tagging, late gadolinium enhancement, and native T1 mapping (Shortened Modified Look-Locker Inversion recovery [ShMOLLI]).ResultsPatients who were newly diagnosed with pheochromocytoma, compared with healthy and HTN control subjects, had impaired left ventricular (LV) ejection fraction (<56% in 38% of patients), peak systolic circumferential strain (p < 0.05), and diastolic strain rate (p < 0.05). They had higher myocardial T1 (974 ± 25 ms, as compared with 954 ± 16 ms in healthy and 958 ± 23 ms in HTN subjects; p < 0.05), areas of myocarditis (median 22% LV with T1 >990 ms, as compared with 1% in healthy and 2% in HTN subjects; p < 0.05), and focal fibrosis (59% had nonischemic late gadolinium enhancement, as compared with 14% in HTN subjects). Post-operatively, impaired LV ejection fraction typically normalized, but systolic and diastolic strain impairment persisted. Focal fibrosis (median 5% LV) and T1 abnormalities (median 12% LV) remained, the latter of which may suggest some diffuse fibrosis. Previously cured patients demonstrated abnormal diastolic strain rate (p < 0.001), myocardial T1 (median 12% LV), and small areas of focal fibrosis (median 1% LV). LV mass index was increased in HTN compared with healthy control subjects (p < 0.05), but not in the 2 pheochromocytoma groups.ConclusionsThis first systematic CMR study characterizing the cardiac phenotype in pheochromocytoma showed that cardiac involvement was frequent and, for some variables, persisted after curative surgery. These effects surpass those of hypertensive heart disease alone, supporting a direct role of catecholamine toxicity that may produce subtle but long-lasting myocardial alterations