#NF-κB pathway

[blueoaknx]

Mitochondria Combat Chronic Inflammation

Introduction

Chronic inflammation is a pathophysiological condition linked to numerous diseases, including obesity, diabetes, cardiovascular diseases, and neurodegenerative disorders. Mitochondria, the cellular powerhouses, are pivotal not only for ATP production but also for regulating cellular metabolism, redox balance, and apoptosis. Recent studies reveal that mitochondria play a crucial role in modulating inflammatory responses, and their dysfunction is often implicated in chronic inflammatory states. This article explores the intricate mechanisms by which mitochondria influence chronic inflammation and their potential as therapeutic targets.

Mitochondrial Structure and Function

Mitochondria possess a double-membrane structure that includes:

Outer Membrane: Contains porins that allow the passage of small molecules.

Inner Membrane: Rich in cardiolipin and contains the electron transport chain (ETC) complexes crucial for oxidative phosphorylation.

Matrix: Contains enzymes for the tricarboxylic acid (TCA) cycle, mitochondrial DNA (mtDNA), and ribosomes.

These structural features enable mitochondria to perform several essential functions, including ATP synthesis, calcium buffering, and reactive oxygen species (ROS) regulation.

Mitochondrial Dysfunction and Chronic Inflammation

Mitochondrial dysfunction is characterized by reduced ATP production, increased ROS generation, and impaired metabolic signaling. Key contributors to mitochondrial dysfunction include:

Oxidative Stress: Excessive ROS can damage mitochondrial components, leading to a vicious cycle of increased inflammation.

Aging: Aging is associated with mitochondrial dysfunction, contributing to the onset of chronic inflammatory diseases.

Environmental Toxins: Exposure to pollutants and toxins can induce mitochondrial damage.

Mitochondrial dysfunction is implicated in the activation of pro-inflammatory pathways, including:

NLRP3 Inflammasome Activation: Mitochondrial ROS and mtDNA release can activate the NLRP3 inflammasome, leading to the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18.

NF-κB Pathway: Mitochondrial stress can activate the NF-κB signaling pathway, promoting the expression of pro-inflammatory genes.

Mechanisms by Which Mitochondria Combat Chronic Inflammation

Energy Homeostasis and Immune Cell Function

Mitochondria are essential for the bioenergetic demands of immune cells, particularly during inflammatory responses. Immune cells like macrophages and T-cells switch from oxidative phosphorylation to glycolysis during activation, a process known as the Warburg effect. Mitochondria facilitate this metabolic flexibility by:

Providing substrates for glycolysis and subsequent oxidative phosphorylation.

Regulating ATP levels to support energy-intensive processes, such as cytokine production and phagocytosis.

Regulation of ROS and Redox Signaling

Mitochondria generate ROS as byproducts of the ETC. While excessive ROS can induce oxidative stress, physiological levels of ROS act as signaling molecules that modulate immune responses:

ROS can activate redox-sensitive transcription factors such as Nrf2, promoting the expression of antioxidant genes that mitigate oxidative stress.

Controlled ROS production aids in the differentiation of T-helper cells and enhances the immune response.

Apoptosis and Clearance of Damaged Cells

Mitochondria are central to the intrinsic apoptotic pathway, releasing cytochrome c and other pro-apoptotic factors that initiate caspase cascades. Effective apoptosis is crucial for:

Removing damaged or dysfunctional cells that could perpetuate inflammation.

Promoting an anti-inflammatory environment through the clearance of dead cells and debris, thereby preventing secondary necrosis and the associated inflammatory response.

Mitophagy: Mitochondrial Quality Control

Mitophagy is the selective autophagic degradation of damaged mitochondria, crucial for maintaining mitochondrial quality. Key mechanisms involved in mitophagy include:

PINK1/Parkin Pathway: PINK1 accumulates on damaged mitochondria, recruiting Parkin, which ubiquitinates mitochondrial proteins, signaling for degradation by the autophagy machinery.

Enhanced mitophagy reduces the release of pro-inflammatory factors and maintains cellular homeostasis.

Mitochondrial Biogenesis and Adaptation

Mitochondrial biogenesis is regulated by PGC-1α and other transcription factors. Increasing mitochondrial biogenesis can enhance cellular energy capacity and improve metabolic flexibility, which is particularly beneficial in inflammation. Strategies to promote mitochondrial biogenesis include:

Exercise: Physical activity enhances PGC-1α expression and mitochondrial function.

Nutritional Interventions: Certain bioactive compounds, like resveratrol and curcumin, have been shown to stimulate mitochondrial biogenesis.

Therapeutic Implications

Given their critical role in modulating inflammation, mitochondria represent promising therapeutic targets. Potential strategies include:

Nutraceuticals: Compounds like Coenzyme Q10 and α-lipoic acid may enhance mitochondrial function and reduce oxidative stress.

Exercise Interventions: Regular physical activity can improve mitochondrial health and reduce chronic inflammation.

Mitochondrial-targeted Therapies: Developing drugs that specifically target mitochondrial pathways could provide new treatment avenues for inflammatory diseases.

Conclusion

Mitochondria are integral to the regulation of chronic inflammation through their roles in energy metabolism, ROS management, apoptosis, mitophagy, and biogenesis. Understanding the complex interplay between mitochondrial function and inflammatory processes is essential for developing effective therapeutic strategies. By targeting mitochondrial health, we can potentially mitigate chronic inflammation and its associated diseases, paving the way for innovative approaches to improve public health outcomes. Continued research into mitochondrial biology will undoubtedly reveal further insights into their role in inflammation and disease.

[willowreader]

Inflamed from Within: How COVID-19 Ignites Heart Damage

Here is a version non-medical language terms.

Scientists recently uncovered something unsettling in a study of 54 heart tissue samples. The virus behind COVID-19 can creep into heart cells too, stirring up a storm of inflammation. These heart cells, called *cardiomyocytes*, are meant to keep our hearts beating strong, but this virus has found a way in, using the *TNF-NF-κB* pathway—a process that, when pushed too far, spells trouble.

Once inside, the virus seems to change the very way these heart cells function, flipping genetic switches that can lead to chaos. One gene, called *CXCL2*, kicks into high gear, summoning immune cells to the heart like soldiers to a battlefield. But sometimes, too many soldiers can cause more damage than they fix.

The protein at the center of this, *NF-κB*, is like the conductor of this chaotic orchestra, fueling inflammation that, if left unchecked, can weaken the heart. It’s as if the body, in trying to defend itself, starts tearing at its own foundation.

This study adds to a growing concern—COVID-19 is leaving its mark on the heart, and some of that damage may linger long after the virus has left. Scientists are sounding the alarm, and they’re urging us to take this more seriously than ever before. Posted by David It Up on X

[helen0086]

Progress in the Study of the Protective Effect and Mechanism of C-phycocyanin on Liver Injury

Abstract: C-phycocyanin (C-phycocyanin) is a pigment-containing protein from marine algae that has shown promising results in the treatment of many inflammatory diseases and tumors. C-alpha-cyanobilin is a pigment-containing protein from marine algae that has been shown to be effective in the treatment of various inflammatory diseases and tumors. C-alpha-cyanobilin has a protective effect on various liver diseases, such as drug-induced or toxic substance-induced liver damage, non-alcoholic fatty liver disease, hepatic fibrosis, and hepatic ischemia-reperfusion injury. The protective effect of C-alginin on liver injury is mainly realized through the regulation of signaling pathways such as nuclear factor (NF)-κB, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and AMP-dependent protein kinase (AMPK), and the inhibition of oxidative stress, etc., and is not toxic to normal cells. Therefore, C-alginin has a broad application prospect as a potential natural hepatoprotective marine active substance. In recent years, the research progress of the protective effect of C-alginin on liver injury and its mechanism is summarized.

 C-phycocyanin (C-phycocyanin) is a complex protein of cyanobacteria and a natural food protein pigment with pharmacological effects such as antioxidant, anti-inflammatory and anti-tumor effects, as well as fast-acting and low-toxicity, it can be used as a functional food [1-2]. C-Alginin can also enhance immunity and is safe, without causing acute and subacute toxic reactions [3]. Selenium-enriched PC has been shown to have stronger pharmacological effects [4]. Therefore, C-alginate has important research value both as a drug and a functional food, and has become a hot spot in the field of pharmaceutical research [5]. In this paper, we summarize the progress of research on the application and mechanism of C-alginin in liver diseases.

1 Ameliorative effect of C-phycocyanin on liver injury caused by drugs and toxic substances

The liver is the metabolic center of drugs and exogenous toxic substances, and metabolites are prone to liver injury. C-PC can inhibit the synthesis and release of inflammatory factors such as tumor necrosis factor (TNF)-α and interferon-γ, and increase the activities of catalase and superoxide dismutase (SOD), which can inhibit hepatic inflammation and alleviate hepatic injury [3]. It has been found that C-PC can significantly prevent thioacetamide-induced liver injury, significantly reduce the levels of alanine aminotransferase (ALT) and aliquot aminotransferase (AST), shorten the prothrombin time and reduce the hepatic histopathological damage, and improve the survival rate of rats with fulminant hepatic failure [6]. C-alginin also has a good effect on thioacetamide-induced hepatic encephalopathy, which can be seen in the reduction of tryptophan and lipid peroxidation indexes in different regions of the brain, and the enhancement of catalase and glutathione peroxidase activities in rats with fulminant hepatic failure [6].

Another study found that C-alginin not only attenuates the oxidative stress induced by 2-acetylaminofluorene and reduces the generation of reactive oxygen species (ROS) radicals, but also inhibits the phosphorylation of protein kinase B (Akt) and the nuclear translocation of nuclear factor (NF)-κB induced by 2-acetylaminofluorene, thus inhibiting the expression of multidrug resistance genes [7]. Osman et al. [8] also showed that C-alginin could normalize the levels of ALT, AST, catalase, urea, creatinine, SOD and glutathione-s-transferase in the livers of rats poisoned with carbon tetrachloride (CCl4). This result was also verified in human liver cell line (L02) [9]. C-phycocyanin can effectively scavenge ROS and inhibit CCl4-induced lipid peroxidation in rat liver [10], and C-PC can improve the antioxidant defense system and restore the structure of hepatocytes and hepatic enzymes in the liver of gibberellic acid-poisoned albino rats [11]. As a PC chromophore, phycocyanin can also significantly inhibit ROS generation and improve liver injury induced by a variety of drugs and toxic substances [10]. Liu et al. [12] found that phycocyanin showed strong anti-inflammatory effects in a CCl4-induced hepatic injury model in mice, which could significantly reduce the levels of ALT, AST, the expression of TNF-α and cytochrome C, increase the levels of albumin and SOD, and proliferate cytosolic nuclei. It can significantly reduce ALT and AST levels and the expression of TNF-α and cytochrome C, increase albumin levels and the expression of SOD and proliferating cell nuclear antigen, promote hepatocyte regeneration and improve the survival rate of mice with acute liver failure.

Gammoudi et al [13] used response surface method to optimize the extraction process of C-phycocyanin, and obtained high extraction recovery. C-phycocyanin extracted by the optimized method has the ability of scavenging hydroxyl, superoxide anion and nitric oxide radicals as well as the ability of metal chelating, and it has stronger antioxidant effect; C-PC significantly increased the activity of SOD and inhibited the increase of ALT, AST, and bilirubin in cadmium-poisoned rats. C-PC significantly increased the activity of SOD and inhibited the increase of ALT, AST and bilirubin in rats with cadmium poisoning. The above studies show that C-phycocyanin can effectively protect liver injury caused by drugs and toxic substances, and has the efficacy as the basis for drug development.

2 Preventive effect of C-alginin on hepatic fibrosis

Liver fibrosis is an inevitable process in the development of various chronic liver diseases and may be reversed with early and timely treatment. The key to liver fibrosis is the activation of hepatic stellate cells. Previous studies have found that low-dose C-alginin combined with soy isoflavones can inhibit hepatic stellate cell activation by inhibiting the activity of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase［14］, but it is not clear whether C-alginin alone can inhibit the activity of NADPH oxidase. Therefore, the combination of C-algin and soy isoflavones at appropriate doses may have a preventive effect on liver fibrosis in high-risk groups. C-alginin may inhibit the progression of NADPH by suppressing oxidative damage, thereby inhibiting the development of hepatic fibrosis [15].

Epithelial mesenchymal transition (EMT) is one of the key mechanisms contributing to the development of fibrotic diseases. C-alginin inhibits transforming growth factor β1 (TGF-β1)-induced human EMT [16]. Although the effect of C-alginin on EMT in hepatic fibrosis has not been reported, it has been found that C-alginin can reduce pulmonary fibrosis by inhibiting epithelial mesenchymal transition [17]. Another study found that C-alginin could reduce the expression of α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) mRNA in human dermal fibroblasts and alleviate fibrous contracture [18]. The results of these studies also have significance for the inhibition of hepatic fibrosis, and provide a theoretical basis for the further study of C-PC as a potential antifibrotic drug.

3 Protective effect of C-alginin on hepatic ischemia-reperfusion injury

Liver ischemia/reperfusion injury is an important clinicopathophysiological phenomenon. It was found that the addition of two different doses (0.1 g/L and 0.2 g/L) of C-alginin to the Krebs Henseleit preservation solution significantly decreased hepatic ALT, AST and alkaline phosphatase activities, and reduced the rate of lipid peroxidation and malondialdehyde content in an isolated perfused rat liver model, and increased the activities of hepatic glutathione-s-transferase and glutathione peroxidase, as well as sulfhydryl groups in hepatic tissue. On the other hand, it can increase the activities of hepatic glutathione-s-transferase and glutathione peroxidase and the content of sulfhydryl groups in liver tissues, therefore, C-alginin can significantly reduce hepatic ischemia/reperfusion injury as an antioxidant [19]. In isolated perfused mouse livers, it was found that C-alginin significantly reduced the phagocytosis and respiratory burst activity of hepatic macrophages (Kupffer cells), attenuated cytotoxicity and inflammation induced by highly active Kupffer cells, and dose-dependently inhibited carbon phagocytosis and carbon-induced oxygen uptake by perfused livers, and then inhibited the increase of hepatic nitric oxide synthase activity induced by gonadotropins [20]. and thus inhibit the thyroid hormone-induced elevation of hepatic nitric oxide synthase activity [20].

However, C-alginin has a very short half-life in vivo, which limits its application in vivo. It was found that the use of polyethylene glycol-b-(polyglutamic acid-g-polyethyleneimine), a macromolecular material with good drug-carrying capacity and slow-release properties, as a nanocarrier of C-alginin could solve this problem, and the release of C-alginin could be delayed by subcutaneous injection into the abdominal region of rats, which could attenuate islet damage caused by hepatic ischemia/reperfusion and enhance the function of the islets [21]. This study broadens the scope of application of C-alginin in vivo and improves the therapeutic effect of C-alginin.

4 Inhibitory effect of C-alginin on hepatocellular carcinoma

It was found that C-alginin significantly reduced the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) mRNA in human hepatocellular carcinoma cells (HepG2 cells) [22]. C-alginin is a natural photosensitizer, and photodynamic therapy (PDT) mediated by alginin microcystin induced a large accumulation of ROS in HepG2 cells, which promoted mitochondrial damage and cytochrome C release, and led to apoptosis of hepatocellular carcinoma cells [23].

Liu et al. [24] used nanoscale C-alginate particles prepared by lactobionic acid grafting and adriamycin loading to enhance the growth inhibition of HepG2 cells when combined with chemo-PDT, and the C-alginate particles could effectively accumulate and diffuse in tumor multicellular spheres. In vitro and in vivo studies on the effects of selenium-enriched PCs on PDT in hepatocellular carcinoma showed that selenium-enriched PCs could migrate from lysosomes to mitochondria in a time-dependent manner, and that selenium-enriched PCs could induce the death of tumor cells through the generation of free radicals in vivo, increase the activities of antioxidant enzymes in vivo, induce mitochondria-mediated apoptosis, and inhibit autophagy, thus offering a relatively safe pathway to tumor treatment and showing new development perspectives [4]. It can provide a relatively safe way to treat tumors and shows a new development prospect [4].

Lin et al. [25] combined C-phycocyanin with single-walled carbon nanohorns and prepared phycocyanin-functionalized single-walled carbon nanohorn hybrids, which enhanced the photostability of C-phycocyanin and protected the single-walled carbon nanohorns from adsorption of plasma proteins, and synergistically used with PDT and photothermal therapy (PTT) to treat tumors. C-phycocyanin covalently coupled with biosilica and PDT or non-covalently coupled with indocyanine green and PTT on tumor-associated macrophages can also increase the apoptosis rate of tumor cells [26-27]. The development of PDT and PTT synergistic methods for the treatment of cancer has broadened the application of C-PC and enhanced its value in the treatment of hepatocellular carcinoma.

In addition, C-phycocyanin can inhibit the expression of multidrug-resistant genes in HepG2 cells through NF-κB and activated protein-1 (AP-1)-mediated pathways, and C-phycocyanin increases the accumulation of adriamycin in HepG2 cells in a dose-dependent manner, which results in a 5-fold increase in the susceptibility of cells to adriamycin [28]. Even in adriamycin-resistant HepG2 cells, C-PC induced the activation of apoptotic pathways such as cytochrome C and caspase-3 [29], and the results of Prabakaran et al. [30] also confirmed the inhibitory effect of C-PC on the proliferation of HepG2 cells, mediated by the inactivation of BCR-ABL signaling and the downstream PI3K/Akt pathway. mediated by BCR-ABL signaling and inactivation of downstream PI3K/Akt pathway. In addition, C-phycocyanin modifies the mitochondrial membrane potential and promotes apoptosis in cancer cells [30]. Currently, C-phycocyanin is a synergistic molecule with other drugs that have been widely used in the treatment of cancer [31]. The above studies demonstrate that C-phycocyanin has good therapeutic potential in the field of hepatocellular carcinoma.

5 Amelioration of metabolic syndrome and non-alcoholic fatty liver disease by C-phycocyanin

It has been found that C-alginin can reduce ALT and AST levels, decrease ROS production and NF-κB activation, and attenuate hepatic fibrosis in rats induced by high-fat choline-deficient diets, and thus C-alginin has a protective effect on NAFLD rats through anti-inflammatory and antioxidant mechanisms [15].

Another study on the effects of aqueous extract of Spirulina (mainly C-alginin) on NAFLD induced by a high-calorie/high-fat Western diet in C57Bl/6J mice showed that aqueous extract of Spirulina significantly improved glucose tolerance, lowered plasma cholesterol, and increased ursodeoxycholic acid in bile in mice [32]. Kaspi-Chadli et al. Kasbi-Chadli et al. [33] showed that aqueous extract of Spirulina could reduce cholesterol and sphingolipid levels in the liver and aortic cholesterol levels in hamsters fed a high-fat diet by significantly decreasing the expression of hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA) gene, a limiting enzyme for cholesterol synthesis, and TGF-β1 gene, and that ursodeoxycholic acid levels in the feces of hamsters fed high-fat diets were increased in the high Spirulina aqueous extract treatment group.

A daily dose of C-alginin-enriched Spirulina can reduce the harmful effects of oxidative stress induced by a diet rich in lipid peroxides [34]. Ma et al. [35] found that C-alginin promoted the phosphorylation of hepatocyte AMP-dependent protein kinase (AMPK) in vivo and ex vivo, and increased the phosphorylation of acetyl coenzyme A carboxylase. In the treatment of NAFLD in mice, C-alginin can improve liver inflammation by up-regulating the expression of phosphorylated AMPK and AMPK-regulated transcription factor peroxisome proliferator-activated receptor α (PPAR-α) and its target gene, CPT1, and by down-regulating the expression of pro-inflammatory factors such as TNF-α and CD36 [35]. This suggests that C-phycocyanin can also improve lipid deposition in the liver through the AMPK pathway.

Endothelial dysfunction is associated with hypertension, atherosclerosis and metabolic syndrome. Studies in animal models of spontaneous hypertension have shown that long-term administration of C-alginin may improve systemic blood pressure in rats by increasing aortic endothelial nitric oxide synthase levels, with a dose-dependent decrease in blood pressure, and thus C-alginin may be useful in preventing endothelial dysfunction-related diseases in the metabolic syndrome [36]. In the offspring of ApoE-deficient mice fed C-alginate during gestation and lactation, male littermates had an elevated hepatic reduced/oxidized glutathione ratio and significantly lower hepatic SOD and glutathione peroxidase gene expression.

C-PC is effective in preventing atherosclerosis in adult hereditary hypercholesterolemic mice [37]. In vitro, C-phycocyanin also improved glucose production and expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) in high-glucose-induced insulin-resistant HepG2 cells [38]. C-alginin also increases glucose uptake in high glucose-induced insulin-resistant HepG2 cells through the insulin receptor substrate (IRS)/PI3K/Akt and Sirtuin-1 (SIRT1)/liver kinase B1 (LKB1)/AMPK signaling pathways, activates glycogen synthase, and increases the amount of glycogen [38]. C-phycocyanin can improve blood glucose and fasting serum insulin levels in tetracycline-induced diabetic mice [39]. Therefore, C-phycocyanin can maintain cellular glucose homeostasis by improving insulin resistance in hepatocytes.

6 Hepatoprotective role of C-phycocyanin in other liver diseases

Studies have shown that C-alginin can inhibit total serum cholesterol, triacylglycerol, LDL, ALT, AST, and malondialdehyde levels in mice modeled with alcoholic liver injury, significantly increase SOD levels in the liver, and promote the activation and proliferation of CD4+ T cells, which can have an ameliorative effect on alcoholic liver injury [40]. In addition, C-phycocyanin may enhance the intestinal barrier function, regulate the intestinal flora, reduce the translocation of bacteria and metabolites to the liver, and inhibit the activity of the Toll-like receptor 4 (TLR4)/NF-κB pathway, which may reduce the inflammation of the liver and prevent the occurrence of hepatic fibrosis in mice [41]. In mice with X-ray radiation-induced liver injury, C-phycocyanin can reduce radiation-induced DNA damage and oxidative stress injury by up-regulating the expression of nuclear factor (NF)-E2-related factor 2 (Nrf2) and downstream genes, such as HO-1, and play a hepatoprotective role by enhancing the activities of SOD and glutathione peroxidase [42].

7 Outlook

Liver fibrosis is the common final process of chronic liver diseases, and there is no effective therapeutic drug at present. Although some research progress has been made in the field of traditional Chinese medicine (TCM) on the reversal of liver fibrosis [43], its toxicological effects have not yet been clarified. Although the incidence of viral hepatitis has gradually decreased with the development and popularization of vaccines and antiviral drugs, the incidence of drug-induced liver injury (DILI) and liver diseases such as NAFLD has been increasing year by year with the improvement of people's living conditions [44]. Therefore, there is an urgent need to find drugs or nutrients that can help maintain normal hepatocyte function and effectively inhibit liver inflammation and fibrosis. C-alginin, with its anti-inflammatory, antioxidant, and antitumor effects, as well as good food coloring, has a wide range of applications in both the pharmaceutical and food industries.

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[30] PRABAKARAN G, SAMPATHKUMAR P, KAVISRI M, et al. Extraction and characterization of phycocyanin from spirulina platensis and evaluation of its anticancer , antidiabetic and antiinflammatory effect[J]. Int J Biol Macromol, 2020, 153: 256- 263. doi: 10. 1016/j.ijbiomac.2020.03.009.

[31] SILVA M R O B D, M DA SILVA G, SILVA A L F D, et al. Bioactive compounds of Arthrospira spp. (spirulina) with potential anticancer activities: a systematic review[J].  ACS Chem Biol, 2021, 16 (11): 2057-2067. doi: 10. 1021/acschembio.1c00568.

[32] COUÉ M, TESSE A, FALEWÉE J, et al. Spirulina liquid extract protects against fibrosis related to non-alcoholic steatohepatitis and increases ursodeoxycholic acid [J]. Nutrients, 2019, 11 (1): 194. doi:10.3390/nu11010194.

[33] KASBI-CHADLI F, COUÉ M, AGUESSE A, et al. Spirulina liquid extract prevents metabolic disturbances and improves liver sphingolipids profile in hamster fed a high-fat diet[J]. Eur J Nutr, 2021, 60(8):4483-4494. doi: 10. 1007/s00394-021-02589-x.

[34] OULD AMARA-LEFFAD L, RAMDANE H, NEKHOUL K, et al. Spirulina effect on modulation of toxins provided by food, impact on hepatic and renal functions [J] . . Arch Physiol Biochem, 2019, 125 (2): 184-194. doi: 10. 1080/13813455.2018.1444059.

[35] MA P, HUANG R, JIANG J, et al. Potential use of C-phycocyanin in non-alcoholic fatty liver disease [J].  Biochem Biophys Res Commun, 2020, 526(4):906-912. doi: 10. 1016/j.bbrc.2020.04.001.

［36］ICHIMURA M, KATO S, TSUNEYAMA K, et al. Phycocyanin prevents hypertension and low serum adiponectin level in a rat model of metabolic syndrome［J］. Nutr Res, 2013, 33(5): 397-405. doi: 10. 1016/j.nutres.2013.03.006.

[37] COUÉ M, CROYAL M, HABIB M, et al. Perinatal administration of C-phycocyanin protects against atherosclerosis in apoE-deficient mice by modulating cholesterol and trimethylamine-N-oxide metabolisms[J]. Arterioscler Thromb Vasc Biol, 2021, 41(12): e512-e523. doi: 10. 1161/ATVBAHA.121.316848.

［38］REN Z, XIE Z, CAO D, et al. C-phycocyanin inhibits hepatic gluconeogenesis and increases glycogen synthesis via activating Akt and AMPK in insulin resistant hepatocytes [J]. Food Funct, 2018, 9(5): 2829-2839. doi: 10. 1039/c8fo00257f.

［39］OU Y, REN Z, WANG J, et al. Phycocyanin ameliorates alloxan- induced diabetes mellitus in mice ：involved in insulin signaling pathway and GK expression [J]. Chem Biol Interact, 2016, 247: 49- 54. doi: 10. 1016/j.cbi.2016.01.018.

[40] XIA D, LIU B, XIN W, et al. Protective effects of C-phycocyanin on alcohol-induced subacute liver injury in mice [J].  Journal of Applied Phycology, 2015, 28(2):765-772. doi: 10. 1007/s10811- 015-0677-3.

[41] XIE Y, LI W, ZHU L, et al. Effects of phycocyanin in modulating  the intestinal microbiota of mice [J].  Microbiologyopen, 2019, 8 (9): e00825. doi: 10. 1002/mbo3.825.

［42］LIU Q, LI W, QIN S. Therapeutic effect of phycocyanin on acute liver oxidative damage caused by X-ray［J］. Biomed Pharmacother, 2020, 130: 110553. doi: 10. 1016/j.biopha.2020.110553.

［43］SONG Y N, CHEN J, CAI F F, et al. A metabolic mechanism analysis of fuzheng-huayu formula for improving liver cirrhosis with traditional chinese medicine syndromes [J]. Acta Pharmacol Sin, 2018, 39(6): 942-951. doi: 10. 1038/aps.2017.101.

［44］XIAO J, WANG F, WONG N K, et al. Global liver disease burdens and research trends : analysis from a chinese perspective［J］. J Hepatol, 2019, 71(1):212-221. doi: 10. 1016/j.jhep.2019.03.004.

#phycocyanin #cphycocyanin #phycocyaninspirulina

[didanawisgi]

SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-β. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.

[consultatiiladomiciliu-ro]

Cine spune ca albastrul de metilen face minuni in leziunile cerebrale - STUDII

Citeste articolul pe https://consultatiiladomiciliu.ro/cine-spune-ca-albastrul-de-metilen-face-minuni-in-leziunile-cerebrale-studii/

Cine spune ca albastrul de metilen face minuni in leziunile cerebrale - STUDII

Albastrul de metilen utilizat in mod curent ca antiseptic urinar (face urina verde sau albastra), are un rol salvator pentru creier. Citeste mai mult despre mecanismele prin care salveaza neuronii.

Neurological Mechanisms of Action and Benefits of Methylene Blue © Chase Hughes, Applied Behavior Research 2023 16

mitochondria after traumatic brain injury and are protected by cyclosporine A. Journal of neurotrauma, 34(7), 1291-1301. Lee, S. W., & Han, H. C. (2021).

Methylene blue application to lessen pain: its analgesic effect and mechanism. Frontiers in Neuroscience, 15, 663650. Liu, Y., Jin, W., Zhao, Y., Zhang, G., & Zhang, W. (2017).

Enhanced catalytic degradation of methylene blue by α-Fe2O3/graphene oxide via heterogeneous photo-Fenton reactions. Applied Catalysis B: Environmental, 206, 642-652. Matsuda, M., Huh, Y., & Ji, R. R. (2019).

Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. Journal of anesthesia, 33, 131-139. Miclescu, A. A., Svahn, M., & Gordh, T. E. (2015).

Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study. Journal of pain research, 387-397. Nakazawa, H., Chang, K., Shinozaki, S., Yasukawa, T., Ishimaru, K., Yasuhara, S., … & Kaneki, M. (2017).

iNOS as a driver of inflammation and apoptosis in mouse skeletal muscle after burn injury: possible involvement of Sirt1 S-nitrosylation-mediated acetylation of p65 NF-κB and p53. PloS one, 12(1), e0170391. Ola, M. S., Nawaz, M., & Ahsan, H. (2011).

Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. Pan, H., Zhao, X., Lei, S., Cai, C., Xie, Y. Z., & Yang, X. (2019).

The immunomodulatory activity of polysaccharides from the medicinal mushroom Amauroderma rude (Agaricomycetes) is mediated via the iNOS and PLA2-AA pathways. International Journal of Medicinal Mushrooms, 21(8).

Neurological Mechanisms of Action and Benefits of Methylene Blue © Chase Hughes, Applied Behavior Research 2023 17 Rojas, J. C., Bruchey, A. K., & Gonzalez-Lima, F. (2012).

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Progress in neurobiology, 96(1), 32-45. Shen, J., Xin, W., Li, Q., Gao, Y., Yuan, L., & Zhang, J. (2019). Methylene blue reduces neuronal apoptosis and improves blood-brain barrier integrity after traumatic brain injury. Frontiers in Neurology, 10, 1133. Talley Watts, L., Long, J. A., Chemello, J., Van Koughnet, S., Fernandez, A., Huang, S., … & Duong, T. Q. (2014).

Methylene blue is neuroprotective against mild traumatic brain injury. Journal of neurotrauma, 31(11), 1063- 1071. Tucker, D., Lu, Y., & Zhang, Q. (2018).

From mitochondrial function to neuroprotection—an emerging role for methylene blue. Molecular neurobiology, 55, 5137-5153. Wang, W. X., Sullivan, P. G., & Springer, J. E. (2017).

Mitochondria and microRNA crosstalk in traumatic brain injury. Progress in Neuro- Psychopharmacology and Biological Psychiatry, 73, 104-108. Yadav, S., & Surolia, A. (2019).

Lysozyme elicits pain during nerve injury by neuronal Toll-like receptor 4 activation and has therapeutic potential in neuropathic pain. Science translational medicine, 11(504), eaav4176. Yonutas, H. M., Vekaria, H. J., & Sullivan, P. G. (2016).

Mitochondrial specific therapeutic targets following brain injury. Brain research, 1640, 77- 93. Zhang, D. X., Ma, D. Y., Yao, Z. Q., Fu, C. Y., Shi, Y. X., Wang, Q. L., & Tang, Q. Q. (2016).

ERK1/2/p53 and NF-κB dependent-PUMA activation involves in doxorubicin-induced cardiomyocyte apoptosis. Eur Rev Med Pharmacol Sci, 20(11), 2435-2442. Zhao, M., Liang, F., Xu, H., Yan, W., & Zhang, J. (2016).

Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting Neurological Mechanisms of Action and Benefits of Methylene Blue © Chase Hughes, Applied Behavior Research 2023 18 autophagy and inhibiting microglial activation. Molecular medicine reports, 13(1), 13-20. Zhu, Y., Wang, H., Fang, J., Dai, W., Zhou, J., Wang, X., & Zhou, M. (2018). SS-31 provides neuroprotection by reversing mitochondrial dysfunction after traumatic brain injury.

Oxidative Medicine and Cellular Longevity, 2018. Zhou, Y., Shao, A., Xu, W., Wu, H., & Deng, Y. (2019). Advance of stem cell treatment for traumatic brain injury. Frontiers in cellular neuroscience, 13, 301.

[colinwilson11]

Necrotising Enterocolitis Market Will Grow At Highest Pace Owing To Rising Prevalence Of Preterm Birth Complications

Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease that primarily affects premature infants. It is characterized by inflammation and necrosis of the intestine. The risk factors associated with NEC include prematurity, formula feeding, and bacterial colonization of the intestine. Infants with very low birth weights have the highest risk. NEC treatment involves management of sepsis, support of vital organ function, bowel rest with no oral feeding, and surgery if necessary.

The Necrotising Enterocolitis Market is estimated to be valued at US$ 7.10 Bn in 2024 and is expected to exhibit a CAGR of 5.6% over the forecast period 2024-2031.

Key Takeaways

Key players operating in the Necrotising Enterocolitis market are AbbVie, AstraZeneca, Baxter International, Bristol-Myers Squibb, Fresenius Kabi. Rising prevalence of preterm birth complications globally is expected to drive the growth of the market during the forecast period. According to the World Health Organization, preterm birth complications are the leading cause of death among children under 5 years of age, responsible for approximately 1 million deaths in 2015. Technological advancements in parenteral nutrition and minimal invasive surgery have provided improved treatment outcomes for NEC.

Market Trends

Increasing research on nutraceuticals and probiotics for NEC prevention: Several clinical studies are evaluating the role of pre and probiotics such as Lactobacillus and Bifidobacterium in reducing the risk of NEC in preterm infants. This presents an opportunity for novel prevention strategies.

Rising adoption of minimal invasive surgery: Advancements in minimal invasive surgical techniques such as laparoscopy has resulted in reduced recovery time and complications for NEC patients undergoing surgery. This trend is expected to drive the future demand.

Market Opportunities

Development of novel therapeutics targeting inflammatory pathways: Researchers are investigating potential drug targets such as Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling pathways to develop novel anti-inflammatory therapies for NEC treatment.

Increasing healthcare expenditure on pediatric care in emerging nations: Emerging countries in Asia Pacific and Latin America are witnessing increased healthcare spending focused on neonatal and pediatric care. This will propel the growth of therapeutics and medical devices market for pediatric gastrointestinal conditions.

Impact Of COVID-19 On Necrotising Enterocolitis Market Growth

The COVID-19 pandemic has adversely impacted the growth of the necrotising enterocolitis market globally. During the peak of pandemic in 2020-2021, the concentration of healthcare resources towards treatment of COVID-19 patients has negatively affected the diagnosis and treatment of other health conditions including necrotising enterocolitis. This led to reduction in number of surgeries and procedures carried out for necrotising enterocolitis management. Moreover, restrictions on non-essential healthcare services along with fear of virus spread stopped patients from visiting hospitals even for emergency cases. This impacted the market growth negatively during the period.

However, with gradual lift of restrictions in 2022 and availability of COVID-19 vaccines, the market is recovering slowly. The healthcare facilities are focusing on clearing backlog of non-COVID cases and regaining lost momentum in treatment of other diseases. The manufacturers are expanding supply chain capabilities and ramping up production to meet the increasing demand. Various initiatives are being taken by governments and healthcare organizations to raise awareness about timely management of necrotising enterocolitis. This will potentially boost the market in the coming years.

The United States holds the major share of necrotising enterocolitis market in terms of value, owing to large patient population, high treatment cost and adequate reimbursement framework. The region accounted for over 35% revenue share of global market in 2024.

Asia Pacific region is poised to witness fastest growth during the forecast period. Factors such as increasing healthcare expenditure, rising medical tourism, growing birth rate and expanding private hospital infrastructure will aid the market growth in Asia Pacific. China, India and Japan are emerging as profitable markets for necrotising enterocolitis treatment.

Get more insights on this topic: https://www.trendingwebwire.com/necrotising-enterocolitis-market-is-estimated-to-witness-high-growth-owing-to-advancements-in-parenteral-nutrition-solutions-and-devices/

About Author:

Ravina Pandya, Content Writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemical and materials, etc. (https://www.linkedin.com/in/ravina-pandya-1a3984191)

What Are The Key Data Covered In This Necrotising Enterocolitis Market Report?

:- Market CAGR throughout the predicted period

:- Comprehensive information on the aspects that will drive the Necrotising Enterocolitis Market's growth between 2024 and 2031.

:- Accurate calculation of the size of the Necrotising Enterocolitis Market and its contribution to the market, with emphasis on the parent market

:- Realistic forecasts of future trends and changes in consumer behaviour

:- Necrotising Enterocolitis Market Industry Growth in North America, APAC, Europe, South America, the Middle East, and Africa

:- A complete examination of the market's competitive landscape, as well as extensive information on vendors

:- Detailed examination of the factors that will impede the expansion of Necrotising Enterocolitis Market vendors

FAQ’s

Q.1 What are the main factors influencing the Necrotising Enterocolitis Market?

Q.2 Which companies are the major sources in this industry?

Q.3 What are the market’s opportunities, risks, and general structure?

Q.4 Which of the top Necrotising Enterocolitis Market companies compare in terms of sales, revenue, and prices?

Q.5 Which businesses serve as the Necrotising Enterocolitis Market’s distributors, traders, and dealers?

Q.6 How are market types and applications and deals, revenue, and value explored?

Q.7 What does a business area’s assessment of agreements, income, and value implicate?

*Note: 1. Source: Coherent Market Insights, Public sources, Desk research 2. We have leveraged AI tools to mine information and compile it

[morriganpostofficial]

Unfold the 5 Unique Health Benefits of Lotus Leaf Tea

Lotus leaf tea, derived from the Nelumbo nucifera plant, is recognized for its myriad health benefits. Initially, it contains powerful antioxidants like flavonoids and carotenoids that protect against cellular aging and boost cardiovascular health. Next, its anti-inflammatory properties, mediated through the JNK/NF-κB pathway, support reduce systemic inflammation. Thirdly, tea regulates blood…

[rodneygoodie]

Osseointegration and Dental Implants

Dental implants can address missing teeth for individuals. An estimated three million Americans have dental implants, which grows annually. Osseointegration helps the implant adhere to the jawbone to remain in place after the procedure.

During the dental implant procedure, dental professionals place a screw-like fixture made of titanium in the jaw. This fixture acts as a replacement tooth root and enables the sturdy and permanent placement of a replacement tooth on the implant post. During treatment and implantation, dental professionals aim to ensure close contact with the jawbone, allowing for osseointegration. It ensures that the teeth implants become stable and anchored as the jawbone cells extend up to the implant and securely grip it. This process can take anywhere from six weeks to six months as the supportive root-like structure fully integrates with the jawbone.

The roots of osseointegration extend to 1952, when Professor Per-Ingvar Branemark, a Swedish orthopaedic surgeon, researched microcirculation. Branemark had inserted a titanium tube from an optical device into a rabbit's leg. When he attempted to remove the tube from the leg, Branemark discovered that the titanium and bone had fused, creating a “direct structural and functional connection between ordered living bone and the surface of a load-carrying implant.” After over a decade of research into osseointegration, which stems from the Greek osteon or bone, and the Latin word integrate or to make whole, Professor Branemark successfully performed the first titanium dental implant in 1965.

Once the area of the dental implant heals, the implants help reduce bone loss. They help individuals maintain a normal chewing function, which remains essential to a healthy, functional jawbone. Missing teeth can cause deterioration of underlying bone as chewing stimulation no longer occurs. Dentures do not have the same positive impact on the jawbone. They place pressure on the gums during chewing, which curtails blood supply, accelerating bone loss.

Cell signaling pathways define how the body reacts to implanted biomaterials through various responses. In a complex, non-linear series of reactions, the cells respond to extracellular signals by regulating intracellular gene expression. The biochemical responses or enzyme-catalyzed protein activations involve a cascading formation of activated proteins that engage in “cross-talk." The process relays information between the cells and transfers it from receptors to targets in the cell, such as mitochondria or nuclei.

A harmoniously coordinated activity, signaling pathways enable cellular responses that underpin human development, immunity, and tissue repair in adults. The osseointegration process captures two of these responses. In the early stages, the immune-inflammatory system modulates cellular responses, treating the implant as a foreign body within its microenvironment. A primary signaling pathway centers on the inflammatory Nuclear Factor Kappa B (NF-κB). Subsequent Wnt cell reactions regulate bone formation.

Titanium implants encourage biointegration by having immunomodulatory properties that respond to the immune-modulated inflammatory process. The biologically active presence of foreign body giant cells and macrophages makes the osseointegration process dynamic rather than static.

While healing, smoking negatively impacts the osseointegration process, impeding healing, bone cell growth, and blood flow and increasing the ultimate potential for implant failure. Lack of dental care and excessive alcohol consumption can also impact the long-term integrity of dental implants.

[y2fear]

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway | Journal of Nanobiotechnology

[jhavelikes]

The innate immune response is vital for the success of prophylactic vaccines and immunotherapies. Control of signaling in innate immune pathways can improve prophylactic vaccines by inhibiting unfavorable systemic inflammation and immunotherapies by enhancing immune stimulation. In this work, we developed a machine learning-enabled active learning pipeline to guide in vitro experimental screening and discovery of small molecule immunomodulators that improve immune responses by altering the signaling activity of innate immune responses stimulated by traditional pattern recognition receptor agonists. Molecules were tested by in vitro high throughput screening (HTS) where we measured modulation of the nuclear factor κ-light-chain-enhancer of activated B-cells (NF-κB) and the interferon regulatory factors (IRF) pathways. These data were used to train data-driven predictive models linking molecular structure to modulation of the NF-κB and IRF responses using deep representational learning, Gaussian process regression, and Bayesian optimization. By interleaving successive rounds of model training and in vitro HTS, we performed an active learning-guided traversal of a 139 998 molecule library. After sampling only ∼2% of the library, we discovered viable molecules with unprecedented immunomodulatory capacity, including those capable of suppressing NF-κB activity by up to 15-fold, elevating NF-κB activity by up to 5-fold, and elevating IRF activity by up to 6-fold. We extracted chemical design rules identifying particular chemical fragments as principal drivers of specific immunomodulation behaviors. We validated the immunomodulatory effect of a subset of our top candidates by measuring cytokine release profiles. Of these, one molecule induced a 3-fold enhancement in IFN-β production when delivered with a cyclic di-nucleotide stimulator of interferon genes (STING) agonist. In sum, our machine learning-enabled screening approach presents an efficient immunomodulator discovery pipeline that has furnished a library of novel small molecules with a strong capacity to enhance or suppress innate immune signaling pathways to shape and improve prophylactic vaccination and immunotherapies.

Data-driven discovery of innate immunomodulators via machine learning-guided high throughput screening - Chemical Science (RSC Publishing)

[cheyannemallas]

BPC-157: A Comprehensive Review of its Biological Role and Therapeutic Potential by Cheyanne Mallas

BPC-157, or Body Protection Compound-157, is a synthetic peptide consisting of 15 amino acids. It was originally derived from a gastric juice protein called BPC, which has been shown to exhibit potent healing properties in various tissues. BPC-157 has gained significant attention in recent years due to its wide range of biological actions and potential therapeutic applications says Cheyanne Mallas. This paper aims to provide a comprehensive review of the biological role and therapeutic potential of BPC-157.

Biological Role:

BPC-157 exerts its effects by modulating several biological pathways involved in tissue repair and regeneration. It has been shown to promote angiogenesis, stimulate fibroblast proliferation, and enhance collagen synthesis, all of which contribute to tissue healing. Additionally, BPC-157 exhibits anti-inflammatory properties by reducing the production of pro-inflammatory cytokines and inhibiting the activation of NF-κB, a key regulator of inflammation. Furthermore, BPC-157 has been found to protect against oxidative stress and promote neurogenesis, suggesting its potential role in the treatment of neurodegenerative diseases.

Therapeutic Potential:

1. Musculoskeletal Disorders:

BPC-157 has demonstrated promising results in the treatment of various musculoskeletal disorders, including tendon and ligament injuries, osteoarthritis, and muscle tears. Studies have shown that BPC-157 accelerates tendon healing, improves tendon-to-bone healing, and reduces inflammation and pain associated with these conditions. Furthermore, it has been shown to enhance the recovery of damaged muscle tissue and improve muscle strength.

2. Gastrointestinal Disorders:

BPC-157 has shown potential therapeutic effects in various gastrointestinal disorders, such as inflammatory bowel disease (IBD), peptic ulcers, and esophagitis. It has been found to promote the healing of damaged intestinal mucosa, reduce inflammation, and improve gastrointestinal motility. Moreover, BPC-157 has exhibited protective effects on the liver and pancreas, suggesting its potential in the treatment of liver and pancreatic diseases.

3. Cardiovascular Disorders:

Studies have indicated that BPC-157 may have beneficial effects on cardiovascular health. It has been shown to promote blood vessel formation, improve cardiac function, and protect against ischemic heart injury. BPC-157 also exhibits anti-thrombotic properties, indicating its potential use in the prevention and treatment of cardiovascular diseases.

4. Central Nervous System Disorders:

BPC-157 has shown promising results in the treatment of various central nervous system disorders, including traumatic brain injury, stroke, and spinal cord injury. It has been found to promote neuronal survival, enhance neurogenesis, and improve functional recovery in animal models. Additionally, BPC-157 has demonstrated neuroprotective effects against neurotoxicity induced by drugs and toxins.

Conclusion:

BPC-157 is a synthetic peptide with diverse biological actions and therapeutic potential. Its ability to promote tissue healing, reduce inflammation, and protect against oxidative stress makes it a promising candidate for the treatment of various disorders, including musculoskeletal, gastrointestinal, cardiovascular, and central nervous system disorders says Cheyanne Mallas. However, further research is needed to elucidate its mechanisms of action, optimize dosing regimens, and evaluate its long-term safety profile. Nevertheless, BPC-157 holds great promise as a potential therapeutic agent in the field of regenerative medicine.

[getbudslegalize]

What Are Cannabis Flavonoids? Health Benefits and Uses

What Are Cannabis Flavonoids? Medical Benefits and Uses

Cannabis flavonoids are a group of natural compounds that give cannabis plants their distinctive colors, aromas, and flavors. They are also responsible for some of the beneficial effects of cannabis, such as anti-inflammatory, antioxidant, and neuroprotective effects.

What Do Flavonoids Do?

Flavonoids have multiple roles in cannabis plants. They protect the plants from UV radiation, pests, pathogens, and environmental stress. They also modulate the production and activity of cannabinoids and terpenes, the main active compounds in cannabis. Flavonoids may also have beneficial effects on human health. They may interact with the endocannabinoid-system, a network of receptors and molecules that regulate various physiological processes such as pain, mood, appetite, memory, and inflammation. They may also modulate the activity of enzymes and transporters that affect the metabolism and bioavailability of cannabinoids and other drugs.

How Do Flavonoids Work In The Body?

Flavonoids work in different ways depending on their structure, concentration, and target.  - Some flavonoids may bind to cannabinoid receptors (CB1 and CB2) or other receptors (such as PPARs, TRPVs, and GPR55) and either activate or inhibit them.  - Some flavonoids may inhibit or induce enzymes (such as CYPs, FAAH, and COX) that break down or synthesize cannabinoids and other compounds.  - Some flavonoids may affect the expression or function of transporters (such as ABCs, SLCs, and GLUTs) that move cannabinoids and other molecules across cell membranes. The effects of flavonoids may also depend on their interactions with other compounds in cannabis or in the body. For example, some flavonoids may enhance or reduce the effects of cannabinoids by modulating their absorption, distribution, metabolism, or excretion. Some flavonoids may also act synergistically or antagonistically with other flavonoids or terpenes to produce entourage effects.

What Are The Benefits and Uses of Flavonoids?

Flavonoids have a range of benefits for different health conditions and wellness goals. Some of the potential health benefits are: - Antioxidant: Flavonoids can scavenge free radicals and protect cells from oxidative damage, which is associated with aging and many diseases. They can also modulate the expression and activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). - Anti-inflammatory: Flavonoids can inhibit the production and release of pro-inflammatory mediators, such as cytokines, prostaglandins, and leukotrienes. They can also suppress the activation of inflammatory pathways, such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and cyclooxygenases (COXs). - Anti-cancer: Flavonoids can induce apoptosis (programmed cell death) and autophagy (self-digestion) of cancer cells, as well as inhibit their proliferation, migration, invasion, and angiogenesis (blood vessel formation). They can also modulate the expression and activity of various oncogenes (cancer-promoting genes) and tumor suppressor genes (cancer-inhibiting genes). - Neuroprotective: Flavonoids can protect neurons from various insults, such as ischemia (lack of blood supply), excitotoxicity (overstimulation by glutamate), neuroinflammation, and neurodegeneration. They can also enhance neurogenesis (new neuron formation), synaptic plasticity (neural adaptation), and cognitive function. - Other effects: Flavonoids may also have anti-diabetic, anti-obesity, anti-allergic, anti-microbial, anti-viral, anti-fungal, anti-parasitic, anti-ulcer, hepatoprotective (liver-protecting), cardioprotective (heart-protecting), and bone-protective effects. Flavonoids may be used as natural supplements or adjuvants for various health conditions, such as chronic pain, inflammation, cancer, neurodegenerative diseases, metabolic disorders, allergic reactions, infections, ulcers, liver diseases, cardiovascular diseases, and osteoporosis. However, more clinical trials are needed to confirm the safety and efficacy of cannabis flavonoids in humans.

How Do Flavonoids Interact With Cannabinoids and Terpenes?

Flavonoids may enhance the effects of cannabinoids and terpenes through a phenomenon called the entourage effect. This means that the combination of different compounds in cannabis may produce synergistic effects that are greater than the sum of their individual effects. For example, some flavonoids may increase the bioavailability of cannabinoids by inhibiting their metabolism or facilitating their absorption. Some flavonoids may also modulate the activity of cannabinoid receptors or other receptors that cannabinoids interact with. Some terpenes may also enhance the absorption or penetration of flavonoids into cells or tissues. The entourage effect may explain why whole-plant cannabis extracts or products may have more benefits than isolated cannabinoids or synthetic versions. However, more research is needed to understand the exact mechanisms and outcomes of the interactions between flavonoids, cannabinoids, and terpenes.

How Many Flavonoids Are in Cannabis?

There are over 10,000 known flavonoids in nature, but those found in cannabis fall into six main subcategories: 1. Chalcones: These flavonoids are brown shade pigments that are found in many plants, such as apples, strawberries, and tomatoes. Chalcones have antioxidant, anti-inflammatory, anti-fungal, and anti-cancer effects.  2. Flavones: These flavonoids are yellow or white pigments that are found in many plants, such as parsley, celery, and chamomile. Flavones have anti-inflammatory, antioxidant, anti-allergic, and anti-cancer effects. Cannaflavin A, B, and C belong to this subcategory. 3. Isoflavonoids:

These flavonoids are mainly found in legumes, such as soybeans, peanuts, and lentils. Isoflavonoids have estrogen-like effects and can modulate hormone levels and metabolism. They also have antioxidant, anti-inflammatory, and anti-cancer properties. 4. Flavanones:

These flavonoids are yellow or orange pigments that are found in citrus fruits, such as oranges, lemons, and grapefruits. Flavanones have antioxidant, anti-inflammatory, anti-microbial, and anti-cancer effects. They can also affect cholesterol levels and blood pressure. 5. Anthoxanthins:

These flavonoids are white or pale yellow pigments that are found in many plants, such as onions, garlic, cauliflower, and cabbage. Anthoxanthins have antioxidant, anti-inflammatory, anti-microbial, and anti-cancer effects. They can also modulate blood sugar levels and prevent oxidative damage. 6. Anthocyanins:

These flavonoids are responsible for the red, purple, or blue color of many fruits and flowers. They are found in berries, grapes, eggplants, and red cabbage. They have antioxidant, anti-inflammatory, anti-cancer, and neuroprotective effects. Cannabis produces several anthocyanins, such as cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin.

These Six Subgroups Contain More Than 20 Different Flavonoids That Have Been Identified in Marijuana Plants

Here are the nine most important ones and their therapeutic effects: 1. Cannflavins A, B, C:

- Cannflavin A: This is a prenylated flavone that is unique to cannabis. Cannflavin A has potent anti-inflammatory effects that are 30 times more effective than aspirin. Cannflavin A may also inhibit the growth of certain cancer cells and protect the brain from oxidative stress. - Cannflavin B: Another prenylated flavone that is unique to cannabis. Cannflavin B has similar anti-inflammatory effects as cannflavin A but with a different chemical structure. Cannflavin B may also have anti-fungal and anti-microbial properties. - Cannflavin C: A geranylated flavone that is unique to cannabis. Cannflavin C has less anti-inflammatory effects than cannflavin A and B but has more antioxidant effects. Cannflavin C may also have neuroprotective effects by reducing the accumulation of amyloid-beta plaques in Alzheimer's disease. 2. Apigenin:

This is a flavone that is also found in chamomile, parsley, celery, and other plants. Apigenin has anti-inflammatory, anti-anxiety, anti-cancer, and estrogenic effects. Apigenin may also modulate the activity of certain enzymes that metabolize cannabinoids, thus affecting their bioavailability and potency. 3. Luteolin:

This is another flavone that is also present in many fruits and vegetables. Luteolin has anti-inflammatory, anti-oxidant, anti-diabetic, and anti-cancer effects. Luteolin may also inhibit the growth of bacteria and fungi that can cause infections or spoilage of cannabis products. 4. Kaempferol:

This is a flavonol that is also abundant in tea, kale, beans, broccoli, spinach,  and other plants. Kaempferol has anti-inflammatory, anti-oxidant, anti-diabetic, anti-cancer, and neuroprotective effects. Kaempferol may also enhance the activity of endocannabinoids, the natural cannabinoids produced by our bodies. 5. Quercetin:

This is another flavonol that is also found in many fruits, vegetables, seeds, and grains; for example, red onions, capers, and cabbage. Read the full article

[david-ojcius]

Free article: A subset of NLRs function to mitigate overzealous pro-inflammatory signaling produced by NF-κB activation. Under normal pathophysiologic conditions, proper signaling by these NLRs protect against potential autoimmune responses. These NLRs associate with several different proteins within both the canonical and noncanonical NF-κB signaling pathways to either prevent activation of the pathway or inhibit signal transduction. Inhibition of the NF-κB pathways ultimately dampens the production of pro-inflammatory cytokines and activation of other downstream pro-inflammatory signaling mechanisms. Dysregulation of these NLRs, including NLRC3, NLRX1, and NLRP12, have been reported in human inflammatory bowel disease (IBD) and colorectal cancer patients, suggesting the potential of these NLRs as biomarkers for disease detection. Mouse models deficient in these NLRs also have increased susceptibility to colitis and colitis-associated colorectal cancer. While current standard of care for IBD patients and FDA-approved therapeutics function to remedy symptoms associated with IBD and chronic inflammation, these negative regulatory NLRs have yet to be explored as potential drug targets. In this review, we describe a comprehensive overview of recent studies that have evaluated the role of NLRC3, NLRX1, and NLRP12 in IBD and colitis-associated colorectal cancer.

[juniperpublishers-nutrition]

Pandanus Conoideus Lamk Protects Inflammation by Regulating Reactive Oxygen Species and Nuclear Factor Kappa B in Lps-Induced Murine Macrophages

Abstract

Background: Pandanus conoideus Lamk (Red fruit) is a Papuan traditional food which has been used to treat various diseases. Despite these various effects of Red fruit, little is known about the physiological mechanism. Aims: The aim of this study was to investigate the anti-inflammatory properties of Red fruit oil (RFO) and establish the signal pathway of leading compounds.

Methods: Raw 264.7 murine macrophage cells were used with lipopolysaccharide (LPS). Cell viability and the pro-inflammatory factors were investigated using MTT assay, real time PCR, western blot analysis, and Enzyme linked immuno-sorbent assay (ELISA). The quantification of leading compounds in RFO was performed using high performance liquid chromatography (HPLC).

Results: RFO did not affect cell viability. RFO significantly reduced the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and both the protein level and mRNA level of iNOS in LPS-induced macrophages. RFO also regulated the reactive oxygen species (ROS) in LPS-induced macrophages. RFO attenuated the translocation of NF-κB p65 subunit, phosphorylation of I-κB, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in a dose-dependent manner. HPLC analysis determined that 1 g of RFO had 14.05±0.8 mg of β-cryptoxanthin and 7.4±0.7 mg of β-carotene.

Conclusion: RFO provides an anti-inflammatory effect by regulating ROS and NF-κB through MAPK due to the antioxidant activity.

Keywords: Pandanus conoideus Lamk; Macrophages; Anti-inflammation; ROS; NF-κB; β-cryptoxanthin

Abbreviations: RFO: Red fruit (Pandanus conoideus Lamk ) oil; LPS: Lipopolysaccharide; NO: Nitric oxide; iNOS: Inducible NO synthase; IL: Interleukin; ROS: Reactive oxygen species; ELISA: Enzyme linked immuno-sorbent assay; HPLC: High performance liquid chromatography; COX-2: Cyclooxygenase-2; PGE2: Prostaglandin E2; ERK: Extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; DMEM: Dulbecco’s modified Eagle medium; FBS: Fetal bovine serum; DCFH-DA: 2’7’-dichlorofluorescein diacetate; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; RT- PCR: Real time polymerase chain reaction

Introduction

The inflammation process is tightly regulated by both initiation and maintenance signals and considered to be a major risk factor in the pathogenesis of chronic diseases where the macrophages are important immune cells which regulate inflammation producing expression of inflammatory proteins and pro-inflammatory chemokines, cytokines, and nitric oxide (NO) [1,2]. Macrophages are highly sensitive to initiators of inflammation as lipopolysaccharide (LPS) which respond by the release of mediators not only interleukins (ILs) and cytokines, but also inducible NO synthase (iNOS) and reactive oxygen species (ROS), which inducing the inflammatory gene expression where each is associated somehow with the pathophysiological of the inflammation [3-5]. Because macrophages produce a wide range of biologically active molecules participated in both beneficial and detrimental outcomes in inflammation, modulation of macrophage activation is a good strategy to prevent this diseases. Red fruit (Pandanus conoideus Lamk) is Papuan traditional food which has been used to treat various diseases such as cancer [6] preeclampsia [7], hepatitis [8], liver cirrhosis [9], diabetes mellitus [10], and sinusitis [11]. This bioavailability of red fruit has been due to unsaturated fatty acids such as palmitoleic acid, oleic acid, linoleic acid, linolenic acid and some carotenoids [10,12]. Despite these many biological effects, few researches were reported on the mechanism of red fruit oil (RFO). β-cryptoxanthin is a typical carotenoid found abundantly in persimmon, papaya, paprika, and carrot. β-cryptoxanthin has been reported to possess several beneficial functions, such as antioxidant, cancer-preventive effects, and anti-metabolic syndrome effects [13-16]. In present study, we hypothesized that the cause of this anti-chronic inflammation and anti-cancer effect is due to antioxidant function of RFO, and evaluated the anti-inflammatory effect of RFO on LPSstimulated RAW 264.7 macrophage cells. We also investigated the mechanism of inflammatory effect of reduced ROS by RFO in LPS-stimulated macrophages and investigated the component of β-cryptoxanthin in RFO.

Materials and Methods

Chemicals and reagents

RFO (APOTEK®) was supplied from Smile international Co., Ltd (Seoul, Korea). Dulbecco’s modified Eagle medium (DMEM), fetal bovine serum (FBS), and penicillin–streptomycin was purchased from Corning (Oneonta, NY, USA). 2’7’-dichlorofluorescein diacetate (DCFH-DA) and anti-iNOS antibody were purchased from BD (San Jose, CA, USA). Peroxidase-conjugated secondary antibodies and TriZol were purchased from Life technologies (Grand island, NY, USA). Phosphor-JNK, phosphor-ERK, phosphor-p38, phosphor-IκB and NF-κB antibodies were purchased from Cell Signaling Technology Inc. (Beverly, MA, USA). The enzyme immunoassay kit used for prostagladin E2 (PGE2) was obtained from R&D Systems (Minneapolis, MN, USA). The ECL detection reagents were purchased from GE Healthcare (Buckinghamshire, UK). LPS (Escherichia coli 0111: B5) was purchased from Creative Biolabs (Shirley, NY, USA). β-actin, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and other chemicals were purchased from Sigma–Aldrich (St. Louis, MO, USA).

Cell culture

RAW 264.7, the murine macrophage cell line was purchased from American Type Culture Collection and maintained in DMEM supplement with 1 mg/mL glucose, 10% FBS, 100 mg/mL penicillin-streptomycin at 37 °C with 5% CO2

Cell viability assay

The cytotoxic effect of RFO against RAW264.7 cell lines was evaluated by MTT assay. Briefly, cells were seeded at a density of 5 × 103 cells/well in a 96-well plate for 24 h. Then, the cells were treated with at various concentrations of fractions with or without 1 μg/mL LPS. After 24 h, 2 mg/mL MTT was added onto each well, then incubated until formazan was constituted for 3h. The formazan was dissolved in dimethyl sulfoxide (DMSO) and the absorbance at 550 nm was measured using microplate reader (Molecular Devices, Sunnyvale, CA). Cell viability was calculated as a percentage of viable cells in drugs treated group versus untreated control. Each experiment was repeated three times.

Nitrite assay

Cells were treated with various concentrations of RFO for 30 min and incubated with 1 μg/mL LPS for 24 h. Because NO production is reflected in the accumulation of nitrite in the cell culture medium, 50 μL of supernatants were removed and mixed with the same volume of Greiss reagent (Promega, Madison, WI). After incubation for 10 min, the absorbance of mixture at 450 nm was measured using a spectrophotometer (TECAN, Austria). The nitrite levels were estimated as the percentage of absorbance of the sample to the respective controls.

Cyclooxygenase2 (COX-2) assay

Cells were treated with various concentrations of RFO for 30 min and incubated with 1 μg/mL LPS for 24 h. After incubation, the supernatants were removed and followed COX-2 measurement. The COX-2 concentrations were evaluated using a specific enzyme immunoassay (EIA) kit (Cayman, Ann Arbor, MI) according to the manufacturer’s instructions.

Prostaglandin E2 assay

Cells were treated with various concentrations of RFO for 30 min and incubated with 1 μg/mL LPS for 24 h. After incubation, the supernatants were removed and followed PGE2 measurement. The PGE2 concentrations were evaluated using a specific enzyme immunoassay (EIA) kit (Cayman, Ann Arbor, MI) according to the manufacturer’s instructions.

iNOS gene measurement by real-time PCR

The cells from the supernatants had been removed were subjected to RNA isolation. RNA isolation was performed using TRIzol reagent according to the manufacturer’s instructions. cDNA was synthesized using hyperscript RT master mix (GeneAll, Daejeon, Korea). The primers were described as; iNOS forward: 5′-ATGTCCGAAGCAAACATCAC-3′, reverse: 5′-TAATGTCCAGGAAGTAGGTG-3′, and GAPDH forward: 5′-TGTGATGGTGGGAATGGGTCAG-3′, reverse: 5′-TTTGATGTCAC GCACGATTTCC-3′. The PCR was amplified using ABI 7500 and Taqman gene expression master mix (Applied Biosystems, Waltham, MA, USA). The quantitative analysis was performed to compare the Δ Δ Ct after the normalization by GAPDH as an internal control. After analysis, PCR products were electrophoresed on 3% agrose gel and images were taken by cybergreen detection using Kodak imagestation FX® (Kodak, Rochester, NY, USA)

Analysis of ROS by flowcytometry

Cells were treated with various concentrations of RFO for 30 min and incubated with 1 μg/mL LPS for 24 h. Cells were followed by the addition of 10 mg/mL DCFH-DA). The suspensions were washed with PBS after incubation for 20 min. The suspensions were then assayed with a flowcytometer (C6 Accuri, BD, Bedford, MA, USA) according to Rhee et al. [4].

Western blot analysis

Cells were treated as described previously, then total lysates were prepared with lysis buffer (50 mM Tris (pH 7.4), 300 mM NaCl, 5 mM EDTA (pH 8.0), 0.5 % Triton X-100, 1 mM aprotinin, 1 mM leupeptin, 1mM pepstatin, 10mM iodoacetamide, and 2 mM phenylmethylsulfonyl fluoride (PMSF). Meanwhile, each nucleus extracts and cytosol extracts were isolated using a NE-PER nuclear and cytoplasmic extraction reagent kit (Pierce, Rockford, IL). Briefly, cells were washed with PBS, and were prepared with ice-cold extraction buffers sequentially. After centrifugation at 16,000xg, the cytoplasmic protein and nuclear extract were separated. Total lysates and nuclear fractions were estimated with Bio-Rad dye reagent concentrate (Bio-Rad Laboratories, Hercules, CA), then resolved on a 10% SDS-PAGE. After electrophoresis, the proteins were electro transferred to a PVDF membrane, blocked with 1% BSA, and probed with anti-iNOS (1:1,000), phospho- JNK (1:1,000), phospho-ERK (1:1,000), phospho-p38 (1:1,000), phospho-IκB (1:1,000), and NF-κB (1:500) antibodies at 4 °C overnight. The blot was washed, exposed to HRP-conjugated secondary antibodies for 2 h, and finally developed through enhanced chemiluminescence. For ß-actin detection, previously used membranes were soaked in stripping buffer (62.5 mM Tris- HCl, pH 6.8, 150 mM NaCl, 2% SDS, 100 mM ß-mercaptoethanol) at 65 ℃ for 30 min and hybridized with anti-ß-actin. The relative protein expression was densitometerically quantified using the BioRad GS-670 densitometer (BioRad, Hercules, CA) and normalized to β-actin.

High performance liquid chromatography (HPLC)

To determine the content of β-cryptoxanthin in RFO, we performed HPLC analysis according to previous studies [17]. HPLC analysis was performed using Agilent 1100 model with a pump (G1311C), auto sampler (G1329B), column, and diode array detector purchased from Agilent (Santa Clara, CA, USA). The analysis conditions are described in Table 1.

Statistical analysis

All results are presented as mean ± S.D. and are representing three or more independent experiments. Data were compared using the one-way ANOVA using Prism® (GraphPad, La Jolla, CA, USA) with p-values less than 0.05 considered statistically significant.

Results

RFO did not affect cell viability

Figure 1A showed the effect of RFO on viability of RAW 264.7 with or without LPS. Cell viability was not affected against 10- 1,000 μg/mL of RFO with or without LPS.

RFO reduced NO in LPS-induced macrophages

To assess the effects of RFO on NO production in LPSinduced RAW 264.7 macrophages, cells were treated with various concentrations of RFO for 30 min, then incubated with 1 μg/mL LPS for 24 h. NO release was elevated 224 ± 19.24% (p < 0.001) following LPS treatment, which was reduced 224 ± 19.24% at 10 μg/mL (p < 0.05), 161.38 ± 21.81% at 25 μg/mL (p < 0.001), and 136.16 ± 30.56% at 50 μg/mL (p < 0.001) with RFO combination (Figure 1B).

RFO decreased COX-2 production in LPS-induced macrophages

COX-2 production was significantly increased from 33.17 ± 5.23 ng/mL to 86.25 ± 1.88 ng/mL (p < 0.001) following LPS treatment. However, it was reduced 60.52 ± 12.49 ng/mL at 10 μg/mL (p < 0.05), 32.16 ± 8.85 pg/mL at 25 μg/mL (p < 0.001), and 13.27 ± 1.67 ng/mL at 50 μg/mL (p < 0.001) with RFO combination (Figure 1C).

RFO also decreased PGE2 production in LPS-induced macrophages

Meanwhile, PGE2 production was significantly increased 440.6 ± 35.36 pg/mL (p < 0.001) following LPS treatment, which was reduced 227.5 ± 13.6 pg/mL at 10 μg/mL (p < 0.001), 180.77 ± 48.95 pg/mL at 25 μg/mL (p < 0.001), and 103.27 ± 51.67 pg/ mL at 50 μg/mL (p < 0.001) with RFO combination (Figure 1D).

RFO suppressed both mRNA and protein levels of iNOS in LPS-induced macrophages

To determine the inhibitory effects of RFO on proinflammatory mediator NO, COX-2, and PGE2 production, the biosynthesis of transcriptional levels of iNOS was performed with semi-quantitative reverse-transcription PCR and western blot analysis on LPS-induced RAW 264.7 macrophages. Figure 1D indicates that both mRNA level and protein level of iNOS were significantly decreased by treatment of RFO (p < 0.001). Consistent with the findings shown in Figure 1E, RFO had a significant concentration-dependent inhibitory effect on the inflammation through pro-inflammatory mediator NO in LPSinduced RAW 264.7 macrophages.

RFO attenuated ROS in LPS-induced macrophages

The excess ROS is known to be injured intracellular proteins, lipids and nucleic acids and induce inflammation [18]. Thus, we investigated the ROS production in response to LPS using flowcytometry. DCFH-DA binds ROS produced cells. Figure 2 showed the DCFH-DA positive cells were increased following LPS treatment from 40.71 ± 2.11% to 70.87 ± 3.09%. However, ROS production was also significantly inhibited by RFO with a dose dependent manner; 47.08 ± 2.45% at 10 μg/mL (p < 0.001),41.34 ± 1.41% at 25 μg/mL (p < 0.001), and 33.76 ± 3.56% at 50 μg/mL (p < 0.001).

RFO suppressed nuclear translocation of the NF-κB p65 subunit via MAPKinase

Since p65 is a major component of NF-κB activated by LPS in macrophages, we evaluated the levels of p65 in nuclear extracts by western blotting analysis. Phosphorylation of IκB results in degradation and release of NF-κB, which then translocates to the nucleus. Therefore, we examined whether RFO could prevent phosphorylation of IκB induced by LPS treatment. Figure 3A shows that IκB phosphorylation was increased by treatment with LPS alone in cytosol level, but that such phosphorylation was significantly inhibited in the presence of RFO, similar to results for the nuclear translocation of p65. Taken together, these data suggest that the inhibitory effect of RFO on the LPS-induced translocation of p65 might be involved in the suppression of IκB phosphorylation. To further investigate whether the inhibition of pro-inflammatory mediators by RFO is modulated through the MAPK pathway, we evaluated the effects of RFO on the LPSinduced phosphorylation of p38, ERK, and JNK (Figure 3B). RFO suppressed LPS-induced phosphorylation of p38, ERK and JNK. These results suggest that RFO blocks MAPK pathways to suppress the inflammatory response in LPS-induced RAW 264.7 macrophages.

HPLC analysis of RFO

Table 2 showed the HPLC analysis of RFO. HPLC revealed that 1 g of RFO had 14.05±0.8 mg of β-cryptoxanthin and 7.4 ± 0.7 mg of β-carotene.

Discussion

Inflammation is an immune response that protects our body against host response to infection and injury [19,20]. All inflammatory responses act through mononuclear cells, macrophages, and lymphocytes. Macrophages play on important innate immune effectors and increase pro-inflammatory factors including nitric oxide (NO), prostaglandin E2 (PGE2) cytokines.

The excessive amounts of NO and PGE2 produced by activation of iNOS and COX-2 in response to LPS play an important role in inflammation [21,22]. The overproduction of iNOS-derived NO is involved in the pathology of various inflammatory disorders and tissue damage conditions. A change in the NO level through the inhibition of iNOS enzyme activity or iNOS induction provides a means of assessing the effect of these agents on the inflammatory process. iNOS is implicated in the synthesis of prostaglandin H2 starting of arachidonic acid, which is a precursor of PGE2, in activated macrophages with LPS [23]. In addition, iNOS leads to overproduction of NO, PGE2, and COX-2 which results in the production of inflammatory diseases. Thus, modulation of iNOS and NO expressions could be one of the strategies to reduce inflammatory diseases. The production of inflammatory cytokines is a crucial part of regulating inflammation and tumor progression. The key signaling pathway mediating the inflammatory response, the NF-κB transcription factor, has been well-established in various inflammatory diseases and cancers [24,25]. It is also well known that NF-κB is a significant role factor regulating the expression of inflammation-associated enzymes and cytokine genes, such as iNOS, COX-2, TNF-α and IL-1β, which contain NF-κB binding motifs within their respective promoters [1,26]. Therefore, this signaling pathway is a good target for anti-cancer and antiinflammatory drug development. Many of the upstream kinases and downstream substrates are the same for the each of the major cascades. Our results revealed that anti-inflammatory activities of RFO are mediated through the inhibition of IκB phosphorylation and nuclear translocation of the NF-κB p65 subunit. Besides, these results also indicate that the inhibitory effects of RFO on MAPK and NF-κB signaling are related to a decrease in ROS. It is well known that oxidative stress stimulates ROS production in RAW 264.7 cell line [11,27]. Our data showed the pretreatment with RFO significantly decreased ROS production in LPS-induced RAW264.7 cells using DCFH-DA staining which demonstrated that RFO had a potent to reduce the oxidative stress. We also suggested that RFO regulated MAPK and NF-κB signaling of inflammation operate through oxidative stress. These results demonstrated that RFO could act as scavenging agents or acting on redox state of the cell and other acting as scavenging agents. In previous study, we already demonstrated that RFO regulated the cellular senescence through ROS modulation in H2O2-induced endothelial cells [5].

Carotenoids such as β-cryptoxanthin, β-carotene are one of the antioxidants which are not produced in the human body that must be ingested from outside. Many studies indicated that healthy people had the higher level of β-cryptoxanthin in blood [28-31]. β-cryptoxanthin is the only provitamin A component of carotenoid-based xanthophylls [14,32]. Carotenoids are lipid soluble components that must be ingested with fat to absorb completely in the body. Carotenoids affect the inflammation levels in blood as strong antioxidants and helps purify the blood. Park et al. showed that the daily oral administration of β-cryptoxanthin prevented the progression of osteoarthritis and inhibited proinflammatory cytokines in mice [33]. Therefore, we examined the effects of RFO on the production of several inflammatory mediators and on the expression levels of iNOS in LPS-induced RAW 264.7 macrophage cells. Our results demonstrated that RFO inhibited the expression of iNOS as well as the production of NO and PGE2 and the mechanisms underlying the suppression of the inflammatory response of the NF-κB and ROS. According to the US USDA database, β-carotene content of RFO was significantly higher at 335 times of blackberry, 119 times of broccoli, 13.9 times of pumpkin, and 5.2 times for carrot [34,36]. In addition, β-cryptoxanthin content of RFO was significantly higher at 76 times of orange and 15 times of papaya [30,37]. These findings suggested that RFO might be a beneficial therapeutic agent in the treatment of a variety of inflammatory diseases.

Conclusion

RFO is Papuan traditional food and had been used to treat various disease for long time. In this study, we suggested RFO had an anti-inflammatory effect through regulating inflammatory mediators such as iNOS, COX-2, PGE2, and excessive ROS for the first time. These physiological benefits of RFO may be attributed by regulation of NF-κB transcription. HPLC indicated that large number of carotenoids such as β-cryptoxanthin, β-carotene. This finding may be a synergistic adjuvant therapy for inflammatory diseases by acting as a radical scavenger, ROS inhibitor.

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[colinwilson11]

The Rise Of CGAS-STING Pathway Market Therapies Will Lead To A Revolution In Cancer Immunotherapy

The CGAS-STING pathway market will grow at the highest pace owing to increasing R&D and growing potential of nucleic-acid sensing pathway modulators in cancer immunotherapy. The innate immune system recognizes nucleic acid species unique to pathogens via cytosolic DNA sensors and mediates type I interferon (IFN) responses that are critical for anti-viral immunity. Of these sensors, the cGAS-STING pathway couples cytosolic DNA sensing to type I IFN induction and downstream transcriptional programs. Once activated, cGAS produces the second messenger cyclic GMP-AMP (cGAMP) which binds and activates stimulator of IFN genes (STING). This signals the activation of downstream IFN regulatory factor 3 (IRF3) and NF-κB, leading to production of type I IFNs and pro-inflammatory cytokines.

The CGAS STING Pathway Market is estimated to be valued at US$ 0.46 Bn in 2024 and is expected to exhibit a CAGR of 25.% over the forecast period 2024-2031.

Growing significance of immunotherapy in cancer treatment and the advantages of targeting the cGAS-STING pathway such as involvement in sensing tumor DNA in the cytoplasm and activation of potent antitumor immunity has augmented the demand of associated drugs and therapies. The success of immunotherapy approaches has led to substantial investment in nucleic acid-sensing pathway modulators by pharmaceutical companies.

Key Takeaways

Key players operating in the cGAS-STING pathway are IFM Therapeutics, Bristol-Myers Squibb, Novartis, AstraZeneca, Merck & Co. Companies are investing heavily in R&D to develop novel therapeutics targeting this pathway. For instance, IFM Therapeutics is developing first-in-class STING agonist focusing on liver and gastrointestinal cancers in phase I/II clinical trial.

The demand for cGAS-STING therapies is increasing rapidly mainly due to growing demand for innovative cancer immunotherapies. According to American Cancer Society, around 1.9 million new cancer cases are diagnosed in the US annually presenting massive market potential. Additionally, improving accessibility of immunotherapy in developing countries will further drive the demand.

Advancements in understanding molecular mechanisms of cGAS-STING pathway activation and development of novel agonist and modulators have expanded therapeutic applications. Ongoing research for developing vaccines and combination therapies with checkpoint inhibitors holds promise to revolutionize cancer treatment through innate immunity activation.

Market Trends

Combination therapies research: There is growing focus on exploring synergies of cGAS-STING agonists with other immunotherapies like checkpoint inhibitors. Ongoing clinical trials evaluating combinations are demonstrating encouraging response rates.

Personalized medicine approach: Efforts are being made to develop biomarkers to predict response and identify patients likely to benefit from cGAS-STING therapies. This personalized approach can improve clinical outcomes.

Geographical expansion: Major players are expanding manufacturing and clinical trials to countries like China and India having huge patient pools. This will boost accessibility and commercialization prospects.

Market Opportunities

First STING agonist approval: IFM Therapeutics' lead molecule will be the first STING agonist examined in registrational trials paving way for first approval in 2026-27.

 Increased adoptability: As clinical evidence demonstrating benefits of cGAS-STING modulation emerges, adoption rate in treatment guidelines and clinical practice is expected to surge exponentially.

New therapeutic areas: Preliminary evidence shows cGAS-STING pathway also plays a role in autoimmune diseases providing scope for therapies in indications beyond oncology.

Impact Of COVID-19 On CGAS STING Pathway Market Growth

The COVID-19 pandemic has profoundly impacted the CGAS STING Pathway Market. During the initial outbreak in early 2020, the market recorded a decline as research activities slowed down and clinical trials faced interruptions due to lockdowns and social distancing norms. However, with shifting focus on immune therapies for tackling novel coronavirus infections, the interest in CGAS STING pathway modulators witnessed rapid growth. Many companies expedited their programs related to IFN activation via cGAS-STING pathway to develop host-directed antiviral therapies against SARS-CoV-2. The pandemic highlighted the need for developing strategies to strengthen innate immune responses via cGAS-STING pathway modulation. While clinical studies faced delays in 2020, collaborations between industry and research institutes intensified to advance immunotherapies targeting this pathway. Moving forward, the high growth projected for this market is expected to accelerate further on the back of strong ongoing research to evaluate potential of cGAS-STING pathway modulators as adjuvant or monotherapy for COVID-19.

Regional Concentration Of CGAS STING Pathway Market

North America currently dominates the CGAS STING Pathway Market and holds over 40% of the global market share in terms of value. This is due to high immunotherapies R&D spending and strong presence of key market players in the US. Moreover, the region is an early adopter of novel immune mechanisms and immune-oncology approaches. Within North America, the United States represents the most lucrative market owing to significant research funding and growing clinical adoption of STING agonists. On the other hand, Asia Pacific region is projected to witness the fastest growth during the forecast period with a CAGR of over 30%. This impressive growth can be attributed to rising healthcare expenditure, expanding clinical research infrastructure and growing focus of global pharma companies on emerging Asian markets. China and India are expected to spearhead the growth of CGAS STING Pathway Market in Asia Pacific region.

Europe currently represents the second largest regional market for CGAS STING pathway modulators globally. Availability of latest healthcare technologies, sophisticated research infrastructure and presence of major industry players have aided the growth of CGAS STING Pathway Market in Europe. Within the region, Germany, United Kingdom and France together hold around half of the total European market in terms of value. However, Eastern Europe is estimated to depict the fastest gains owing to increasing government spending to strengthen native research capabilities. Moreover, growing collaborations between European and US pharmaceutical firms will further stimulate market growth during the forecast period.

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Author Bio

Vaagisha brings over three years of expertise as a content editor in the market research domain. Originally a creative writer, she discovered her passion for editing, combining her flair for writing with a meticulous eye for detail. Her ability to craft and refine compelling content makes her an invaluable asset in delivering polished and engaging write-ups. (LinkedIn: https://www.linkedin.com/in/vaagisha-singh-8080b91)

What Are The Key Data Covered In This CGAS STING Pathway Market Report?

:- Market CAGR throughout the predicted period

:- Comprehensive information on the aspects that will drive the CGAS STING Pathway Market's growth between 2024 and 2031.

:- Accurate calculation of the size of the CGAS STING Pathway Market and its contribution to the market, with emphasis on the parent market

:- Realistic forecasts of future trends and changes in consumer behaviour

:- CGAS STING Pathway Market Industry Growth in North America, APAC, Europe, South America, the Middle East, and Africa

:- A complete examination of the market's competitive landscape, as well as extensive information on vendors

:- Detailed examination of the factors that will impede the expansion of CGAS STING Pathway Market vendors

FAQ’s

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Q.4 Which of the top CGAS STING Pathway Market companies compare in terms of sales, revenue, and prices?

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*Note: 1. Source: Coherent Market Insights, Public sources, Desk research 2. We have leveraged AI tools to mine information and compile it