Apricot melanoidins prevent oxidative endothelial cell death by counteracting mitochondrial oxidation and membrane depolarization

The cardiovascular benefits associated with diets rich in fruit and vegetables are thought to be due to phytochemicals contained in fresh plant material. However, whether processed plant foods provide the same benefits as unprocessed ones is an open question. Melanoidins from heat-processed apricots were isolated and their presence confirmed by colorimetric analysis and browning index. Oxidative injury of endothelial cells (ECs) is the key step for the onset and progression of cardiovascular diseases (CVD), therefore the potential protective effect of apricot melanoidins on hydrogen peroxide-induced oxidative mitochondrial damage and cell death was explored in human ECs. The redox state of cytoplasmic and mitochondrial compartments was detected by using the redox-sensitive, fluorescent protein (roGFP), while the mitochondrial membrane potential (MMP) was assessed with the fluorescent dye, JC-1. ECs exposure to hydrogen peroxide, dose-dependently induced mitochondrial and cytoplasmic oxidation. Additionally detected hydrogen peroxide-induced phenomena were MMP dissipation and ECs death. Pretreatment of ECs with apricot melanoidins, significantly counteracted and ultimately abolished hydrogen peroxide-induced intracellular oxidation, mitochondrial depolarization and cell death. In this regard, our current results clearly indicate that melanoidins derived from heat-processed apricots, protect human ECs against oxidative stress

Nitric Oxide Confers Therapeutic Activity to Dendritic Cells in a Mouse Model of Melanoma

Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs

Graphene oxide doped polysulfone membrane adsorbers for the removal of organic contaminants from water

This work explored polysulfone (PS) – graphene oxide (GO) based porous membranes (PS-GO) as adsorber of seven selected organic contaminants of emerging concern (EOCs) including pharmaceuticals, personal care products, a dye and a surfactant from water. PS-GO was prepared by phase inversion method starting from a PS and GO mixture (5% w/w of GO). The porous PS-GO membranes showed asymmetric and highly porous micrometer sized pores on membrane top (diameter ≈20 μm) and bottom (diameter ≈2–5 μm) surfaces and tens of microns length finger like pores in the section. Nanomechanical mapping reveals patches of a stiffer material with Young modules comprised in the range 15–25 GPa, not present in PS pure membranes that are compatible with the presence of GO flakes on the membrane surfaces. PS-GO was immersed in EOCs spiked tap water and the adsorbance efficiency at different contact times and pH evaluated by HPLC analysis. Ofloxacin (OFLOX), benzophenone-3 (BP-3), rhodamine b (Rh), diclofenac (DCF) and triton X-100 (TRX) were removed with efficiency higher than 90% after 4 h treatments. Regeneration of PS-GO and reuse possibilities were demonstrated by washing with ethanol. The adsorption efficiencies toward OFLOX, Rh, DCF and carbamazepine (CBZ) were significantly higher than those of pure PS membrane. Moreover, PS-GO outperformed a commercial granular activated carbon (GAC) at low contact times and compared well at longer contact time for OFLOX, Rh, BP-3 and TRX suggesting the suitability of the newly introduced material for drinking water treatment

Immune Regulatory Neural Stem/Precursor Cells Protect from Central Nervous System Autoimmunity by Restraining Dendritic Cell Function

The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific–BMP-4-dependent–mechanism hindering the DC maturation.The study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway

Short-Term Variations in Neutrophil-to-Lymphocyte and Urea-to-Creatinine Ratios Anticipate Intensive Care Unit Admission of COVID-19 Patients in the Emergency Department

Background: Timely assessment of COVID-19 severity is crucial for the rapid provision of appropriate treatments. Definitive criteria for the early identification of severe COVID-19 cases that require intensive care unit admission are lacking. Methods: This was a single-center, retrospective case-control study of 95 consecutive adults admitted to the intensive care unit (cases) or a medical ward (controls) for laboratory-confirmed COVID-19. Clinical data were collected and changes in laboratory test results were calculated between presentation at the emergency department and admission. Univariate and multivariable logistic regression was performed to calculate odds ratios for intensive care unit admission according to changes in laboratory variables. Results: Of the 95 adults with COVID-19, 25 were admitted to intensive care and 70 to a medical ward after a median 6 h stay in the emergency department. During this interval, neutrophil counts increased in cases and decreased in controls (median, 934 vs. −295 × 106/L; P = 0.006), while lymphocyte counts decreased in cases and increased in controls (median, −184 vs. 109 × 106/L; P < 0.001). In cases, the neutrophil-to-lymphocyte ratio increased 6-fold and the urea-to-creatinine ratio increased 20-fold during the emergency department stay, but these ratios did not change in controls (P < 0.001 for both comparisons). By multivariable logistic regression, short-term increases in the neutrophil-to-lymphocyte ratio (OR = 1.43; 95% CI, 1.16–1.76) and urea-to-creatinine ratio (OR = 1.72; 95% CI, 1.20–2.66) were independent predictors of intensive care unit admission. Conclusion: Short-time changes in neutrophil-to-lymphocyte ratio and urea-to-creatinine ratio emerged as stand-alone parameters able to identify patients with aggressive disease at an early stage

Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition

Tumor microenvironment is fundamental for cancer progression and chemoresistance. Among stromal cells tumor-associated macrophages (TAMs) represent the largest population of infiltrating inflammatory cells in malignant tumors, promoting their growth, invasion, and immune evasion. M2-polarized TAMs are endowed with the nitric oxide (NO)-generating enzyme inducible nitric oxide synthase (iNOS). NO has divergent effects on tumors, since it can either stimulate tumor cells growth or promote their death depending on the source of it; likewise the role of iNOS in cancer differs depending on the cell type. The role of NO generated by TAMs has not been investigated. Using different tumor models in vitro and in vivo we found that NO generated by iNOS of M2-polarized TAMs is able to protect tumor cells from apoptosis induced by the chemotherapeutic agent cisplatin (CDDP). Here, we demonstrate that the protective effect of NO depends on the inhibition of acid sphingomyelinase (A-SMase), which is activated by CDDP in a pathway involving the death receptor CD95. Mechanistic insights indicate that NO actions occur via generation of cyclic GMP and activation of protein kinase G (PKG), inducing phosphorylation of syntaxin 4 (synt4), a SNARE protein responsible for A-SMase trafficking and activation. Noteworthy, phosphorylation of synt4 at serine 78 by PKG is responsible for the proteasome-dependent degradation of synt4, which limits the CDDP-induced exposure of A-SMase to the plasma membrane of tumor cells. This inhibits the cytotoxic mechanism of CDDP reducing A-SMase-triggered apoptosis. This is the first demonstration that endogenous NO system is a key mechanism through which TAMs protect tumor cells from chemotherapeutic drug-induced apoptosis. The identification of the pathway responsible for A-SMase activity downregulation in tumors leading to chemoresistance warrants further investigations as a means to identify new anti-cancer molecules capable of specifically inhibiting synt4 degradation

Hydroxyl Radical vs. One-Electron Oxidation Reactivities in an Alternating GC Double-Stranded Oligonucleotide: A New Type Electron Hole Stabilization

: We examined the reaction of hydroxyl radicals (HO•) and sulfate radical anions (SO4•-), which is generated by ionizing radiation in aqueous solutions under anoxic conditions, with an alternating GC doubled-stranded oligodeoxynucleotide (ds-ODN), i.e., the palindromic 5'-d(GCGCGC)-3'. In particular, the optical spectra of the intermediate species and associated kinetic data in the range of ns to ms were obtained via pulse radiolysis. Computational studies by means of density functional theory (DFT) for structural and time-dependent DFT for spectroscopic features were performed on 5'-d(GCGC)-3'. Comprehensively, our results suggest the addition of HO• to the G:C pair moiety, affording the [8-HO-G:C]• detectable adduct. The previous reported spectra of one-electron oxidation of a variety of ds-ODN were assigned to [G(-H+):C]• after deprotonation. Regarding 5'-d(GCGCGC)-3' ds-ODN, the spectrum at 800 ns has a completely different spectral shape and kinetic behavior. By means of calculations, we assigned the species to [G:C/C:G]•+, in which the electron hole is predicted to be delocalized on the two stacked base pairs. This transient species was further hydrated to afford the [8-HO-G:C]• detectable adduct. These remarkable findings suggest that the double-stranded alternating GC sequences allow for a new type of electron hole stabilization via delocalization over the whole sequence or part of it