Metabolic syndrome has increased at a worrisome level. Lifestyle changes are not sufficient to prevent and improve the adverse effects of obesity, thus novel interventions are necessary. The aim of ...this study was to investigate the use and metabolic outcomes of a non-pharmacological intervention in a high-fat diet (HFD) fed mouse model, capable of recapitulating key aspects of metabolic syndrome. We show that Policaptil Gel Retard has remarkable, beneficial effects on metabolic dysfunction caused by consumption of HFD. We describe the mechanism by which such effects are obtained, highlighting the fact that the amelioration of metabolic function observed upon Policaptil Gel Retard administration is profound and of systemic nature, despite being originated by sequestering, therefore non-pharmacological events elicited in the gut lumen.
Current pharmacological therapies for the management of chronic articular diseases are far from being satisfactory, so new strategies need to be investigated. We tested the intra-articular pain ...relieving properties of a system of molecules from a characterized
extract (14G1862) in a rat model of osteoarthritis induced by monoiodoacetate (MIA). 14G1862 (0.2-2 mg mL
) was intra-articularly (i.a.) injected 7 days after MIA, behavioural and histological evaluations were performed 14, 30 and 60 days after treatments. Moreover, the effect of 14G1862 on nitrate production and iNOS expression in RAW 264.7 macrophages stimulated with LPS was assessed.
, 14G1862 treatment attenuated LPS-induced NO production and iNOS expression in a comparable manner to celecoxib.
, 14G1862 significantly reduced mechanical allodynia and hyperalgesia, spontaneous pain and motor alterations starting on day 14 up to day 60. The efficacy was higher or comparable to that evoked by triamcinolone acetonide (100 μg i.a.) used as reference drug. Histological evaluation highlighted the improvement of several morphological parameters in MIA + 14G1862-treated animals with particularly benefic effects on joint space and fibrin deposition. In conclusion, i.a. treatment with
is a candidate to be a novel effective approach for osteoarthritis therapy.
The evolution of medical devices has led to the introduction of medical devices that include "substances" and which, due to their presentation and sites of application may resemble medicinal ...products. The difference between substance-based medical devices and medicinal products lies in the proper definition of the principal mechanism of action. The major problem at the moment is the lack of a proper procedure for the demonstration of a mechanism that is "not pharmacological, immunological or metabolic." We aimed to design an experimental set up to demonstrate the difference between the mechanism of action of two substances used commonly for the treatment of constipation, lubiprostone (example of medicinal product) and glycerine (example of medical device). By implementing cellular models and molecular analyses we demonstrate the difference in their mechanism of action. This set up can be considered an example on the possibility to define a paradigm for the case by case study of the mechanism of action of substances and combination of substances in medical devices.
Wheat germ oil (WGO) is rich in α-tocopherol (vitamin E, VE), a vitamin that has long been suggested to exert hepatoprotective effects. In this study, this function of WGO-VE and its transcriptomics ...fingerprint were investigated in comparison with RRR−α-tocopherol and all-rac-α-tocopherol (nVE and sVE, respectively), in human liver cells treated with oleic acid (OA) to develop steatosis and lipotoxicity. Used in chemoprevention mode, all the VE formulations afforded significant reduction of the OA-induced steatosis and its consequent impact on lipotoxicity indicators, including ROS production and efflux (as H2O2), and apoptotic and necrotic cell death. A trend toward a better control of lipotoxicity was observed for WGO-VE and nVE compared to sVE.
Gene microarray data demonstrated that these effects of VE formulations were associated with significantly different responses of the cellular transcriptome to compensate for the modifications of OA treatment, including the downregulation of cellular homeostasis genes and the induction of genes associated with defects of liver cell metabolism, fibrosis and inflammation, liver disease and cancer. Ingenuity Pathway Analysis data showed that WGO-VE modulated genes associated with liver carcinogenesis and steatosis, whereas nVE modulated genes involved in liver cell metabolism and viability biofunctions; sVE did not significantly modulate any gene dataset relevant to such biofunctions.
In conclusion, WGO-VE prevents lipotoxicity in human liver cells modulating genes that differ from those affected by the natural or synthetic forms of pure VE. These differences can be captured by precision nutrition tools, reflecting the molecular complexity of this VE-rich extract and its potential in preventing specific cues of hepatocellular lipotoxicity.
Vitamin E; Alpha-tocopherol; Wheat germ oil; Lipotoxicity; NAFLD; NASH; Transcriptomics; Liver; Nutrigenomics; Human hepatocytes; Reactive oxygen species; Precision nutrition.
Vitamin D (VD) has been used to prevent nonalcoholic fatty liver disease (NAFLD), a condition of lipotoxicity associated with a defective metabolism and function of this vitamin. Different forms of ...VD are available and can be used for this scope, but their effects on liver cell lipotoxicity remain unexplored. In this study we compared a natural formulation rich in VD2 (Shiitake Mushroom extract or SM-VD2) with a synthetic formulation containing pure VD3 (SV-VD3) and the bioactive metabolite 1,25(OH)2-D3. These were investigated in chemoprevention mode in human HepaRG liver cells supplemented with oleic and palmitic acid to induce lipotoxicity. All the different forms of VD showed similar efficacy in reducing the levels of lipotoxicity and the changes that lipotoxicity induced on the cellular transcriptome. However, the three forms of VD generated different gene fingerprints suggesting diverse, even if functionally convergent, cytoprotective mechanisms. Main differences were (1) the number of differentially expressed genes (SV-VD3 > 1,25OH2-D3 > SM-VD2), (2) their identity that demonstrated significant gene homology between SM-VD2 and 1,25(OH)2-D3, and (3) the number and type of biological functions identified by ingenuity pathway analysis as relevant to liver metabolism and cytoprotection annotations. Immunoblot confirmed a different response of VDR and other VDR-related proteins to natural and synthetic VD formulations, including FXR, PXR, PPARγ/PGC-1α, and CYP3A4 and CYP24A1. In conclusion, different responses of the cellular transcriptome drive the cytoprotective effect of natural and synthetic formulations of VD in the free fatty acid-induced lipotoxicity of human hepatocytes.
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Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to ...the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1‐G93A co‐cultures. Deleting TNFR2 from SOD1‐G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1‐G93A/TNFR2−/− mice showed high phospho‐TAR DNA‐binding protein 43 (TDP‐43) accumulation and low levels of acetyl‐tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane‐bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.
We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co‐cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1‐G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi‐intervention therapies.
We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co‐cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1‐G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi‐intervention therapies.
Cover Image for this issue: doi: 10.1111/jnc.12905.
•56 °C hyperthermia of TRAMP-C2 tumour cells (56°T-C2) induces DAMP secretion.•Preventive vaccination with 56°T-C2-pulsed DCs improves tumour protection.•Only docetaxel plus 56°T-C2-pulsed DCs ...therapeutic vaccination delays tumour growth.
Most active cancer immunotherapies able to induce a long-lasting protection against tumours are based on the activation of tumour-specific cytotoxic T lymphocytes (CTLs). Cell death by hyperthermia induces apoptosis followed by secondary necrosis, with the production of factors named “danger associated molecular pattern” (DAMP) molecules (DAMPs), that activate dendritic cells (DCs) to perform antigen uptake, processing and presentation, followed by CTLs cross priming. In many published studies, hyperthermia treatment of tumour cells is performed at 42–45 °C; these temperatures mainly promote cell surface expression of DAMPs. Treatment at 56 °C of tumour cells was shown to induce DAMPs secretion rather than their cell surface expression, improving DC activation and CTL cross priming in vitro.
Thus we tested the relevance of this finding in vivo on the generation of a tumour-specific memory immune response, in the TRAMP-C2 mouse prostate carcinoma transplantable model. TRAMP-C2 tumour cells treated at 56 °C were able not only to activate DCs in vitro but also to trigger a tumour-specific CTL-dependent immune response in vivo. Prophylactic vaccination with 56 °C-treated TRAMP-C2 tumour cells alone provided protection against TRAMP-C2 tumour growth in vivo, whilst in the therapeutic regimen, control of tumour growth was achieved combining immunization with adjuvant chemotherapy.
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