Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts.

INTRODUCTION: Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress. AREAS COVERED: This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects. EXPERT OPINION: CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.

Antimicrobial sensitisers: Gatekeepers to avoid the development of multidrug-resistant bacteria.

The resistance of multidrug-resistant bacteria to existing antibiotics forces the continued development of new antibiotics and antibacterial agents, but the high costs and long timeframe involved in the development of new agents renders the hope that existing antibiotics may again play a part. The "antibiotic adjuvant" is an indirect antibacterial strategy, but its vague concept has, in the past, limited the development speed of related drugs. In this review article, we put forward an accurate concept of a "non-self-antimicrobial sensitisers (NSAS)", to distinguish it from an "antibiotic adjuvant", and then discuss several scientific methods to restore bacterial sensitivity to antibiotics, and the sources and action mechanism of existing NSAS, in order to guide the development and further research of NSAS.

Dopaminergic and serotoninergic systems as preferential targets of the pyrethroid tefluthrin exposure in the rat brain.

The monoaminergic systems dopamine (DA) and serotonin (5-HT) play important roles in neuromodulation, such as motor control, cognitive, affective, and neuroendocrine functions. In the present research study, we addressed the hypothesis that exposure to Type I pyrethroid tefluthrin may specifically target the dopaminergic and serotoninergic systems. Tefluthrin could modify brain monoamine neurotransmitters, DA and 5-HT levels as well as dopaminergic and serotoninergic signaling pathways. Adult male Wistar rats were treated with tefluthrin [2.2, 4.4 and 5.5 mg/kg bw, equivalent to 1/10, 1/5 and 1/4 of the acute oral rat lethal dose 50 (LD50) value] by oral gavage, six days. After last dose of tefluthrin, DA and 5-HT and metabolites levels were determined in brain regions (striatum, hippocampus, prefrontal cortex and hypothalamus). Tefluthrin induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in prefrontal cortex tissue. Here, we studied that in vivo exposure to tefluthrin may alter DA and 5-HT neurotransmission in prefrontal cortex. Transcripts related to (i) dopaminergic [dopamine transporter 1 (Dat1), tyrosine hydroxylase (TH), dopamine receptors (Drd1, Drd2)], (ii) serotoninergic [serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2), serotonin receptors (5-HT1A, 5-HT2A)] and (iii) DA and 5-HT degradation [monoamine oxidases (MAOA, MAOB)] signaling pathways were investigated. Results showed that tefluthrin induced down-regulation of transcripts responsible for the synthesis and action of DA (TH, Drd1, Drd2) and 5-HT (SERT, TPH2). In contrast, tefluthrin treatment induced up-regulation of genes involved in DA transporter (Dat1), 5-HT receptors (5-HT1A, 5-HT2A) and monoamine oxidases (MAOA, MAOB). Given the integral roles of mitochondrial dysfunction and dopaminergic and serotoninergic alterations as hallmarks of neurodegenerative diseases, our data suggest that tefluthrin may be a candidate for pesticides contributing to neurodegenerative disorders pathogenesis by causing damage to the DA and 5-HT systems.

Oxidative stress and mitochondrial damage in lambda-cyhalothrin toxicity: A comprehensive review of antioxidant mechanisms.

Lambda-cyhalothrin, also known as cyhalothrin, is an efficient, broad-spectrum, quick-acting pyrethroid insecticide and acaricide and the most powerful pyrethroid insecticide in the world. However, there is increasing evidence that lambda-cyhalothrin is closely related to a variety of toxicity drawbacks (hepatotoxicity, nephrotoxicity, neurotoxicity and reproductive toxicity, among others) in non-target organisms, and oxidative stress seems to be the main mechanism of toxicity. This manuscript reviews the oxidative and mitochondrial damage induced by lambda-cyhalothrin and the signalling pathways involved in this process, indicating that oxidative stress occupies an important position in lambda-cyhalothrin toxicity. The mechanism of antioxidants to alleviate the toxicity of lambda-cyhalothrin is also discussed. In addition, the metabolites of lambda-cyhalothrin and the major metabolic enzymes involved in metabolic reactions are summarized. This review article reveals a key mechanism of lambda-cyhalothrin toxicity-oxidative damage and suggests that the use of antioxidants seems to be an effective method for preventing toxicity.

Oxidative stress, the blood-brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants.

In recent years, growing awareness of the role of oxidative stress in brain health has prompted antioxidants, especially dietary antioxidants, to receive growing attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied dietary antioxidants include active substances such as vitamins, carotenoids, flavonoids and polyphenols. Dietary antioxidants are found in usually consumed foods such as fresh fruits, vegetables, nuts and oils and are gaining popularity due to recently growing awareness of their potential for preventive and protective agents against NDs, as well as their abundant natural sources, generally non-toxic nature, and ease of long-term consumption. This review article examines the role of oxidative stress in the development of NDs, explores the 'two-sidedness' of the blood-brain barrier (BBB) as a protective barrier to the nervous system and an impeding barrier to the use of antioxidants as drug medicinal products and/or dietary antioxidants supplements for prevention and therapy and reviews the BBB permeability of common dietary antioxidant suplements and their potential efficacy in the prevention and treatment of NDs. Finally, current challenges and future directions for the prevention and treatment of NDs using dietary antioxidants are discussed, and useful information on the prevention and treatment of NDs is provided.

Conjugated linoleic acid (CLA) as a functional food: Is it beneficial or not?

Conjugated linoleic acid (CLA) has attracted great attention in recent years as a popular class of functional food that is broadly used. It refers to a group of geometric and positional isomers of linoleic acid (LA) with a conjugated double bond. The main natural sources of CLA are dairy products, beef and lamb, whereas only trace amounts occur naturally in plant lipids. CLA has been shown to improve various health issues, having effects on obesity, inflammatory, anti-carcinogenicity, atherogenicity, immunomodulation, and osteosynthesis. Also, compared to studies on humans, many animal researches reveal more positive benefits on health. CLA represents a nutritional avenue to improve lifestyle diseases and metabolic syndrome. Most of these effects are attributed to the two major CLA isomers [conjugated linoleic acid cis-9,trans-11 isomer (c9,t11), and conjugated linoleic acid trans-10,cis-12 isomer (t10,c12)], and their mixture (CLA mix). In contrast, adverse effects of CLA have been also reported, such as glucose homeostasis, insulin resistance, hepatic steatosis and induction of colon carcinogenesis in humans, as well as milk fat inhibition in ruminants, lowering chicken productivity, influencing egg quality and altering growth performance in fish. This review article aims to discuss the health benefits of CLA as a nutraceutical supplement and highlight the possible mechanisms of action that may contribute to its outcome. It also outlines the feasible adverse effects of CLA besides summarizing the recent peer-reviewed publications on CLA to ensure its efficacy and safety for proper application in humans.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells.

Cancer is a huge challenge for people worldwide. High reactive oxygen species (ROS) levels are a recognized hallmark of cancer and an important aspect of cancer treatment research. Abnormally elevated ROS levels are often attributable to alterations in cellular metabolic activities and increased oxidative stress, which affects both the development and maintenance of cancer. Moderately high levels of ROS are beneficial to maintain tumor cell genesis and development, while toxic levels of ROS have been shown to be an important force in destroying cancer cells. ROS has become an important anticancer target based on the proapoptotic effect of toxic levels of ROS. Therefore, this review summarizes the role of increased ROS in DNA damage and the apoptosis of cancer cells caused by changes in cancer cell metabolism, as well as various anticancer therapies targeting ROS generation, in order to provide references for cancer therapies based on ROS generation.

Bifurcaria bifurcata extract exerts antioxidant effects on human Caco-2 cells.

The present research study investigated the potential protective effect of Bifurcaria bifurcata extract on cell viability and antioxidant defences of cultured human Caco-2 cells submitted to oxidative stress induced by tert-butylhydroperoxide (tert-BOOH). Aqueous extracts were firstly characterized in terms of total phenolic contents. Concentrations of reduced glutathione (GSH) and malondialdehyde (MDA), generation of reactive oxygen species (ROS), nitric oxide (NO) production, antioxidant enzymes activities [NADPH quinone dehydrogenase 1 (NQO1) and glutathione S-transferase (GST)], caspase 3/7 activity and gene expression linked to apoptosis, proinflammation and oxidative stress signaling pathways were used as markers of cellular oxidative status. B. bifurcata extract prevented the cytotoxicity, the decrease of GSH, the increase of MDA levels and the ROS generation induced by tert-BOOH. B. bifurcata extract prevented the significant decrease of NQO1 and GST activities, and the significant increase of caspase 3/7 activity induced by tert-BOOH. B. bifurcata extract also caused an over-expression of GSTM2, Nrf2 and AKT1 transcriptors, as well as reduced ERK1, JNK1, Bax, BNIP3, NFκB1, IL-6 and HO-1 gene expressions induced by tert-BOOH suggesting an increase in cellular resistance against oxidative stress. The results of the biomarkers analyzed show that treatment of Caco-2 cells with B. bifurcata extract enhance antioxidant defences, which imply an improved cell response to an oxidative challenge. B. bifurcata extract possesses strong antioxidant properties and may be a potential effective alternative to oxidant agents in the functional food industry.

The potential of CD38 protein as a target for autoimmune diseases.

Cluster of differentiation 38 (CD38) is a multifunctional cell surface protein involved in nicotinamide adenine dinucleotide (NAD+) homeostasis in types of cells and tissues, which can be found in many immune cells and non-immune cells. Previous studies have shown that CD38 plays an important role in regulating innate immunity. Recently, many studies have revealed the importance of CD38 in autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease, among others. In this report, we will briefly discuss the complex immunological functions of CD38 and focus on recent advances in the role of CD38 in the development and pathogenesis of autoimmune diseases, as well as their potential as therapeutic targets for systemic diseases, intending to make a comprehensive understanding of CD38 and its promising therapeutic potential in these systemic diseases.

MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia.

Alimentary toxic aleukia (ATA) is correlated with consuming grains contaminated by Fusarium species, particularly T-2 toxin, which causes serious hurt to human and animal health, chiefly in disorders of the haematopoietic system. However, the mechanism of haematopoietic dysfunction induced by T-2 toxin and the possible target pathway for the treatment of T-2 toxin-induced haematopoietic disorder of ATA remains unclear. In this study, genomes and proteomics were used for the first time to investigate the key differential genes and proteins that inhibit erythroid differentiation of K562 cells caused by T-2 toxin, and it was found that heat shock protein 27 (HSP27) and membrane-spanning 4-domains, subfamily A, member 3 (MS4A3) may play an important role in erythroid differentiation. Meanwhile, MS4A3 interference can inhibit the occurrence of erythroid differentiation of K562 cells and promote the phosphorylation of HSP27. Moreover, the binding of HSP27 to MS4A3 in natural state can activate the phosphorylation site of HSP27 (Ser-83), while T-2 toxin can abolish the activation of phosphorylation site by inhibiting the expression of MS4A3. These findings for the first time demonstrated that the MS4A3-HSP27 pathway may function an efficient therapeutic target pathway for treating T-2 toxin elicited haematopoietic disorders of ATA.