ABSTRACTGiven the growing evidence that gut dysfunction, including changes in gut microbiota composition, plays a critical role in the development of inflammation and metabolic diseases, the ...identification of novel probiotic bacteria with immunometabolic properties has recently attracted more attention. Herein, bacterial strains were first isolated from dairy products and human feces and then screened in vitro for their immunomodulatory activity. Five selected strains were further analyzed in vivo, using a mouse model of diet‐induced obesity. C57BL/6 mice were fed a high‐fat high‐sucrose diet, in combination with 1 of 3 Lactobacillus strains (Lb38, L. plantarum; L79, L. paracaseil casei; Lbl02, L. rhamnosus) or Bifidobacterium strains (Bf26, Bfl41, 2 different strains of B. animalis ssp. lactis species) administered for 8 wk at 109 colony‐forming units/d. Whereas 3 strains showed only modest (Lb38, Bf26) or no (L79) effects, Lbl02 and Bfl41 reduced diet‐induced obesity, visceral fat accretion, and inflammation, concomitant with improvement of glucose tolerance and insulin sensitivity. Further analysis revealed that Lbl02 and Bf141 enhanced intestinal integrity markers in association with selective changes in gut microbiota composition. We have thus identified 2 new potential probiotic bacterial strains with immunometabolic properties to alleviate obesity development and associated metabolic disturbances.—Le Barz, M., Daniel, N., Varin, T. V., Naimi, S., Demers‐Mathieu, V., Pilon, G., Audy, J., Laurin, E., Roy, D., Urdaci, M. C., St‐Gelais, D., Fliss, I, Marette, A. In vivo screening of multiple bacterial strains identifies Lactobacillus rhamnosus Lbl02 and Bifidobacterium animalis ssp. lactis Bf 141 as probiotics that improve metabolic disorders in a mouse model of obesity. FASEB J. 33, 4921—4935 (2019). www.fasebj.org
In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed ...in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.
Ultrafiltration permeate of whey protein tryptic hydrolyzate was processed by nanofiltration (NF) to obtain retentate (NFR) and permeate (NFP) that were then tested as inhibitors of Listeria, ...Staphylococcus aureus and Escherichia coli. NFR at 20 mg mL−1 was most effective as an inhibitor (P < 0.001); whereas E. coli was relatively resistant, the effect on Listeria and S. aureus was greater at 20 mg mL−1 than at 10 mg mL−1 (P < 0.01). Peptide analysis revealed that NFR was rich in anionic peptides over eight amino acid residues in length. The antibacterial activity of two anionic peptides (84–91 and 125–135) and a cationic peptide (36–42) derived from β-lactoglobulin was tested. Peptide 125–135 was more inhibitory (P < 0.05) than peptide 84–91 against Listeria monocytogenes and S. aureus; peptide 36–42 was not inhibitory. NFR appears to have potential as a natural bio-preservative.
Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up‐regulated expression of sodium pump α sub‐units has previously ...been demonstrated when comparing metastatic to non‐metastatic melanomas. Our previous data revealed that impairing sodium pump α1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis‐resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump α sub‐units in melanoma clinical samples and cell lines and also to characterize the role of α1 sub‐units in melanoma cell biology. Quantitative RT‐PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump α sub‐units. In vitro cytotoxicity of various cardenolides and of an anti‐α1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the α1 sub‐unit, and 33% of human melanomas displayed significant α1 sub‐unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti‐tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti‐tumour activity in the aggressive human metastatic brain melanoma model in vivo. The α1 sodium pump sub‐unit could represent a potential novel target for combating melanoma.
Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, ...we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.
Abstract RNA interference currently offers new opportunities for gene therapy by the specific extinction of targeted gene(s) in cancer diseases. However, the main challenge for nucleic acid delivery ...still remains its efficacy through intravenous administration. Over the last decade, many delivery systems have been developed and optimized to encapsulate siRNA and to specifically promote their delivery into tumor cells and improve their pharmacokinetics for anti-cancer purposes. This review aims to sum up the potential targets in numerous pathways and the properties of recently optimized siRNA synthetic nanomedicines with their preclinical applications and efficacy. Future perspectives in cancer treatment are discussed including promising concomitant treatment with chemotherapies or other siRNA. The outcomes in human clinical trials are also presented.
It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer. For many years cytotoxic agents have been developed to target apoptotic cell death as a main method ...of treating cancer. However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents. Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis. In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. These novel anticancer agents are critically discussed by the authors, and therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established proapoptotic therapeutic agents.
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