Natural Compounds as Regulators of NLRP3 Inflammasome-Mediated IL-1[béta] Production

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The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed

The potential use of melatonin for preventing cisplatin ototoxicity : an insight for a clinical approach

Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side effects, such as nephrotoxicity and ototoxicity. Ototoxicity produced by cisplatin is usually persistent, depending on the age of the patient, the cumulative number of doses, the number of chemotherapy cycles, the history of noise exposure, and deteriorating renal function. The mechanism of the ototoxicity caused by cisplatin is based on the generation of reactive oxygen species, which interfere with the antioxidant protection of the organ of Corti. Thus, protecting the cochlea with antioxidants ameliorates ototoxicity from cisplatin. In this context, melatonin appears as a therapeutic option for preventing the ototoxic effects of cisplatin, since the research in the last decade has proven its ability to be both a direct free radical scavenger and indirect antioxidant. In this sense, some of the evidence suggesting that melatonin is efficient for combating cisplatin-induced ototoxicity is summarized and discussed in this paper

Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review.

Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd

A Tale Of Two Sirtuins: The Impact Of Sirt1 And Sirt3 On The Pathophysiology Of Shock

Both acute blood loss and severe infection activate common cellular pathways leading to shock – a pathologic condition characterized by systemic inflammation, oxidative stress, and mitochondrial dysfunction. Sirtuins, a highly conserved group of NAD-dependent enzymes, play a critical role in cellular survival and many of the benefits associated with sirtuin activation are thought to be secondary to decreased inflammation, reduced oxidative stress, and improved mitochondrial physiology. As such, we hypothesized that sirtuin pathways play a crucial role in shock and could be could be targeted to improve outcomes following acute blood loss and severe infection. In a series of in vivo and in vitro experiments recapitulating hemorrhagic shock and severe sepsis, we explored the impact of sirtuin activation on inflammation, mitochondrial function, and survival. Following decompensated hemorrhagic shock, resuscitation with resveratrol, a SIRT1 activator, significantly improved renal mitochondrial function and decreased oxidative damage. Similarly, resuscitation with nicotinamide monononucleotide (NMN), a key biosynthetic NAD precursor, was found to mitigate inflammation, support cellular energetics and improve both physiologic resilience and survival. In contrast, impaired expression of either SIRT1 or SIRT3 resulted in a pro-inflammatory phenotype with accelerated mortality in sepsis. Interestingly, deletion of SIRT1 did not significantly worsen the degree of mitochondrial dysfunction observed in septic liver, but was associated with decreased CI and CII respiration in kidney. Deletion of SIRT3 did not significantly impact the degree of mitochondrial dysfunction observed in either liver or kidney. Taken together, these data strongly suggest that SIRT1 and SIRT3 play a key role in the pathophysiology of shock. Although further research is needed to determine if SIRT1 and SIRT3 overexpression improves outcomes or if pharmacologically manipulating NAD metabolism in conjunction with sirtuin activation provides added benefit, targeting sirtuins appears beneficial in hemorrhagic and septic shock

Environmental toxicity, redox signaling and lung inflammation:the role of glutathione

Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox sensitive transcription factors such as Nrf2, NF-κB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-L-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease

Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan‐polysaccharide rat model of Crohn's disease

Background: Resveratrol has antiinflammatory and antifibrotic effects. Resveratrol decreases proliferation and collagen synthesis by intestinal smooth muscle cells. We hypothesized that resveratrol would decrease inflammation and fibrosis in an animal model of Crohn's disease. Methods: Peptidoglycan‐polysaccharide (PG‐PS) or human serum albumin (HSA) was injected into the bowel wall of Lewis rats at laparotomy. Resveratrol or vehicle was administered daily by gavage 1–27 days postinjection. On day 28, gross abdominal and histologic findings were scored. Cecal collagen content was measured by colorimetric analysis of digital images of trichrome‐stained sections. Cecal levels of procollagen, cytokine, and growth factor mRNAs were determined. Results: PG‐PS‐injected rats (vehicle‐treated) developed more fibrosis than HSA‐injected rats by all measurements: gross abdominal score ( P < 0.001), cecal collagen content ( P = 0.04), and procollagen I and III mRNAs ( P ≤ 0.0007). PG‐PS‐injected rats treated with 40 mg/kg resveratrol showed a trend toward decreased gross abdominal score, inflammatory cytokine mRNAs, and procollagen mRNAs. PG‐PS‐injected rats treated with 100 mg/kg resveratrol had lower inflammatory cytokine mRNAs (IL‐1β [3.50 ± 1.08 vs. 10.79 ± 1.88, P = 0.005], IL‐6 [17.11 ± 9.22 vs. 45.64 ± 8.83, P = 0.03], tumor necrosis factor alpha (TNF‐α) [0.80 ± 0.14 vs. 1.89 ± 0.22, P = 0.002]), transforming growth factor beta 1 (TGF‐β1) mRNA (2.24 ± 0.37 vs. 4.06 ± 0.58, P = 0.01), and histologic fibrosis score (6.4 ± 1.1 vs. 9.8 ± 1.0; P = 0.035) than those treated with vehicle. There were trends toward decreased gross abdominal score and decreased cecal collagen content. Procollagen I, procollagen III, and IGF‐I mRNAs also trended downward. Conclusions: Resveratrol decreases inflammatory cytokines and TGF‐β1 in the PG‐PS model of Crohn's disease and demonstrates a promising trend in decreasing tissue fibrosis. These findings may have therapeutic applications in inflammatory bowel disease. (Inflamm Bowel Dis 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90530/1/21843_ftp.pd

Plants’ bioactive secondary metabolites in the management of sepsis: Recent findings on their mechanism of action

Sepsis is a severe inflammatory response to systemic infection and is a threatening cause of death in intensive care units. In recent years, a number of studies have been conducted on the protective effect of natural products against sepsis-induced organ injury. However, a comprehensive review of these studies indicating the mechanisms of action of the bioactive compounds is still lacking. In this context, this review aimed to provide an updated analysis of the mechanism of action of plants’ secondary metabolites in the management of sepsis. Scopus, Science Direct, Google Scholar, and PubMed were searched from inception to July 2022. A variety of secondary metabolites were found to be effective in sepsis management including allicin, aloin, cepharanthine, chrysin, curcumin, cyanidin, gallic acid, gingerol, ginsenoside, glycyrrhizin, hesperidin, kaempferol, narciclasine, naringenin, naringin, piperine, quercetin, resveratrol, rosmarinic acid, shogaol, silymarin, sulforaphane, thymoquinone, umbelliferone, and zingerone. The protective effects exerted by these compounds can be ascribed to their antioxidant properties as well as induction of endogenous antioxidant mechanisms, and also via the downregulation of inflammatory response and reduction of biochemical and inflammatory markers of sepsis. These findings suggest that these secondary metabolites could be of potential therapeutic value in the management of sepsis, but human studies must be performed to provide strength to their potential clinical relevance in sepsis-related morbidity and mortality reduction