Polyphenols and Their Effects on Muscle Atrophy and Muscle Health

Skeletal muscle atrophy is the decrease in muscle mass and strength caused by reduced protein synthesis/accelerated protein degradation. Various conditions, such as denervation, disuse, aging, chronic diseases, heart disease, obstructive lung disease, diabetes, renal failure, AIDS, sepsis, cancer, and steroidal medications, can cause muscle atrophy. Mechanistically, inflammation, oxidative stress, and mitochondrial dysfunction are among the major contributors to muscle atrophy, by modulating signaling pathways that regulate muscle homeostasis. To prevent muscle catabolism and enhance muscle anabolism, several natural and synthetic compounds have been investigated. Recently, polyphenols (i.e., natural phytochemicals) have received extensive attention regarding their effect on muscle atrophy because of their potent antioxidant and anti-inflammatory properties. Numerous in vitro and in vivo studies have reported polyphenols as strongly effective bioactive molecules that attenuate muscle atrophy and enhance muscle health. This review describes polyphenols as promising bioactive molecules that impede muscle atrophy induced by various proatrophic factors. The effects of each class/subclass of polyphenolic compounds regarding protection against the muscle disorders induced by various pathological/physiological factors are summarized in tabular form and discussed. Although considerable variations in antiatrophic potencies and mechanisms were observed among structurally diverse polyphenolic compounds, they are vital factors to be considered in muscle atrophy prevention strategies.     

Anthocyanins from Aristotelia chilensis Prevent Olanzapine-Induced Hepatic-Lipid Accumulation but Not Insulin Resistance in Skeletal Muscle Cells

Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 μg/mL or DS 50 μg/mL plus olanzapine 50 μg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.     

Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion‐Targeted Platinum(II) Complex

Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium‐modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin‐insensitive human ovarian cancer cells in a caspase‐3‐independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.     

Cranberry: Chemical Composition,Antioxidant Activity and Impact on Human Health: Overview

Cranberries are a rich source of bioactive compounds that comprise a healthy diet. Cranberry is abundant in nutritional components and many bioactive compounds that have antioxidant properties. Both American (Vaccinium macrocarpon) and European (Vaccinium oxycoccus) cranberry species are rich in polyphenols such as phenolic acids, anthocyanins and flavonoids, and is one of the few fruits that is high in proanthocyanidins, which is linked to many health benefits. The review systematizes information on the chemical composition of cranberry, its antioxidant effect, and the beneficial impact on human health and disease prevention after cranberry consumption, and in particular, its effect against urinary tract inflammation with both adults and children, cardiovascular, oncology diseases, type 2 diabetes, metabolic syndrome, obesity, tooth decay and periodontitis, Helicobacter pylori bacteria in the stomach and other diseases. Additional research needs to study cranberry proteomics profiling, polyphenols interaction and synergism with other biologically active compounds from natural ingredients and what is important in formulation of new functional foods and supplements.     

Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer †

Ovarian cancer is the most lethal gynecologic malignancy with a stubborn mortality rate of ~65%. The persistent failure of multiline chemotherapy, and significant tumor heterogeneity, has made it challenging to improve outcomes. A target of increasing interest is the mitochondrion because of its essential role in critical cellular functions, and the significance of metabolic adaptation in chemoresistance. This review describes mitochondrial processes, including metabolic reprogramming, mitochondrial transfer and mitochondrial dynamics in ovarian cancer progression and chemoresistance. The effect of malignant ascites, or excess peritoneal fluid, on mitochondrial function is discussed. The role of photodynamic therapy (PDT) in overcoming mitochondria-mediated resistance is presented. PDT, a photochemistry-based modality, involves the light-based activation of a photosensitizer leading to the production of short-lived reactive molecular species and spatiotemporally confined photodamage to nearby organelles and biological targets. The consequential effects range from subcytotoxic priming of target cells for increased sensitivity to subsequent treatments, such as chemotherapy, to direct cell killing. This review discusses how PDT-based approaches can address key limitations of current treatments. Specifically, an overview of the mechanisms by which PDT alters mitochondrial function, and a summary of preclinical advancements and clinical PDT experience in ovarian cancer are provided.     

Cherry antioxidants: from farm to table

The dietary consumption of fruits and vegetables is associated with a lower incidence of degenerative diseases such as cardiovascular disease and certain types of cancers. Most recent interest has focused on the bioactive phenolic compounds found in vegetable products. Sweet and sour cherries contain several antioxidants and polyphenols that possess many biological activities, such as antioxidant, anticancer and anti-inflammation properties. The review describes the effect of environment and other factors (such as production, handling and storage) on the nutritional properties of cherries, with particular attention to polyphenol compounds. Moreover the health benefits of cherries and their polyphenols against human diseases such as heart disease, cancers, diabetes are reviewed.     

Polyphenols and Visual Health: Potential Effects on Degenerative Retinal Diseases

Dietary polyphenols are a group of natural compounds that have been proposed to have beneficial effects on human health. They were first known for their antioxidant properties, but several studies over the years have shown that these compounds can exert protective effects against chronic diseases. Nonetheless, the mechanisms underlying these potential benefits are still uncertain and contradictory effects have been reported. In this review, we analyze the potential effects of polyphenol compounds on some visual diseases, with a special focus on retinal degenerative diseases. Current effective therapies for the treatment of such retinal diseases are lacking and new strategies need to be developed. For this reason, there is currently a renewed interest in finding novel ligands (or known ligands with previously unexpected features) that could bind to retinal photoreceptors and modulate their molecular properties. Some polyphenols, especially flavonoids (e.g., quercetin and tannic acid), could attenuate light-induced receptor damage and promote visual health benefits. Recent evidence suggests that certain flavonoids could help stabilize the correctly folded conformation of the visual photoreceptor protein rhodopsin and offset the deleterious effect of retinitis pigmentosa mutations. In this regard, certain polyphenols, like the flavonoids mentioned before, have been shown to improve the stability, expression, regeneration and folding of rhodopsin mutants in experimental in vitro studies. Moreover, these compounds appear to improve the integration of the receptor into the cell membrane while acting against oxidative stress at the same time. We anticipate that polyphenol compounds can be used to target visual photoreceptor proteins, such as rhodopsin, in a way that has only been recently proposed and that these can be used in novel approaches for the treatment of retinal degenerative diseases like retinitis pigmentosa; however, studies in this field are limited and further research is needed in order to properly characterize the effects of these compounds on retinal degenerative diseases through the proposed mechanisms.     

Dietary Polyphenols: Extraction,Identification, Bioavailability,and Role for Prevention and Treatment of Colorectal and Prostate Cancers

Fruits, vegetables, and other edible plants in our diet have numerous health benefits, due to the bioactive compounds in these food items, including polyphenols. These plants are a rich and promising source of natural products and phytochemicals that can be used to treat and prevent numerous diseases and prevent the progression of cancer. Dietary polyphenols exhibit chemo-preventive and therapeutic effects against various ailments, including several types of cancer. The current study focuses on polyphenol’s traditional and advanced extraction methods, with supercritical extraction as a novel approach. It also deals with their identification, bioavailability, and role in preventing and treating colorectal and prostate cancers. Additionally, the article covers the literature that deals with the anticancer activities of polyphenols, as well as their potential use as anticancer agents.     

Histone deacetylase (HDAC) inhibitor curcumin upregulates mitochondrial uncoupling protein1 (UCP1) and mitochondrial function in brown adipocytes,in-silico study and screening natural drug library

Mitochondrial dysfunction has been associated with diverse pathological conditions globally. Specifically, in adipose tissues, mitochondrial dysfunction is the primary cause of obesity and obesity-related illnesses. An existing drugs such as atorvastatin and other lipid-lowering drugs demonstrated adverse effects and initiated other diseases. Thus, we need to explore new methods to prevent and treat obesity. In this study, we used the cell screening method to identify several natural compounds that increase adipocyte UCP1 gene expression. The identified drug Curcumin was evaluated in cell models and the In-silico model. We found curcumin is an active compound of turmeric belonging to Zingiberaceae (ginger family), which activates the Nrf2 mechanism. Curcumin potentially endorses the expression of UCP1 in the brown adipocyte in vitro cellular model. Curcumin plays an important role that modulating mitochondrial function and improving mitochondrial DNA quantification, ATP production, and cell viability. We have established an efficient in vitro cell experiment system to study the metabolic regulation of UCP1. The in-silico model revealed curcumin-UCP1 interaction. Curcumin, via enhancing mitochondrial activity, could be a helpful therapeutic molecule against metabolic disorders or obesity-related diseases. Curcumin will be the subject of more research in both human and murine models, which will provide novel therapeutic pathways for the treatment of metabolic illnesses by modulating the control of mitochondrial function.     

Dinitroso and polynitroso compounds

The growing interest in the chemistry of C-nitroso compounds (RN=O; R = alkyl or aryl group) is due in part to the recognition of their participation in various metabolic processes of nitrogen-containing compounds. C-Nitroso compounds have a rich organic chemistry in their own right, displaying interesting intra- and intermolecular dimerization processes and addition reactions with unsaturated compounds. In addition, they have a fascinating coordination chemistry. While most of the attention has been directed towards C-nitroso compounds containing a single -NO moiety, there is an emerging area of research dealing with dinitroso and polynitroso compounds. In this critical review, we present and discuss the synthetic routes and properties of these relatively unexplored dinitroso and polynitroso compounds, and suggest areas of further development involving these compounds. (126 references.).     

Caffeoylquinic Acid Derivatives of Purple Sweet Potato as Modulators of Mitochondrial Function in Mouse Primary Hepatocytes

Owing to their antioxidant properties, caffeoylquinic acid (CQA)-derivatives could potentially improve the impaired metabolism in hepatic cells, however, their effect on mitochondrial function has not been demonstrated yet. Here, we evaluated the impact of three CQA-derivatives extracted from purple sweet potato, namely 5-CQA, 3,4- and 4,5-diCQA, on mitochondrial activity in primary hepatocytes using an extracellular flux analyzer. Notably, an increase of maximal respiration and spare respiratory capacity were observed when 5-CQA and 3,4-diCQA were added to the system indicating the improved mitochondrial function. Moreover, 3,4-diCQA was shown to considerably increase glycolytic reserve which is a measure of cell capability to respond to an energy demand through glycolysis. Conversely, 4,5-diCQA did not modify mitochondrial activity but increased glycolysis at low concentration in primary hepatocytes. All compounds tested improved cellular capacity to oxidize fatty acids. Overall, our results demonstrated the potential of test CQA-derivatives to modify mitochondrial function in hepatic cells. It is especially relevant in case of dysfunctional mitochondria in hepatocytes linked to hepatic steatosis during obesity, diabetes, and metabolic syndrome.     

Flavonoids in Treatment of Chronic Kidney Disease

Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.     

Could Polyphenols Really Be a Good Radioprotective Strategy?

Currently, radiotherapy is one of the most effective strategies to treat cancer. However, deleterious toxicity against normal cells indicate for the need to selectively protect them. Reactive oxygen and nitrogen species reinforce ionizing radiation cytotoxicity, and compounds able to scavenge these species or enhance antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) should be properly investigated. Antioxidant plant-derived compounds, such as phenols and polyphenols, could represent a valuable alternative to synthetic compounds to be used as radio-protective agents. In fact, their dose-dependent antioxidant/pro-oxidant efficacy could provide a high degree of protection to normal tissues, with little or no protection to tumor cells. The present review provides an update of the current scientific knowledge of polyphenols in pure forms or in plant extracts with good evidence concerning their possible radiomodulating action. Indeed, with few exceptions, to date, the fragmentary data available mostly derive from in vitro studies, which do not find comfort in preclinical and/or clinical studies. On the contrary, when preclinical studies are reported, especially regarding the bioactivity of a plant extract, its chemical composition is not taken into account, avoiding any standardization and compromising data reproducibility.     

Glycyrrhizin (Glycyrrhizic Acid) HMGB1 (high mobility group box 1) inhibitor upregulate mitochondrial function in adipocyte,cell viability and in-silico study

BackgroundMitochondrial plays a vital role in regulating obesity and related comorbidity. Targeting mitochondrial function could be a potent therapeutic approach to inhibit metabolic-related diseases like obesity, liver disease. Prolonged use of existing drug moieties demonstrated severe adverse effects.MethodsWe apply Ucp1-A-GFP immortalized reporter cell lines and HEK293T cell lines to evaluate cell viability, mitochondrial ATP production, and the in-silico model.ResultsWe found Glycyrrhizin, an HMGB1 (high mobility group box 1) inhibitor, plays a significant role in modulating mitochondrial function against obesity. At the cellular level, the adipocytes treated with Glycyrrhizin have increased mitochondrial function. Further analysis shows that compared with the control group, the cells in the treatment group contain more mitochondria. Glycyrrhizin demonstrated a nontoxic effect on the HEK293T cell line, upregulating mitochondrial DNA and reducing mitochondrial ATP production levels. In-silico study exhibited drug-protein interaction and binding side with UCP1.ConclusionGlycyrrhizin improves mitochondrial function that would be an effective drug candidate to treat metabolic diseases and obesity-related diseases. Further investigation will require both the human and animal models to reveal new insight into the mechanism against obesity, metabolic diseases or mitochondrial dysfunction-related diseases.     

Rooibos Flavonoids,Aspalathin, Isoorientin,and Orientin Ameliorate Antimycin A-Induced Mitochondrial Dysfunction by Improving Mitochondrial Bioenergetics in Cultured Skeletal Muscle Cells

The current study investigated the physiological effects of flavonoids found in daily consumed rooibos tea, aspalathin, isoorientin, and orientin on improving processes involved in mitochondrial function in C2C12 myotubes. To achieve this, C2C12 myotubes were exposed to a mitochondrial channel blocker, antimycin A (6.25 µM), for 12 h to induce mitochondrial dysfunction. Thereafter, cells were treated with aspalathin, isoorientin, and orientin (10 µM) for 4 h, while metformin (1 µM) and insulin (1 µM) were used as comparators. Relevant bioassays and real-time PCR were conducted to assess the impact of treatment compounds on some markers of mitochondrial function. Our results showed that antimycin A induced alterations in the mitochondrial respiration process and mRNA levels of genes involved in energy production. In fact, aspalathin, isoorientin, and orientin reversed such effects leading to the reduced production of intracellular reactive oxygen species. These flavonoids further enhanced the expression of genes involved in mitochondrial function, such as Ucp 2, Complex 1/3, Sirt 1, Nrf 1, and Tfam. Overall, the current study showed that dietary flavonoids, aspalathin, isoorientin, and orientin, have the potential to be as effective as established pharmacological drugs such as metformin and insulin in protecting against mitochondrial dysfunction in a preclinical setting; however, such information should be confirmed in well-established in vivo disease models.     

Wafer-scale mitochondrial membrane potential assays

It has been reported that mitochondrial metabolic and biophysical parameters are associated with degenerative diseases and the aging process. To evaluate these biochemical parameters, current technology requires several hundred milligrams of isolated mitochondria for functional assays. Here, we demonstrate manufacturable wafer-scale mitochondrial functional assay lab-on-a-chip devices, which require mitochondrial protein quantities three orders of magnitude less than current assays, integrated onto 4' standard silicon wafer with new fabrication processes and materials. Membrane potential changes of isolated mitochondria from various well-established cell lines such as human HeLa cell line (Heb7A), human osteosarcoma cell line (143b) and mouse skeletal muscle tissue were investigated and compared. This second generation integrated lab-on-a-chip system developed here shows enhanced structural durability and reproducibility while increasing the sensitivity to changes in mitochondrial membrane potential by an order of magnitude as compared to first generation technologies. We envision this system to be a great candidate to substitute current mitochondrial assay systems.     

Polyphenols Extracted from Shanxi-Aged Vinegar Inhibit Inflammation in LPS-Induced RAW264.7 Macrophages and ICR Mice via the Suppression of MAPK/NF-κB Pathway Activation

Shanxi-aged vinegar, a traditional Chinese grain-fermented food that is rich in polyphenols, has been shown to have therapeutic effects on a variety of diseases. However, there has been no comprehensive evaluation of the anti-inflammatory activity of polyphenols extracted from Shanxi-aged vinegar (SAVEP) to date. The anti-inflammatory activities of SAVEP, both in RAW 264.7 macrophages and mice, were extensively investigated for the potential application of SAVEP as a novel anti-inflammatory agent. In order to confirm the notion that polyphenols could improve inflammatory symptoms, SAVEP was firstly detected by gas chromatography mass spectrometry (GC-MS). In total, 19 polyphenols were detected, including 12 phenolic acids. The study further investigated the protective effect of SAVEP on lipopolysaccharide-induced inflammation in RAW264.7 macrophages and ICR mice. The results showed that compared with those of the model group, SAVEP could remarkably recover the inflammation of macrophage RAW264.7 and ICR mice. SAVEP can normalise the expression of related proteins via the suppression of MAPK/NF-κB pathway activation, inhibiting the expression of iNOS and COX-2 proteins, and consequently the production of inflammatory factors, thus alleviating inflammatory stress. These results suggest that SAVEP may have a potential function against inflammation.