Sulforaphane Exposure Prevents Cadmium-Induced Toxicity and Mitochondrial Dysfunction in the Nematode Caenorhabditis elegans by Regulating the Insulin/Insulin-like Growth Factor Signaling (IIS) Pathway.

Cadmium (Cd) is a heavy metal that is highly toxic to humans and animals. Its adverse effects have been widely associated with mitochondrial alterations. However, there are not many treatments that target mitochondria. This study aimed to evaluate the impact of sulforaphane (SFN) pre-exposure against cadmium chloride (CdCl2)-induced toxicity and mitochondrial alterations in the nematode Caenorhabditis elegans (C. elegans), by exploring the role of the insulin/insulin-like growth factor signaling pathway (IIS). The results revealed that prior exposure to SFN protected against CdCl2-induced mortality and increased lifespan, body length, and mobility while reducing lipofuscin levels. Furthermore, SFN prevented mitochondrial alterations by increasing mitochondrial membrane potential (Δψm) and restoring mitochondrial oxygen consumption rate, thereby decreasing mitochondrial reactive oxygen species (ROS) production. The improvement in mitochondrial function was associated with increased mitochondrial mass and the involvement of the daf-16 and skn-1c genes of the IIS signaling pathway. In conclusion, exposure to SFN before exposure to CdCl2 mitigates toxic effects and mitochondrial alterations, possibly by increasing mitochondrial mass, which may be related to the regulation of the IIS pathway. These discoveries open new possibilities for developing therapies to reduce the damage caused by Cd toxicity and oxidative stress in biological systems, highlighting antioxidants with mitochondrial action as promising tools.

Protective Effect of Curcumin on D-Galactose-Induced Senescence and Oxidative Stress in LLC-PK1 and HK-2 Cells.

D-galactose has been widely used as an inducer of cellular senescence and pathophysiological processes related to aging because it induces oxidative stress. On the other hand, the consumption of antioxidants such as curcumin can be an effective strategy to prevent phenotypes related to the enhanced production of reactive oxygen species (ROS), such as aging and senescence. This study aimed to evaluate the potential protective effect of curcumin on senescence and oxidative stress and endoplasmic reticulum stress induced by D-galactose treatment in Lilly Laboratories Culture-Porcine Kidney 1 (LLC-PK1) and human kidney 2 (HK-2) proximal tubule cell lines from pig and human, respectively. For senescence induction, cells were treated with 300 mM D-galactose for 120 h and, to evaluate the protective effect of the antioxidant, cells were treated with 5 µM curcumin for 24 h and subsequently treated with curcumin + D-galactose for 120 h. In LLC-PK1 cells, curcumin treatment decreased by 20% the number of cells positive for senescence-associated (SA)-ß-D-galactosidase staining and by 25% the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and increased by 40% lamin B1 expression. In HK-2 cells, curcumin treatment increased by 60% the expression of proliferating cell nuclear antigen (PCNA, 50% Klotho levels, and 175% catalase activity. In both cell lines, this antioxidant decreased the production of ROS (20% decrease for LLC-PK1 and 10 to 20% for HK-2). These data suggest that curcumin treatment has a moderate protective effect on D-galactose-induced senescence in LLC-PK1 and HK-2 cells.

Effects of Vegetal Extracts and Metabolites against Oxidative Stress and Associated Diseases: Studies in Caenorhabditis elegans.

Oxidative stress is a natural physiological process where the levels of oxidants, such as reactive oxygen species (ROS) and nitrogen (RNS), exceed the strategy of antioxidant defenses, culminating in the interruption of redox signaling and control. Oxidative stress is associated with multiple pathologies, including premature aging, neurodegenerative diseases, obesity, diabetes, atherosclerosis, and arthritis. It is not yet clear whether oxidative stress is the cause or consequence of these diseases; however, it has been shown that using compounds with antioxidant properties, particularly compounds of natural origin, could prevent or slow down the progress of different pathologies. Within this context, the Caenorhabditis elegans (C. elegans) model has served to study the effect of different metabolites and natural compounds, which has helped to decipher molecular targets and the effect of these compounds on premature aging and some diseases such as neurodegenerative diseases and dyslipidemia. This article lists the studies carried out on C. elegans in which metabolites and natural extracts have been tested against oxidative stress and the pathologies associated with providing an overview of the discoveries in the redox area made with this nematode.

Divide et Impera: Drp1-mediated Mitochondrial Fission in Glioma Malignancy.

Mitochondria are pivotal organelles involved in vital cellular functions, including energy generation, reactive oxygen species and calcium signaling, as well as intermediate biosynthesis. They are dynamic organelles that adapt their shape, size, and distribution to changes in intracellular conditions, being able to divide, fuse, or move along the cell, processes known as mitochondrial dynamics. Mitochondrial dynamics are involved in cell division and migration, as well as maintenance of pluripotency in stem (non-differentiated) cells. Thus, its central role in carcinogenesis is not surprising. Particularly, mitochondrial dynamics have been found to be pivotal to the development of gliomas, a lethal group of tumors developed from glial cells, which are nervous system cells that provide support to neurons. Unfortunately, prognosis of glioma patients is poor, most of them do not survive more than five years after diagnosis. In this context, it is fundamental to understand the cellular mechanisms involved in this pathology, in order to develop an appropriate clinical approach. As previously mentioned, mitochondrial dynamics is central to glioma development, particularly, mitochondrial division (fission) and one of its central effectors, dynamin-related protein 1 (Drp1), have been observed to be enhanced in gliomas and involved in the maintenance of stem cells (which initiate and maintain the tumor), as well as in migration and invasiveness, being central to gliomagenesis. In this review, we discuss the findings on mitochondrial fission role in these processes, further, we analyze the potential use of Drp1 as a novel prognostic biomarker in glioma patients.

Role of food-derived antioxidants against cisplatin induced-nephrotoxicity.

Cancer is a relevant public health problem that represents the second leading cause of global death. In this regard, cisplatin is a highly effective antineoplastic drug used in treatment of several types of cancer, such as head and neck, testicular, ovarian, gastric, lung and breast cancer. Nevertheless, treatment with this compound leads to nephrotoxicity, which limits its use. Oxidative stress plays a pivotal role in cisplatin-induced renal damage and several dietary antioxidants have been reported to ameliorate this secondary effect. Relevant findings on the protective effects of these antioxidant agents in cisplatin-induced nephrotoxicity are summarized in this paper. Further, limitations of animal models used in these studies are discussed. Additionally, clinical studies on the protective effect of these antioxidants, as well as future directions for these kind of trials are also considered.

New highlights on the health-improving effects of sulforaphane.

In this paper, we review recent evidence about the beneficial effects of sulforaphane (SFN), which is the most studied member of isothiocyanates, on both in vivo and in vitro models of different diseases, mainly diabetes and cancer. The role of SFN on oxidative stress, inflammation, and metabolism is discussed, with emphasis on those nuclear factor E2-related factor 2 (Nrf2) pathway-mediated mechanisms. In the case of the anti-inflammatory effects of SFN, the point of convergence seems to be the downregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), with the consequent amelioration of other pathogenic processes such as hypertrophy and fibrosis. We emphasized that SFN shows opposite effects in normal and cancer cells at many levels; for instance, while in normal cells it has protective actions, in cancer cells it blocks the induction of factors related to the malignity of tumors, diminishes their development, and induces cell death. SFN is able to promote apoptosis in cancer cells by many mechanisms, the production of reactive oxygen species being one of the most relevant ones. Given its properties, SFN could be considered as a phytochemical at the forefront of natural medicine.

Medicinal properties of mangosteen (Garcinia mangostana L.): A comprehensive update.

Garcinia mangostana L. (Clusiaceae) is a tropical tree native to Southeast Asia known as mangosteen which fruits possess a distinctive and pleasant taste that has granted them the epithet of "queen of the fruits". The seeds and pericarps of the fruit have a long history of use in the traditional medicinal practices of the region, and beverages containing mangosteen pulp and pericarps are sold worldwide as nutritional supplements. The main phytochemicals present in the species are isoprenylated xanthones, a class of secondary metabolites with multiple reports of biological effects, such as antioxidant, pro-apoptotic, anti-proliferative, antinociceptive, anti-inflammatory, neuroprotective, hypoglycemic and anti-obesity. The diversity of actions displayed by mangosteen xanthones shows that these compounds target multiple signaling pathways involved in different pathologies, and place them as valuable sources for developing new drugs to treat chronic and degenerative diseases. This review article presents a comprehensive update of the toxicological findings on animal models, and the preclinical anticancer, analgesic, neuroprotective, antidiabetic and hypolipidemic effects of G. mangostana L. extracts and its main isolates. Pharmacokinetics, drug delivery systems and reports on dose-finding human trials are also examined.

Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity.

Context Acetaminophen (APAP), also known as paracetamol and N-acetyl p-aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. It is safe and effective at recommended doses but has the potential for causing hepatotoxicity and acute liver failure (ALF) with overdose. To solve this problem, different strategies have been developed, including the use of compounds isolated from food, which have been studied to characterize their efficacy as natural dietary antioxidants. Objective The objective of this study is to show the beneficial effects of a variety of natural compounds and their use against acetaminophen-induced hepatotoxicity. Methods PubMed database was reviewed to compile data about natural compounds with hepatoprotective effects against APAP toxicity. Results and conclusion As a result, the health-promoting properties of 13 different food-derived compounds with protective effect against APAP-induced hepatotoxicity were described as well as the mechanisms involved in hepatoprotection.

Curcumin prevents paracetamol-induced liver mitochondrial alterations.

OBJECTIVE: In the present study was evaluated if curcumin is able to attenuate paracetamol (PCM)-induced mitochondrial alterations in liver of mice. METHODS: Mice (n = 5-6/group) received curcumin (35, 50 or 100 mg/kg bw) 90 min before PCM injection (350 mg/kg bw). Plasma activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was measured; histological analyses were done; and measurement of mitochondrial oxygen consumption, mitochondrial membrane potential, ATP synthesis, aconitase activity and activity of respiratory complexes was carried out. KEY FINDINGS: Curcumin prevented in a dose-dependent manner PCM-induced liver damage. Curcumin (100 mg/kg) attenuated PCM-induced liver histological damage (damaged hepatocytes from 28.3 ± 7.7 to 8.3 ± 0.7%) and increment in plasma ALT (from 2300 ± 150 to 690 ± 28 U/l) and AST (from 1603 ± 43 to 379 ± 22 U/l) activity. Moreover, curcumin attenuated the decrease in oxygen consumption using either succinate or malate/glutamate as substrates (evaluated by state 3, respiratory control ratio, uncoupled respiration and adenosine diphosphate/oxygen ratio), in membrane potential, in ATP synthesis, in aconitase activity and in the activity of respiratory complexes I, III and IV. CONCLUSIONS: These results indicate that the protective effect of curcumin in PCM-induced hepatotoxicity is associated with attenuation of mitochondrial dysfunction.