Sorbents in acute renal failure and end-stage renal disease: middle molecule and cytokine removal

Renal replacement therapy in acute renal failure (ARF) and chronic renal failure (end-stage renal disease; ESRD) has been based on the use of modifications of dialysis (continuous arteriovenous hemofiltration and hemodiafiltration) to remove middle-molecular-weight toxins, consisting of low-molecular-weight proteins and peptides (LMWP) and cytokines involved in inflammation. High-flux dialyzers are not efficient at removing LMWP, and for this reason, sorbents have been studied to augment or replace dialysis. Removal of LMWP such as beta2-microglobulin, leptin, complement factor D, angiogenin and cytokines such as interleukin (IL)-1, IL-6, IL-10, IL-18 and tumor necrosis factor-alpha has been established in animal models of sepsis and in ESRD patients using sorbents. Sorbent devices added to hemodialysis, or the use of such devices alone in inflammatory states, including sepsis, ARF, cardiopulmonary bypass, pre-explantation of donor organs and ESRD, are being studied.     

Magnetic field-controlled gene expression in encapsulated cells

Cell and gene therapies have an enormous range of potential applications, but as for most other therapies, dosing is a critical issue, which makes regulated gene expression a prerequisite for advanced strategies. Several inducible expression systems have been established, which mainly rely on small molecules as inducers, such as hormones or antibiotics. The application of these inducers is difficult to control and the effects on gene regulation are slow. Here we describe a novel system for induction of gene expression in encapsulated cells. This involves the modification of cells to express potential therapeutic genes under the control of a heat inducible promoter and the co-encapsulation of these cells with magnetic nanoparticles. These nanoparticles produce heat when subjected to an alternating magnetic field; the elevated temperatures in the capsules then induce gene expression. In the present study we define the parameters of such systems and provide proof-of-principle using reporter gene constructs. The fine-tuned heating of nanoparticles in the magnetic field allows regulation of gene expression from the outside over a broad range and within short time. Such a system has great potential for advancement of cell and gene therapy approaches.     

Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor gamma2 subunit

The regulation of the number of gamma2-subunit-containing GABA(A) receptors (GABA(A)Rs) present at synapses is critical for correct synaptic inhibition and animal behavior. This regulation occurs, in part, by the controlled removal of receptors from the membrane in clathrin-coated vesicles, but it remains unclear how clathrin recruitment to surface gamma2-subunit-containing GABA(A)Rs is regulated. Here, we identify a gamma2-subunit-specific Yxxvarphi-type-binding motif for the clathrin adaptor protein, AP2, which is located within a site for gamma2-subunit tyrosine phosphorylation. Blocking GABA(A)R-AP2 interactions via this motif increases synaptic responses within minutes. Crystallographic and biochemical studies reveal that phosphorylation of the Yxxvarphi motif inhibits AP2 binding, leading to increased surface receptor number. In addition, the crystal structure provides an explanation for the high affinity of this motif for AP2 and suggests that gamma2-subunit-containing heteromeric GABA(A)Rs may be internalized as dimers or multimers. These data define a mechanism for tyrosine kinase regulation of GABA(A)R surface levels and synaptic inhibition.     

Patient Nutrition and Probiotic Therapy in COVID-19: What Do We Know in 2021?

Background: The main nutritional consequences of COVID-19 include reduced food intake, hypercatabolism, and rapid muscle wasting. Some studies showed that malnutrition is a significant problem among patients hospitalized due to COVID-19 infection, and the outcome of patients with SARS-CoV-2 is strongly associated with their nutritional status. The purpose of this study was to collect useful information about the possible elements of nutritional and probiotic therapy in patients infected with the SARS-CoV-2 virus. Methods: A narrative review of the literature, including studies published up to 13 September 2021. Results: Probiotics may support patients by inhibiting the ACE2 receptor, i.e., the passage of the virus into the cell, and may also be effective in suppressing the immune response caused by the proinflammatory cytokine cascade. In patients’ diet, it is crucial to ensure an adequate intake of micronutrients, such as omega-3 fatty acids (at 2–4 g/d), selenium (300–450 μg/d) and zinc (30–50 mg/d), and vitamins A (900–700 µg/d), E (135 mg/d), D (20,000–50,000 IU), C (1–2 g/d), B6, and B12. Moreover, the daily calorie intake should amount to ≥1500–2000 with 75–100 g of protein. Conclusion: In conclusion, the treatment of gut dysbiosis involving an adequate intake of prebiotic dietary fiber and probiotics could turn out to be an immensely helpful instrument for immunomodulation, both in COVID-19 patients and prophylactically in individuals with no history of infection.     

A diamino-functionalized silsesquioxane pillared graphene oxide for CO2 capture

In the race for viable solutions that could slow down carbon emissions and help in meeting the climate change targets a lot of effort is being made towards the development of suitable CO₂ adsorbents with high surface area, tunable pore size and surface functionalities that could enhance selective adsorption. Here, we explored the use of silsesquioxane pillared graphene oxide for CO₂ capture; we modified silsesquioxane loading and processing parameters in order to obtain pillared structures with nanopores of the tailored size and surface properties to maximize the CO₂ sorption capacity. Powder X-ray diffraction, XPS and FTIR spectroscopies, thermal analysis (DTA/TGA), surface area measurements and CO₂ adsorption measurements were employed to characterize the materials and evaluate their performance. Through this optimisation process, materials with good CO₂ storage capacities of up to 1.7/1.5 mmol g⁻¹ at 273 K/298 K in atmospheric pressure, were achieved.

Study of the CO₂ uptake performance of silsesquioxane pillared graphene oxide prepared with different pillar loading and way of drying.     

The impact of citrate concentration on adhesion of platelets and leukocytes to adsorbents in whole blood lipoprotein apheresis

Lipoprotein apheresis is applied to deplete low density lipoprotein and other apolipoprotein B containing lipoproteins in patients with severe familial hypercholesterolemia, hypertriglyceridemia associated pancreatitis, or lipoprotein (a)‐hyperlipoproteinemia. Anticoagulation of the extracorporeal circuit may influence cellular activation, as evidenced by a reduction of inflammatory parameters during regional citrate anticoagulation with acid citrate dextrose A (ACD‐A) commonly used in whole blood lipid apheresis. While the citrate concentration in the extracorporeal circuit has to ensure efficient anticoagulation, citrate infusion into the patient should be limited to avoid citrate overload. We assessed the influence of citrate concentration on cellular activation during in vitro circulation of whole blood containing 2.8 mM citrate (ACD‐A 1:40), 5.6 mM citrate (ACD‐A 1:20), or 13 mM citrate over polyacrylate‐based adsorbents for lipoprotein apheresis. We found increased platelet adhesion for anticoagulation with 2.8 mM citrate as compared to 5.6 or 13 mM citrate, as shown by cell counting and confirmed by scanning electron microscopy of adsorbent beads as well as by elevated levels of platelet activation markers and of platelet‐derived microvesicles. Leukocytes showed an equivalent adhesion pattern, while red blood cells remained unaffected at all citrate concentrations. Passage of blood over two consecutive columns resulted in enhanced platelet adhesion to the second column, presumably due to upstream preactivation. In conclusion, citrate influences activation and adhesion of platelets and leukocytes in a concentration‐dependent manner, and ACD‐A 1:20, equivalent to a citrate concentration of 5.6 mM in whole blood, ensures minimal cellular activation during passage of whole blood over polyacrylate‐based adsorbents.