The inhibitory effects of trehalose liposomes (TL) comprising l-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glucopyranosyl-α-D-glucopyranoside mon…

Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.

Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.

Immunomodulation involves two mechanisms, immunostimulation and immunosuppression. It is a complex mechanism that regulates the pathophysiology and pathogenesis of various diseases affecting the immune system. Immunomodulators can be used as immunostimulators to reduce the side effects of drugs that induce immunosuppression. In this study, we characterized the chemical composition of high molecular weight fucoidan (HMWF) and low molecular weight fucoidan and compared their functions as natural killer (NK) cell-derived immunostimulators in vitro. We also tested the effectiveness of HMWF, which has a relatively high function in vitro, as an immunostimulator in immunosuppressed animal models. In these models, HWMF significantly restored NK cell cytotoxicity and granzyme B release to the control group level. In addition, the expression of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α also increased in the spleen. This study suggests that HMWF acts as an effective immunostimulant under immunosuppressive conditions.

Methotrexate (MTX) is commonly used as a standard chemotherapy for many cancers, however its usage required high doses thereby leading to severe adverse effects. In a trial to find a suitable neoadjuvant therapy to decrease MTX dosage without lowering its chemotherapeutic efficacy, we investigated t …

Trehalose solution was an effective and safe eyedrop for the treatment of moderate to severe dry eye syndrome in this group of patients.

Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegen …

Trehalose is a natural disaccharide synthesized in various life forms, but not found in vertebrates. An increasing body of evidence demonstrates exceptional bioprotective characteristics of trehalose. This review discusses the scientific findings on potential ...

Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age. Here, we present laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging data showing modulation of brain Zn levels by the disaccharide trehalose

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is currently no effective treatment. Studies indicate that enhancing autophagy in mouse models of neurodegenerative disease can ameliorate the behavioral symptoms and pathological damage associated with the acc …

The T-cell adjuvanticity of mycobacterial cord factor trehalose 6,6'-dimycolate (TDM) is well established. The identification of the C-type lectin Mincle on inn...

Cornea acts as a structural barrier and protects the eye from environmental stresses. Inflammation in ocular surface causes discomfort and visual dist…

This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition …

In this study, we observed that brown seaweed fucoidan inhibited human breast cancer progression by upregulating microRNA (miR)-29c and downregulating miR-17-5p, thereby suppressing their target genes, a disintegrin and metalloproteinase 12 (ADAM12) and ...

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccha...

A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of Abeta is being actively pursued as a primary therapeutic strategy for treating AD. T …

Many degenerative disorder such as Parkinsons, Alzheimers, Huntingtons disease, etc are caused due to the deposition of amyloid fibrils, formed due to the ordered aggregation of misfolded/unfolded proteins. Misfolded or unfolded proteins aggregate mostly through hydrophobic interactions which are unexposed in native state, but become exposed upon unfolding. To counteract amyloid related diseases, inhibition of the protein self assembly into fibril is a potential therapeutic strategy. The study aims at investigating the effect of selected compounds, namely trehalose and magnesium chloride hexahydrate towards inhibition and disaggregation of amyloid fibrils using Hen Egg White Lysozyme as a model. We further attempted to understand the mechanism of action with the help of various biophysical, microscopic as well as computational studies. A common mechanism of action was identified where the selected compounds exert their anti-amyloidogenic effects by altering HEWL conformations characterized by reduction in the beta sheet content and decrease in exposed hydrophobic surfaces. The altered conformation seems to have lesser amyloidogenic propensity leading to inhibition as well as disaggregation of amyloids.

Parkinson's disease (PD) is a progressive movement disorder resulting primarily from loss of nigrostriatal dopaminergic neurons. PD is characterized by the accumulation of protein aggregates, and evidence suggests that aberrant protein deposition in dopaminergic neurons could be related to the dysre …

Lafora disease (LD) is one of the progressive and fatal forms of a neurodegenerative disorder and is characterized by teenage-onset myoclonic seizures. Neuropathological changes in LD include the formation of abnormal glycogen as Lafora bodies, gliosis, and neuroinflammation. LD is caused by defects in the gene coding for phosphatase (laforin) or ubiquitin ligase (malin). Mouse models of LD, developed by targeted disruption of these two genes, develop most symptoms of LD and show increased susceptibility to induced seizures. Studies on mouse models also suggest that defective autophagy might contribute to LD etiology. In an attempt to understand the specific role of autophagy in LD pathogenesis, in this study, we fed LD animals with trehalose, an inducer of autophagy, for 3 months and looked at its effect on the neuropathology and seizure susceptibility. We demonstrate here that trehalose ameliorates gliosis, neuroinflammation, and endoplasmic reticulum stress and reduces susceptibility to induced seizures in LD animals. However, trehalose did not affect the formation of Lafora bodies, suggesting the epileptic phenotype in LD could be either secondary to or independent of Lafora bodies. Taken together, our results suggest that autophagy inducers can be considered as potential therapeutic molecules for Lafora disease.

Oxidative stress-related apoptosis and autophagy play crucial roles in the development of osteoarthritis (OA), a progressive cartilage degenerative disease with multifactorial etiologies. Here, we determined autophagic flux changes and apoptosis in human OA and tert-Butyl hydroperoxide (TBHP)-treate …

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA+ myofibroblasts that was reduced by trehalose. The number of Wt1+ α-SMA+ cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA+ myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1+ α-SMA+ cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα1 mRNA expression induced by TGF-β1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.

(2017). Trehalose as antifungal target: The picture is still incomplete. Virulence: Vol. 8, New Antifungal Compounds, pp. 237-238.

Fucoidan, a sulfated polysaccharide present in marine brown seaweed, has been demonstrated to inhibit in vivo and in vitro growth of cells. The present study was conducted in HT‑29 human colon cancer cells cultured at a high density, and examined the potential underlying mechanisms by which fucoidan exerts its anti‑proliferative effects, which remain poorly understood. Fucoidan treatment of high‑density HT‑29 cells resulted in the inhibition of cell growth and increased apoptotic cell death. Flow cytometric analysis revealed that fucoidan treatment led to sub‑G1 phase cell cycle arrest. This was associated with decreased protein expression levels of Retinoblastoma protein and E2 factor protein. In conclusion, the results of the present study demonstrated that fucoidan possesses anticancer activity against high density HT‑29 cells by inhibiting cell growth and cell cycle progression.

The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, …

Background/Aim: Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. Materials and Methods: DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. Results: The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Conclusion: Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo.

Sulfated polysaccharides and their lower molecular weight oligosaccharide derivatives from marine macroalgae have been shown to possess a variety of biological activities. The present paper will review the recent progress in research on the structural ...

Trehalose, a non-reducing disaccharide, induces autophagy. Trehalose mitigates insulin resistance and adipocyte hypertrophy in obese mice; however, it…

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This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition …