Natural killer cell-mimic nanoparticles can actively target and kill acute myeloid leukemia cells.

Natural killer (NK) cells play a crucial role in recognizing and killing emerging tumor cells. However, tumor cells develop mechanisms to inactivate NK cells or hide from them. Here, we engineered a modular nanoplatform that acts as NK cells (NK cell-mimics), carrying the tumor-recognition and death ligand-mediated tumor-killing properties of an NK cell, yet without being subject to tumor-mediated inactivation. NK cell mimic nanoparticles (NK.NPs) incorporate two key features of activated NK cells: cytotoxic activity via the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and an adjustable tumor cell recognition feature based on functionalization with the NK cell Fc-binding receptor (CD16, FCGR3A) peptide, enabling the NK.NPs to bind antibodies targeting tumor antigens. NK.NPs showed potent in vitro cytotoxicity against a broad panel of cancer cell lines. Upon functionalizing the NK.NPs with an anti-CD38 antibody (Daratumumab), NK.NPs effectively targeted and eliminated CD38-positive patient-derived acute myeloid leukemia (AML) blasts ex vivo and were able to target and kill CD38-positive AML cells in vivo, in a disseminated AML xenograft system and reduced AML burden in the bone marrow compared to non-targeted, TRAIL-functionalized liposomes. Taken together, NK.NPs are able to mimicking key antitumorigenic functions of NK cells and warrant their development into nano-immunotherapeutic tools.

Impact of endogenous stress on albumin structure in systemic lupus erythematosus (SLE) patients.

Systemic lupus erythematosus (SLE) is an inflammatory, autoimmune disorder of unknown etiology. The inflammatory stress in SLE patients may modify macromolecules and produce structural/functional abnormalities. The present study is aimed at examining the consequences of stresses on the structure of albumin in SLE patients. Albumin was isolated from the sera of SLE/healthy subjects. Multiple physicochemical techniques were used to elucidate, structure of albumin. Advanced glycation end products in SLE patients' albumin were identified by the AGE specific fluorescence. Quenching of tryptophan, tyrosine fluorescence and surface protein hydrophobicity was observed in SLE patients' albumin. Protein-bound carbonyls were elevated while free thiol, lysine, arginine, and alpha helicity was found to be decreased in SLE albumin. Furthermore, changes in the secondary structure of SLE albumin were observed as shift in the position of amide I/II bands. Functionality of SLE albumin was also compromised as its cobalt-binding ability was substantially declined. Adduction of moieties was detected by dynamic light scattering (DLS) and confirmed by matrix assisted laser desorption/ionization. DLS, thioflavin T and transmission electron microscopy results confirmed aggregates in SLE patients' albumin. This study may be helpful in understanding the role of modified albumin in the cofounding pathologies associated with SLE.

N-Pyrazoloyl and N-thiopheneacetyl hydrazone of isatin exhibited potent anti-inflammatory and anti-nociceptive properties through suppression of NF-κB, MAPK and oxidative stress signaling in animal models of inflammation.

BACKGROUND: Hydrazide derivatives constitute an important class of compounds for new drug development as they are reported to possess good anti-inflammatory and analgesic activity. The present study was aimed to investigate the role of newly synthesized hydrazide derivatives N-pyrazoloyl hydrazone of isatin (PHI) and N-thiopheneacetyl hydrazone of isatin (THI) in acute and chronic inflammatory pain models induced by carrageenan and complete Freud's adjuvant (CFA). MATERIALS: PHI and THI (0.1, 1 and 10 mg/kg) pretreatments were provided intraperitoneally to male BALB/c mice prior to inflammatory inducers. Behavioral responses to inflammation and pain were evaluated by assessment of paw edema, mechanical allodynia, mechanical and thermal hyperalgesia. Cytokines production and NF-κB levels were evaluated by ELISA. Western blot analysis was performed for the detection of IκBα, p38, JNK and ERK. Hematoxylin and eosin (H&E) staining and radiographic analysis were performed to evaluate the effect of PHI and THI treatment on bone and soft tissues. Oxidative stress was determined by reduced glutathione, glutathione-S-transferase and catalase assays. Evans blue dye was used to monitor vascular protein leakage. RESULT: PHI and THI dose dependently (0.1, 1 and 10 mg/kg) reduced inflammation and pain in mice, however, the dose of 10 mg/kg exhibited significant activity. The anti-inflammatory and analgesic effects were attributed to suppression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) production levels. PHI and THI significantly blocked CFA-induced activation of NF-κB and MAPK signaling pathways. Oxidative stress and plasma nitrite levels were reduced remarkably. The PHI and THI (10 mg/kg) treatment did not exhibit any apparent toxicity on the liver, kidney, muscles strength, and motor co-ordination in mice. CONCLUSION: Both PHI and THI possess significant anti-inflammatory and analgesic activity via inhibition of inflammatory mediators.