The past decade has been marked by an intense scientific interest in the use of compounds or micronutrients of natural origin and their potential effects on human health, both from researchers and ...industry ....
Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current ...knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle-thus forcing them to evolve towards a process of cell death-and accumulating cancer cells in a phase of the cell cycle-thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways.
Significant evidence from epidemiological investigations showed that dietary polyphenols might manage and prevent type 2 diabetes (T2D). This review summarizes human studies and clinical trials of ...polyphenols as anti-diabetic agents. Polyphenols from coffee, guava tea, whortleberry, olive oil, propolis, chocolate, red wine, grape seed, and cocoa have been reported to show anti-diabetic effects in T2D patients through increasing glucose metabolism, improving vascular function as well as reducing insulin resistance and HbA1c level. However, individual flavonoid or isoflavonoid compounds appear to have no therapeutic effect on diabetes, based on the limited clinical data. Preliminary clinical trials provided evidence that resveratrol had anti-diabetic activity in humans by improving glycemic control in subjects with insulin resistance. Besides, anthocyanins exhibited anti-diabetic properties by reducing blood glucose and HbA1c levels or the improvement of insulin secretion and resistance. The structure-activity relationship of polyphenols as anti-diabetic agents in humans has been rarely reported.
Eye diseases are currently a major public health concern due to the growing number of cases resulting from both an aging of populations and exogenous factors linked to our lifestyles. Thus, many ...treatments including surgical pharmacological approaches have emerged, and special attention has been paid to prevention, where diet plays a preponderant role. Recently, potential antioxidants such as resveratrol have received much attention as potential tools against various ocular diseases. In this review, we focus on the mechanisms of resveratrol against ocular diseases, in particular age-related macular degeneration, glaucoma, cataract, diabetic retinopathy, and vitreoretinopathy. We analyze, in relation to the different steps of each disease, the resveratrol properties at multiple levels, such as cellular and molecular signaling as well as physiological effects. We show and discuss the relationship to reactive oxygen species, the regulation of inflammatory process, and how resveratrol can prevent ocular diseases through a potential epigenetic action by the activation of sirtuin-1. Lastly, various new forms of resveratrol delivery are emerging at the same time as some clinical trials are raising more questions about the future of resveratrol as a potential tool for prevention or in therapeutic strategies against ocular diseases. More preclinical studies are required to provide further insights into RSV's potential adjuvant activity.
Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under ...chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8
T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
In recent years, a particular interest has focused on the accumulation of fatty acids with very long chains (VLCFA) in the occurrence of neurodegenerative diseases such as Alzheimer's disease, ...multiple sclerosis or dementia. Indeed, it seems increasingly clear that this accumulation of VLCFA in the central nervous system is accompanied by a progressive demyelination resulting in death of neuronal cells. Nevertheless, molecular mechanisms by which VLCFA result in toxicity remain unclear. This study highlights for the first time in 3 different cellular models (oligodendrocytes 158 N, primary mouse brain culture, and patient fibroblasts) the types of cell death involved where VLCFA-induced ROS production leads to autophagy. The autophagic process protects the cell from this VLCFA-induced toxicity. Thus, autophagy in addition to oxidative stress can offer new therapeutic approaches.
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•VLCFA induce cell death, whose early events are not associated with apoptosis/necrosis.•VLCFA induce reactive oxygen species production and activation of antioxidant defences.•Changes in relocation and aggregation of lysosomes with VLCFA treatment.•Autophagy protect against toxicities induced by VLCFA.•DHA counteract VLCFA-induced toxicity.
Abstract Purpose Recent studies have shown an increased incidence of congenital hypothyroidism over the past 2 or 3 decades. The etiology of this change is unknown, but it has been related by several ...authors to lowering of cutoffs. We sought to determine whether the incidence of congenital hypothyroidism (CH) in France has changed. Methods We analyzed data from the nationwide neonatal screening program for CH during the period 1982–2012. We included all children having thyroid-stimulating hormone values above the threshold and for whom diagnosis of CH confirmed by the pediatrician. We estimated multicentric temporal trends in the annual incidence rates adjusted for screening methods for thyroid dysgenesis and eutopic gland. Results We found 6622 cases of CH (28.0 per 100,000 newborns); 1895 had a eutopic gland, and 4727 had thyroid dysgenesis. The incidence of eutopic glands showed a significant annual average increase of (5.1%; 95% confidence interval: 4.3–5.9) regardless of the screening method or screening center. This increase was confirmed in severe cases (thyroid-stimulating hormone ≥50: 2.1%; 95% confidence interval, 1.4–2.9). The incidence of dysgenesis remained constant. Conclusions The incidence of eutopic glands increased in France, not only in mild forms but also in severe cases.
The human gastrointestinal tract is inhabited by a vast number of microorganisms that are called as the microbiota. Each individual harbors a unique gut microbial composition, this composition ...evolves throughout the host's lifetime and it is easily affected by internal or external changes. It has been shown that gut microbiota plays a crucial role in host's health and as this complex community has the ability to interact with each other and with the host's immune system, the presence or absence of some major species can affect the homeostasis. Diet can be considered as one of the pivotal factors in modulating the functionality, integrity, and composition of the gut microbiota as the gastrointestinal tract is the first organ exposed to components of the diet. In this review, we have focused on the effects of polyphenols, key compounds of a healthy diet with several biological activities, on the gut microbial composition, their biotransformation by the gut microbiota, and the effect of their reciprocal interactions in human health and disease.
Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ...ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of “responders” (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies.
Numerous studies have reported interesting properties of trans‐resveratrol, a phytoalexin, as a preventive agent of several important pathologies: vascular diseases, cancers, viral infections, and ...neurodegenerative processes. These beneficial effects of resveratrol have been supported by observations at the cellular and molecular levels in both cellular and in vivo models, but the cellular fate of resveratrol remains unclear. We suggest here that resveratrol uptake, metabolism, and stability of the parent molecule could influence the biological effects of resveratrol. It appears that resveratrol stability involves redox reactions and biotransformation that influence its antioxidant properties. Resveratrol's pharmacokinetics and metabolism represent other important issues, notably, the putative effects of its metabolites on pathology models. For example, some metabolites, mainly sulfate‐conjugated resveratrol, show biological effects in cellular models. The modifications of resveratrol stability, chemical structure, and metabolism could change its cellular and molecular targets and could be crucial for improving or decreasing its chemopreventive properties.
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