greenmedinfo--2020-08-24--Crucial Viewing: Understanding the COVID-19 "CASEDEMIC"

Ivor Cummins explains how despite mainstream media claims to the contrary , the epidemic has waned and has been replaced @ @ @ @ @ Casedemic .
Please consider supporting the work of Ivor Cummins at his Patreon Link : @ @ @ @

Visit our Re-post guidelines This article is copyrighted by GreenMedInfo LLC, 2020
Ivor Cummins explains how despite mainstream media claims to the contrary, the epidemic has waned and has been replaced with an irrational, unscientific Casedemic
Please consider supporting the work of Ivor Cummins at his Patreon Link: https://www.patreon.com/IvorCummins.


greenmedinfo--2020-08-24--Strawberry leaf extract may be a potential drug candidate for the treatment of diabetes-associated c

Strawberry leaf extract may be a potential drug candidate for the treatment of diabetes-associated cognitive impairment.

Diabetes-associated cognitive impairment ( DACI ) is a common complication of diabetes mellitus ( DM ) that affects the central nervous system .
Cognitive impairment , such as learning and memory impairment , and even dementia , is the main clinical manifestation of DACI .
Unfortunately , there is no effective means by which to delay the cognitive symptoms of DM .
Evidence has shown that strawberry leaf extract could alleviate cognitive decline , suppress oxidative stress , and reduce inflammatory responses in rats .
In the present study , we evaluated the effect of strawberry leaf extract on cognitive @ @ @ @ @ @ @ ( STZ ) -induced diabetes .
After the continuous administration of strawberry leaf extract for 4 weeks , the Morris Water Maze ( MWM ) test results showed that the cognitive impairment of the rats was alleviated .
Moreover , strawberry leaf extract significantly reduced the level of reactive oxygen species ( ROS ) , decreased the level of malondialdehyde ( MDA ) , improved the activity of superoxide dismutase ( SOD ) and catalase ( CAT ) , decreased the mRNA expression of interleukin-6 ( IL-6 ) and tumor necrosis factor-α ( @ @ @ @ @ @ @ of caspase-3 and caspase-9 in the hippocampus of DM rats .
Also , transcription factor nuclear factor erythroid 2 ( NF-E2 ) -related factor 2 ( Nrf2 ) /hemeoxygenase-1 ( HO-1 ) signaling was activated by the administration of strawberry leaf extract .
Our findings indicate that strawberry leaf extract may be a potential drug candidate for the treatment of DACI and may be used as a basis for further research on the development of drugs for cognitive impairment in diabetes .

Diabetes-associated cognitive impairment (DACI) is a common complication of diabetes mellitus (DM) that affects the central nervous system. Cognitive impairment, such as learning and memory impairment, and even dementia, is the main clinical manifestation of DACI. Unfortunately, there is no effective means by which to delay the cognitive symptoms of DM. Evidence has shown that strawberry leaf extract could alleviate cognitive decline, suppress oxidative stress, and reduce inflammatory responses in rats. In the present study, we evaluated the effect of strawberry leaf extract on cognitive function in a rat model of streptozotocin (STZ)-induced diabetes. After the continuous administration of strawberry leaf extract for 4 weeks, the Morris Water Maze (MWM) test results showed that the cognitive impairment of the rats was alleviated. Moreover, strawberry leaf extract significantly reduced the level of reactive oxygen species (ROS), decreased the level of malondialdehyde (MDA), improved the activity of superoxide dismutase (SOD) and catalase (CAT), decreased the mRNA expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and decreased the protein expression of caspase-3 and caspase-9 in the hippocampus of DM rats. Also, transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)/hemeoxygenase-1(HO-1) signaling was activated by the administration of strawberry leaf extract. Our findings indicate that strawberry leaf extract may be a potential drug candidate for the treatment of DACI and may be used as a basis for further research on the development of drugs for cognitive impairment in diabetes.


greenmedinfo--2020-08-24--The gut microbiota metabolite urolithin A induces p53-dependent cellular senescence in human colon c

The gut microbiota metabolite urolithin A induces p53-dependent cellular senescence in human colon cancer cells.

The promotion of senescence in cancer cells by dietary ( poly ) phenols gained attention as a promising chemopreventive strategy against colorectal ( CRC ) and other cancers .
Urolithins ( Uros ) are ellagitannins and ellagic acid-derived gut microbiota metabolites that reach high concentrations in the human colon .
They were postulated to be as potential anticancer agents in different CRC models , but their role as promoters of cellular senescence has never been comprehensively evaluated .
We evaluated long-term senescent-mediated chemoprevention of physiologically relevant doses of different Uros and representative mixtures of human urolithin metabotypes in human CRC @ @ @ @ @ @ @ ) and non-tumorigenic ( CCD18-Co ) cell lines .
Our results show that Uro-A ( but not Uro-C , IsoUro-A , or Uro-B ) leads to a dose-dependent anti-clonogenic effect through the increase of the senescence-associatedβ-galactosidase activity , rather than by reversible cell cycle arrest and ( or ) apoptosis which require much higher concentrations .
Senescence was accompanied by an elevated p53 and p21expression in HCT-116 cells ( p53-wild type ) , but not in other CRC lines with p53 mutated or non-tumorigenic cells , which suggests that long-term senescence-mediated chemoprevention is @ @ @ @ @ @ @ ATP-binding cassette transporters and the phase-II metabolism of Uros limited the induction of senescence , which anticipates lower effects of conjugated Uros against systemic cancers .

The promotion of senescence in cancer cells by dietary (poly)phenols gained attention as a promising chemopreventive strategy against colorectal (CRC) and other cancers. Urolithins (Uros) are ellagitannins and ellagic acid-derived gut microbiota metabolites that reach high concentrations in the human colon. They were postulated to be as potential anticancer agents in different CRC models, but their role as promoters of cellular senescence has never been comprehensively evaluated. We evaluated long-term senescent-mediated chemoprevention of physiologically relevant doses of different Uros and representative mixtures of human urolithin metabotypes in human CRC (HCT-116, Caco-2, and HT-29) and non-tumorigenic (CCD18-Co) cell lines. Our results show that Uro-A (but not Uro-C, IsoUro-A, or Uro-B) leads to a dose-dependent anti-clonogenic effect through the increase of the senescence-associatedβ-galactosidase activity, rather than by reversible cell cycle arrest and(or) apoptosis which require much higher concentrations. Senescence was accompanied by an elevated p53 and p21expression in HCT-116 cells (p53-wild type), but not in other CRC lines with p53 mutated or non-tumorigenic cells, which suggests that long-term senescence-mediated chemoprevention is a p53-dependent manner. Moreover, the ATP-binding cassette transporters and the phase-II metabolism of Uros limited the induction of senescence, which anticipates lower effects of conjugated Uros against systemic cancers.


greenmedinfo--2020-08-27--Antioxidant and neuroprotective effects induced by cannabidiol and cannabigerol in rat CTX-TNA2 astr

Antioxidant and neuroprotective effects induced by cannabidiol and cannabigerol in rat CTX-TNA2 astrocytes and isolated cortexes.

Cannabidiol ( CBD ) and cannabigerol ( CBG ) areterpenophenols .
Although CBD 's effectiveness against neurological diseases has already been demonstrated , nothing is known about CBG .
Therefore , a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases .
Rat astrocytes were exposed to hydrogen peroxide and cell viability , reactive oxygen species production and apoptosis occurrence were investigated .
Cortexes were exposed to K60 mM depolarizing stimulus and serotonin ( 5-HT ) turnover , 3-hydroxykinurenine and kynurenic acid levels were measured .
@ @ @ @ @ @ @ studies were performed .
Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli , whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid .
CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis .
Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor.The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions , whereas findings in the ex vivo @ @ @ @ @ @ @ roles of CBD and CBG as neuroprotective agents .

Cannabidiol (CBD) and cannabigerol (CBG) areterpenophenols. Although CBD's effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases. Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed. Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor.The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.


greenmedinfo--2020-08-27--Rapid antibacterial activity of cannabichromenic acid against methicillin-resistant Staphylococcus a

Rapid antibacterial activity of cannabichromenic acid against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant ( MRSA ) has proven to be an imminent threat to public health , intensifying the need for novel therapeutics .
Previous evidence suggests that cannabinoids harbour potent antibacterial activity .
In this study , a group of previously inaccessible phytocannabinoids and synthetic analogues were examined for potential antibacterial activity .
The minimum inhibitory concentrations and dynamics of bacterial inhibition , determined through resazurin reduction and time-kill assays , revealed the potent antibacterial activity of the phytocannabinoids against gram-positive antibiotic-resistant bacterial species , including MRSA .
One phytocannabinoid , cannabichromenic acid ( CBCA ) , demonstrated faster and more @ @ @ @ @ @ @ currently recommended antibiotic for the treatment of MRSA infections .
Such bactericidal activity was sustained against low-and high-dose inoculums as well as exponential- and stationary-phase MRSA cells .
Further , mammalian cell viability was maintained in the presence of CBCA .
Finally , microscopic evaluation suggests that CBCA may function through the degradation of the bacterial lipid membrane and alteration of the bacterial nucleoid .
The results of the current study provide encouraging evidence that cannabinoids may serve as a previously unrecognised resource for the generation of novel antibiotics active against MRSA .

Methicillin-resistant(MRSA) has proven to be an imminent threat to public health, intensifying the need for novel therapeutics. Previous evidence suggests that cannabinoids harbour potent antibacterial activity. In this study, a group of previously inaccessible phytocannabinoids and synthetic analogues were examined for potential antibacterial activity. The minimum inhibitory concentrations and dynamics of bacterial inhibition, determined through resazurin reduction and time-kill assays, revealed the potent antibacterial activity of the phytocannabinoids against gram-positive antibiotic-resistant bacterial species, including MRSA. One phytocannabinoid, cannabichromenic acid (CBCA), demonstrated faster and more potent bactericidal activity than vancomycin, the currently recommended antibiotic for the treatment of MRSA infections. Such bactericidal activity was sustained against low-and high-dose inoculums as well as exponential- and stationary-phase MRSA cells. Further, mammalian cell viability was maintained in the presence of CBCA. Finally, microscopic evaluation suggests that CBCA may function through the degradation of the bacterial lipid membrane and alteration of the bacterial nucleoid. The results of the current study provide encouraging evidence that cannabinoids may serve as a previously unrecognised resource for the generation of novel antibiotics active against MRSA.


greenmedinfo--2020-08-27--Cognitive protective mechanism of crocin pretreatment in rat submitted to acute high-altitude hypoxi

Cognitive protective mechanism of crocin pretreatment in rat submitted to acute high-altitude hypoxia exposure.

Inadequate oxygen availability at high altitude leads to oxidative stress , resulting in hippocampal neurodegeneration and memory impairment .
In our previous study , we found that the cognitive dysfunction occurred when male SD rat was rapidly exposed to 4200 m of high altitude for 3 days .
And we also found that crocin showed a cognitive protective effect under hypoxia by regulating SIRT1/PGC-1pathways in rat 's hippocampus .
In this article , focused on factors related to SIRT1/PGC-1pathways , we proposed to further elucidate crocin 's pharmacological mechanism .
Adult male Sprague-Dawley rats were randomly divided into five groups @ @ @ @ @ @ @ rats were rapidly transported to high altitude of 4200 m for 72 h ) , and crocins+hypoxia groups ( pretreatment with crocin of 25 , 50 , and 100 mg/kg/d for 3 days ) .
The learning and memory ability was tested by Morris water maze analysis .
Hippocampal histopathological changes were observed by HE staining and Nissl staining .
The expression of NRF1 , TFAM , Bcl-2 , Bax , and caspase-3 was detected by immunohistochemistry , RT-PCR , and western blotting test .
The contents of malondialdehyde ( MDA ) , @ @ @ @ @ @ @ ( GSH ) , and glutathione peroxidase ( GSHPx ) were detected by the TBA , WST , and colorimetry method .
Neuronal apoptosis was observed by TUNEL staining .
After crocin pretreatment , the traveled distance was significantly reduced and the percentage of time in the target quadrant was significantly increased tested by Morris water maze .
And neuronal damage in the hippocampus was also significantly ameliorated based on HE staining and Nissl staining .
Furthermore , in hippocampus tissue , mitochondrial biosynthesis-related factors of NRF1 , TFAM expression was increased ; @ @ @ @ @ @ @ , and GSHPx expression level were increased , and MDA and glutathione disulfide ( GSSG ) level were decreased ; antiapoptotic protein Bcl-2 expression was increased , and proapoptotic proteins Bax and caspase-3 expression were decreased , with a manner of crocin dose dependent .
Therefore , the cognitive protective mechanism of crocin in rat under acute hypoxia was related to promoting mitochondrial biosynthesis , ameliorating oxidative stress injury , and decreasing neuronal apoptosis .

Inadequate oxygen availability at high altitude leads to oxidative stress, resulting in hippocampal neurodegeneration and memory impairment. In our previous study, we found that the cognitive dysfunction occurred when male SD rat was rapidly exposed to 4200 m of high altitude for 3 days. And we also found that crocin showed a cognitive protective effect under hypoxia by regulating SIRT1/PGC-1pathways in rat's hippocampus. In this article, focused on factors related to SIRT1/PGC-1pathways, we proposed to further elucidate crocin's pharmacological mechanism. Adult male Sprague-Dawley rats were randomly divided into five groups: control group, hypoxia group (rats were rapidly transported to high altitude of 4200 m for 72 h), and crocins+hypoxia groups (pretreatment with crocin of 25, 50, and 100 mg/kg/d for 3 days). The learning and memory ability was tested by Morris water maze analysis. Hippocampal histopathological changes were observed by HE staining and Nissl staining. The expression of NRF1, TFAM, Bcl-2, Bax, and caspase-3 was detected by immunohistochemistry, RT-PCR, and western blotting test. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSHPx) were detected by the TBA, WST, and colorimetry method. Neuronal apoptosis was observed by TUNEL staining. After crocin pretreatment, the traveled distance was significantly reduced and the percentage of time in the target quadrant was significantly increased tested by Morris water maze. And neuronal damage in the hippocampus was also significantly ameliorated based on HE staining and Nissl staining. Furthermore, in hippocampus tissue, mitochondrial biosynthesis-related factors of NRF1, TFAM expression was increased; oxidative stress factors of SOD, GSH, and GSHPx expression level were increased, and MDA and glutathione disulfide (GSSG) level were decreased; antiapoptotic protein Bcl-2 expression was increased, and proapoptotic proteins Bax and caspase-3 expression were decreased, with a manner of crocin dose dependent. Therefore, the cognitive protective mechanism of crocin in rat under acute hypoxia was related to promoting mitochondrial biosynthesis, ameliorating oxidative stress injury, and decreasing neuronal apoptosis.


greenmedinfo--2020-08-27--Crocin improves insulin sensitivity and ameliorates adiposity.

Crocin is a carotenoid compound which possesses multiple biological activities .
Our and other laboratory 's previous findings show that crocin alleviates obesity and type 2 diabetes-related complications .
We have found that crocin activates AMP-activated protein kinase ( AMPK ) signaling and inhibition of AMPK suppresses crocin-induced protective effects .
However , the causal role of AMPK activation in the biological role of crocin is still not verified .
In the present study , we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice .
In AMPKKO diabetic @ @ @ @ @ @ @ against glucose and lipid metabolic dysfunction were abolished .
These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction .
Moreover , we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPK .
We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice , while this effect was abolished in AMPKKO diabetic mice .
The regulation of downstream targets of CDK5/PPARby crocin was abolished by the deficiency of AMPK .
In conclusion @ @ @ @ @ @ @ AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction .
Activation of AMPK downregulates the protein level of CDK5 , followed by the decrease of PPARphosphorylation , leading to the inhibition of adipose formation and metabolic dysfunction .
Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARsignaling .

Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory's previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKKO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPK. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKKO diabetic mice. The regulation of downstream targets of CDK5/PPARby crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARphosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARsignaling.


greenmedinfo--2020-08-27--Dietary crocin is protective in pancreatic cancer while reducing radiation-induced hepatic oxidative

Dietary crocin is protective in pancreatic cancer while reducing radiation-induced hepatic oxidative damage.

Pancreatic cancer is one of the fatal causes of global cancer-related deaths .
Although surgery and chemotherapy are standard treatment options , post-treatment outcomes often end in a poor prognosis .
In the present study , we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin .
Crocin is a carotenoid isolated from the dietary herb saffron , a prospect for novel leads as an anti-cancer agent .
Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2 .
It modulated the expression of cell cycle signaling proteins P53 , @ @ @ @ @ @ @ , Cyt-c and P38 .
Concomitantly , crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol .
Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints ( 723 ) are significantly affected by crocin .
In mice bearing pancreatic tumors , crocin significantly reduced tumor burden without a change in body weight .
Additionally , it showed significant protection against radiation-induced hepatic oxidative damage , reduced the levels of hepatic toxicity and preserved @ @ @ @ @ @ @ crocin has a potential role in the treatment , prevention and management of pancreatic cancer .

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.


greenmedinfo--2020-08-27--Crocin attenuates CCl 4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fi

Crocin attenuates CCl 4-induced liver fibrosis via PPAR-γ mediated modulation of inflammation and fibrogenesis in rats.

BACKGROUND : Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide .
In the present study , we have evaluated the antifibrotic effect of crocin , a carotenoid present in the stigma of , and also explored its putative mechanism of action .
METHODS : Liver fibrosis was induced by intraperitoneal administration of 30 % carbon tetrachloride ( CCl ) .
The crocin was administered orally at 20 , 40 and 80 mg/kg body weight along with CClup to 8 weeks .
RESULTS : Chronic exposure to CClresulted in elevated levels of liver enzymes @ @ @ @ @ @ @ ) activity in the liver .
The liver tissue showed cellular swelling , vacuolization , necrosis , infiltration of inflammatory cells and fibrotic changes .
The crocin treatment significantly lowered the levels of liver enzymes in serum and improved the liver CYP2E1 mRNA levels .
The pathological changes in the liver were also lowered by crocin treatment .
The level of pro-inflammatory cytokines , nuclear factor-kappa B , interleukin-6 and tumor necrosis factorα and fibrogenic factor , transforming growth factor β , and α-smooth muscle actin were elevated by the CClin the liver @ @ @ @ @ @ @ different doses significantly reduced the expression of these factors .
The increased caspase 3/7 activity was also lowered by crocin .
CCladministration decreased the expression of peroxisome proliferator-activated receptorγ ( PPAR-γ ) in liver tissue .
The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin .
CONCLUSIONS : Crocin attenuated the various events in the progression of liver fibrosis via PPAR-γ mediated modulation of inflammatory and fibrogenic pathways .

BACKGROUND: Liver fibrosis is a chronic pathological condition with a leading cause of liver-related mortality worldwide. In the present study, we have evaluated the antifibrotic effect of crocin, a carotenoid present in the stigma of, and also explored its putative mechanism of action.
METHODS: Liver fibrosis was induced by intraperitoneal administration of 30% carbon tetrachloride (CCl). The crocin was administered orally at 20, 40 and 80 mg/kg body weight along with CClup to 8 weeks.
RESULTS: Chronic exposure to CClresulted in elevated levels of liver enzymes and reduced cytochrome P450 2E1 (CYP2E1) activity in the liver. The liver tissue showed cellular swelling, vacuolization, necrosis, infiltration of inflammatory cells and fibrotic changes. The crocin treatment significantly lowered the levels of liver enzymes in serum and improved the liver CYP2E1 mRNA levels. The pathological changes in the liver were also lowered by crocin treatment. The level of pro-inflammatory cytokines, nuclear factor-kappa B, interleukin-6 and tumor necrosis factorα and fibrogenic factor, transforming growth factor β, and α-smooth muscle actin were elevated by the CClin the liver tissue. However, crocin treatment at different doses significantly reduced the expression of these factors. The increased caspase 3/7 activity was also lowered by crocin. CCladministration decreased the expression of peroxisome proliferator-activated receptorγ (PPAR-γ) in liver tissue. The improved PPAR-γ expression in the liver by crocin treatment indicates its role in the therapeutic effect of crocin.
CONCLUSIONS: Crocin attenuated the various events in the progression of liver fibrosis via PPAR-γ mediated modulation of inflammatory and fibrogenic pathways.


greenmedinfo--2020-08-27--Crocin: A fighter against inflammation and pain.

Crocin , a water-soluble carotenoid , is known as a pharmacologically active compound , particularly for its potent anti-oxidant activity .
The present work provides a comprehensive review of the available literature concerning the anti-inflammatory properties of crocin in various organs/systems as well as its anti-nociceptive effects .
PubMed , Scopus , and Web of Science electronic databases were systematically searched up to 28 March 2020 to detect all relevant preclinical and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses ( PRISMA ) statement .
In total , 104 studies were included for qualitative @ @ @ @ @ @ @ indicated that crocin not only combats reactive oxygen species production and suppresses pro-inflammatory cytokines secretion but also alleviates inflammation in various organs ( e.g .
the lung , heart , brain , and kidney ) , in a series of animal models and in vitro experiments , via regulating mainly NF-κB pathway and NF-κBp65 translocation to the cell nucleus .
In this context , modulation of PI3K/Akt appears to be a favorable crocin target contributing to NF-κB pathway inhibition .
Even though data is limited in humans with only one clinically relevant study @ @ @ @ @ @ @ anti-inflammatory/anti-nociceptive effects of crocin are promising and warrant further testing in clinical settings .

Crocin, a water-soluble carotenoid, is known as a pharmacologically active compound, particularly for its potent anti-oxidant activity. The present work provides a comprehensive review of the available literature concerning the anti-inflammatory properties of crocin in various organs/systems as well as its anti-nociceptive effects. PubMed, Scopus, and Web of Science electronic databases were systematically searched up to 28 March 2020 to detect all relevant preclinical and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 104 studies were included for qualitative synthesis. This systematic search and review indicated that crocin not only combats reactive oxygen species production and suppresses pro-inflammatory cytokines secretion but also alleviates inflammation in various organs (e.g. the lung, heart, brain, and kidney), in a series of animal models and in vitro experiments, via regulating mainly NF-κB pathway and NF-κBp65 translocation to the cell nucleus. In this context, modulation of PI3K/Akt appears to be a favorable crocin target contributing to NF-κB pathway inhibition. Even though data is limited in humans with only one clinically relevant study retrieved, the results of preclinicalstudies regarding anti-inflammatory/anti-nociceptive effects of crocin are promising and warrant further testing in clinical settings.


greenmedinfo--2020-08-27--The findings indicate that crocin supplementation can improve glycemic control and insulin resistanc

Background : Crocin as a carotenoid exerts anti-oxidant , anti-inflammatory , anti-cancer , neuroprotective and cardioprotective effects .
Besides , the increasing prevalence of diabetes mellitus and its allied complications , and also patients ' desire to use natural products for treating their diseases , led to the design of this study to evaluate the efficacy of crocin on glycemic control , insulin resistance and active adenosine monophosphate-activated protein kinase ( AMPK ) levels in patients with type-2 diabetes ( T2D ) .
Methods : In this clinical trial with a parallel-group design , 50 patients with T2D received either @ @ @ @ @ @ @ , for 12 weeks .
Anthropometric measurements , dietary intake , physical activity , blood pressure , glucose homeostasis parameters , active form of AMPK were assessed at the beginning and at the end of the study .
Results : Compared with the placebo group , crocin improved fasting glucose level ( = 0.015 ) , hemoglobin A1c ( = 0.045 ) , plasma insulin level ( = 0.046 ) , insulin resistance ( = 0.001 ) , and insulin sensitivity ( = 0.001 ) .
Based on the within group analysis , @ @ @ @ @ @ @ levels of glucose , insulin , hemoglobin A1c , systolic blood pressure , insulin resistance and insulin sensitivity .
The active form of AMPK did not change within and between groups after intervention .
Conclusions : The findings indicate that crocin supplementation can improve glycemic control and insulin resistance in patients with T2D .
Further studies are needed to confirm these findings.This study has been registered at Clinicaltrial.gov with registration number NCT04163757 .

Background: Crocin as a carotenoid exerts anti-oxidant, anti-inflammatory, anti-cancer, neuroprotective and cardioprotective effects. Besides, the increasing prevalence of diabetes mellitus and its allied complications, and also patients' desire to use natural products for treating their diseases, led to the design of this study to evaluate the efficacy of crocin on glycemic control, insulin resistance and active adenosine monophosphate-activated protein kinase (AMPK) levels in patients with type-2 diabetes (T2D).
Methods: In this clinical trial with a parallel-group design, 50 patients with T2D received either 15-mg crocin or placebo, twice daily, for 12 weeks. Anthropometric measurements, dietary intake, physical activity, blood pressure, glucose homeostasis parameters, active form of AMPK were assessed at the beginning and at the end of the study.
Results: Compared with the placebo group, crocin improved fasting glucose level ( = 0.015), hemoglobin A1c ( = 0.045), plasma insulin level ( = 0.046), insulin resistance ( = 0.001), and insulin sensitivity ( = 0.001). Based on the within group analysis, crocin led to significant improvement in plasma levels of glucose, insulin, hemoglobin A1c, systolic blood pressure, insulin resistance and insulin sensitivity. The active form of AMPK did not change within and between groups after intervention.
Conclusions: The findings indicate that crocin supplementation can improve glycemic control and insulin resistance in patients with T2D. Further studies are needed to confirm these findings.This study has been registered at Clinicaltrial.gov with registration number NCT04163757.


greenmedinfo--2020-08-27--Beneficial effects of crocin against depression.

Depression is one of the foremost psychological illness , and the exact mechanism is unclear .
Recent studies have reported that the pituitary adenylate cyclase-activating polypeptide ( PACAP ) signaling pathway is involved in the progression of depression .
In the present study , we extracted crocin from the traditional Chinese medicine ( TCM ) , Ellis , to evaluate its antidepressant effect and clarify the underlying mechanism .
Here , we established a chronic unpredictable mild stress ( CUMS ) mouse model to assess whether crocin can improve depression-like behavior in an open field test ( OFT ) , @ @ @ @ @ @ @ forced swimming test ( FST ) , and sucrose preference test ( SPT ) .
A corticosterone ( CORT ) model of PC12 was set up to explore the antidepressant mechanism of crocin .
We pretreated PC12 cells with crocin for 1 hour and then stimulated the cells with CORT for 24 hours .
Cell survival was detected by Hoechst staining and MTT assay .
The expression of PACAP , cyclic adenosine monophosphate ( cAMP ) response element binding protein ( CREB ) , and extracellular regulated protein kinases ( ERK ) were @ @ @ @ @ @ @ was used to interfere with PC12 cells to downregulate the content of PACAP .
The results showed that crocin ( 30 mg/kg ) significantly reversed the decrease of body weight and elevation of serum CORT , mitigated CUMS induced depression-like behaviors of mice , and crocin ( 12.5 mol/L ) protected PC12 cells against CORT ( 200 mol/L ) -induced injury .
Furthermore , crocin greatly increased the protein expression of PACAP and phosphorylation of ERK and CREB in the CORT model .
PACAP RNAi cancelled the neuroprotective effect of crocin .
In @ @ @ @ @ @ @ exerted an antidepressant effect via upregulating PACAP and its downstream ERK and CREB signaling pathways .

Depression is one of the foremost psychological illness, and the exact mechanism is unclear. Recent studies have reported that the pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathway is involved in the progression of depression. In the present study, we extracted crocin from the traditional Chinese medicine (TCM),Ellis, to evaluate its antidepressant effect and clarify the underlying mechanism. Here, we established a chronic unpredictable mild stress (CUMS) mouse model to assess whether crocin can improve depression-like behavior in an open field test (OFT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT). A corticosterone (CORT) model of PC12 was set up to explore the antidepressant mechanism of crocin. We pretreated PC12 cells with crocin for 1 hour and then stimulated the cells with CORT for 24 hours. Cell survival was detected by Hoechst staining and MTT assay. The expression of PACAP, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and extracellular regulated protein kinases (ERK) were analyzed by western blotting. PACAP RNAi was used to interfere with PC12 cells to downregulate the content of PACAP. The results showed that crocin (30 mg/kg) significantly reversed the decrease of body weight and elevation of serum CORT, mitigated CUMS induced depression-like behaviors of mice, and crocin (12.5 mol/L) protected PC12 cells against CORT (200 mol/L)-induced injury. Furthermore, crocin greatly increased the protein expression of PACAP and phosphorylation of ERK and CREB in the CORT model. PACAP RNAi cancelled the neuroprotective effect of crocin. In conclusion, these results indicated that crocin exerted an antidepressant effect via upregulating PACAP and its downstream ERK and CREB signaling pathways.


greenmedinfo--2020-08-27--Crocin increases gastric cancer cells' sensitivity to doxorubicin.

BACKGROUND : Crocin is one of the substantial constituents of saffron extract .
It has multiple clinical effects including anti-cancer effects .
The development of the multidrug resistance ( MDR ) phenotype is one of the principal causes of cancer chemotherapy failure .
The multidrug resistance protein 1 ( MDR1 ) is one of the MDR-related protein and is often overexpressed in different cancers .
In the present study , we aimed to evaluate the influence of crocin on the expression and function of MDR1 protein in EPG85-257 and EPG85-257RDB gastric cancer cell lines .
METHODS : The cytotoxicity effect @ @ @ @ @ @ @ assay .
The impacts of crocin on the expression and function of MDR1 were assessed by Real-time RT-PCR and MTT assay , respectively .
RESULTS : The results demonstrated that crocin decreased cell viability in a dose-dependent manner with higher intensity on the EPG85-257 than the EPG85-257RDB cells .
Crocin did not make any significant changes in the MDR1 gene expression level in EPG85-257 and EPG85-257RDB cell lines .
In contrast , crocin increased doxorubicin cytotoxicity in drug-resistant cells , which might be induced by reduced MDR1 activity .
CONCLUSION : In summary @ @ @ @ @ @ @ expression of MDR1 , results of MTT assay suggest that it might inhibit the MDR1 function .

BACKGROUND: Crocin is one of the substantial constituents of saffron extract. It has multiple clinical effects including anti-cancer effects. The development of the multidrug resistance (MDR) phenotype is one of the principal causes of cancer chemotherapy failure. The multidrug resistance protein 1 (MDR1) is one of the MDR-related protein and is often overexpressed in different cancers. In the present study, we aimed to evaluate the influence of crocin on the expression and function of MDR1 protein in EPG85-257 and EPG85-257RDB gastric cancer cell lines.
METHODS: The cytotoxicity effect of crocin was evaluated by the MTT assay. The impacts of crocin on the expression and function of MDR1 were assessed by Real-time RT-PCR and MTT assay, respectively.
RESULTS: The results demonstrated that crocin decreased cell viability in a dose-dependent manner with higher intensity on the EPG85-257 than the EPG85-257RDB cells. Crocin did not make any significant changes in the MDR1 gene expression level in EPG85-257 and EPG85-257RDB cell lines. In contrast, crocin increased doxorubicin cytotoxicity in drug-resistant cells, which might be induced by reduced MDR1 activity.
CONCLUSION: In summary, although crocin did not affect mRNA expression of MDR1, results of MTT assay suggest that it might inhibit the MDR1 function.


greenmedinfo--2020-08-27--Crocin can be suggested as a promising therapy for ischemic cerebrovascular accidents.

Although the memory- improving effect of crocin has been suggested by previous evidences , the association between this effect and @ @ @ @ @ level and apoptosis is not well investigated .
This study aimed to determine the protective @ @ @ @ @ , hippocampal Ach level , and apoptosis in a rat model of cerebral ischemia .
@ @ @ @ @ into sham group received saline , and other 3 groups underwent 4-vessel occlusion brain ischemia @ @ @ @ @ oral administration of either saline or crocin in doses of 30 mg/day and 60 mg/day @ @ @ @ @ were memory , determined by radial eight-arm maze ( RAM ) task and Morris water @ @ @ @ @ , Ach release in the dorsal hippocampus ( evaluated by microdialysis-HPLC ) and apoptosis ( @ @ @ @ @ .
4VOI impaired memory reduced dorsal hippocampus Ach level , and induced apoptosis .
Crocin @ @ @ @ @ ( F = 343.20 ; P

Although the memory- improving effect of crocin has been suggested by previous evidences, the association between this effect and hippocampal acetylcholine (Ach) level and apoptosis is not well investigated. This study aimed to determine the protective effects of crocin on memory, hippocampal Ach level, and apoptosis in a rat model of cerebral ischemia. Male Wistar rats were divided into sham group received saline, and other 3 groups underwent 4-vessel occlusion brain ischemia (4VOI), received oral administration of either saline or crocin in doses of 30 mg/day and 60 mg/day for 7 days. Outcomes were memory, determined by radial eight-arm maze (RAM) task and Morris water maze (MWM) test, Ach release in the dorsal hippocampus (evaluated by microdialysis-HPLC) and apoptosis (investigated by TUNEL assay). 4VOI impaired memory reduced dorsal hippocampus Ach level, and induced apoptosis. Crocin, significantly improved the memory (F = 343.20; P < 0.001 for RAM error choices and F = 182.5; P < 0.0001 for MWM), increased Ach level (F = 115.1; P < 0.001) and prevented hippocampal neuronal apoptosis (W = 183.50; P < 0.001) as compared statistically by ANOVA test. Crocin can be suggested as a promising therapy for ischemic cerebrovascular accidents by its memory preserving, Ach-increasing, and neuroprotective effects.


greenmedinfo--2020-08-27--Saffron crudes and compounds restrict MACC1-dependent cell proliferation and migration of colorectal

Saffron crudes and compounds restrict MACC1-dependent cell proliferation and migration of colorectal cancer cells.

The high mortality rate of colorectal cancer ( CRC ) patients is directly associated with metastatic dissemination .
However , therapeutic options specifically for metastasis are still limited .
We previously identified Metastasis-Associated in Colon Cancer 1 ( MACC1 ) as a major causal metastasis-inducing gene .
Numerous studies confirmed its value as a biomarker for metastasis risk .
We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility .
Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner .
Saffron delays cell cycle progression at G2/M-phase and @ @ @ @ @ @ @ showed that these effects are reversible .
Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects .
We showed the interaction of MACC1 with the cancer stem cell ( CSC ) marker DCLK1 , which contributes to metastasis formation in different tumor entities .
Saffron extracts reduced DCLK1 with crocin being responsible for this reduction .
Saffron 's anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation .
This research is the first identification of saffron-based compounds restricting cancer @ @ @ @ @ @ @ novel target MACC1 .

The high mortality rate of colorectal cancer (CRC) patients is directly associated with metastatic dissemination. However, therapeutic options specifically for metastasis are still limited. We previously identified Metastasis-Associated in Colon Cancer 1 (MACC1) as a major causal metastasis-inducing gene. Numerous studies confirmed its value as a biomarker for metastasis risk. We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility. Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner. Saffron delays cell cycle progression at G2/M-phase and does not induce apoptosis. Rescue experiments showed that these effects are reversible. Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects. We showed the interaction of MACC1 with the cancer stem cell (CSC) marker DCLK1, which contributes to metastasis formation in different tumor entities. Saffron extracts reduced DCLK1 with crocin being responsible for this reduction. Saffron's anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation. This research is the first identification of saffron-based compounds restricting cancer cell proliferation and motility progression via the novel target MACC1.


greenmedinfo--2020-08-27--Crocin ameliorates oxidative stress and suppresses renal damage in streptozotocin induced diabetic m

Crocin ameliorates oxidative stress and suppresses renal damage in streptozotocin induced diabetic male rats.

Diabetes mellitus ( DM ) is a prevalent metabolic disorder with complications including nephropathy , neuropathy , retinopathy and peripheral vascular disease .
Crocin is a water soluble carotenoid that exhibits strong antioxidant activity .
I investigated the potential hypoglycemic and reno-protective effects of crocin for type 1 diabetic male rats using periodic acid-Schiff and hematoxylin staining ; metalloproteinase-7 ( MMP-7 ) , phosphatase and tensin homolog ( PTEN ) and phospho-Akt ( p-Akt ) immunohistochemistry ; measurement of blood glucose , malondialdehyde ( MDA ) , superoxide dismutase ( SOD ) , total antioxidant and total oxidant status ; @ @ @ @ @ @ @ four groups of rats : control ( saline treated ) , diabetic ( single dose of 65 mg/kg streptozotocin ) , crocin ( treated with 50 mg/kg ) and diabetic + crocin .
Crocin decreased levels of MDA , SOD , oxidative stress index and glucose significantly in diabetic animals .
Renal damage from DM also was decreased by crocin treatment .
MMP-7 and p-Akt immunoreactivity were stronger in the diabetic group compared to other groups , but PTEN immunoreactivity was weaker .
Crocin treatment returned MMP-7 and PTEN expression to near normal @ @ @ @ @ @ @ attributed to its stimulation of the antioxidant defense system and its ability to regulate the MMP-7/PTEN/Akt signaling cascade .

Diabetes mellitus (DM) is a prevalent metabolic disorder with complications including nephropathy, neuropathy, retinopathy and peripheral vascular disease. Crocin is a water soluble carotenoid that exhibits strong antioxidant activity. I investigated the potential hypoglycemic and reno-protective effects of crocin for type 1 diabetic male rats using periodic acid-Schiff and hematoxylin staining; metalloproteinase-7 (MMP-7), phosphatase and tensin homolog (PTEN) and phospho-Akt (p-Akt) immunohistochemistry; measurement of blood glucose, malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant and total oxidant status; and oxidative stress index. I used four groups of rats: control (saline treated), diabetic (single dose of 65 mg/kg streptozotocin), crocin (treated with 50 mg/kg) and diabetic + crocin. Crocin decreased levels of MDA, SOD, oxidative stress index and glucose significantly in diabetic animals. Renal damage from DM also was decreased by crocin treatment. MMP-7 and p-Akt immunoreactivity were stronger in the diabetic group compared to other groups, but PTEN immunoreactivity was weaker. Crocin treatment returned MMP-7 and PTEN expression to near normal. The ameliorative effect of crocin is attributed to its stimulation of the antioxidant defense system and its ability to regulate the MMP-7/PTEN/Akt signaling cascade.


greenmedinfo--2020-08-27--These findings suggest that crocetin ameliorates arsenic trioxide-induced hepatic injury.

Purpose : Arsenic trioxide ( ATO ) has been shown to induce hepatic injury .
Crocetin is a primary constituent of saffron , which has been verified to have antioxidant and anti-inflammatory effects .
In the current experiment , we evaluated the efficacy of crocetin against ATO-induced hepatic injury and explored the potential molecular mechanisms in rats .
Methods : Rats were pretreated with 25 or 50 mg/kg crocetin 6 h prior to treating with 5 mg/kg ATO to induce hepatic injury daily for 7 days .
Results : Treatment with crocetin attenuated ATO-induced body weight loss , decreases in @ @ @ @ @ @ @ ATO-induced hepatic pathological damage .
Crocetin significantly inhibited ATO-induced alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) , and alkaline phosphatase ( ALP ) increases .
Crocetin prevented ATO-induced liver malondialdehyde ( MDA ) and reactive oxygen species ( ROS ) levels .
Crocetin abrogated the ATO-induced decrease of catalase ( CAT ) and superoxide dismutase ( SOD ) activity .
Crocetin was found to significantly restore the protein levels of interleukin 6 ( IL-6 ) , interleukin 1β ( IL-1β ) , and tumor necrosis factor-alpha ( TNF-α ) @ @ @ @ @ @ @ of nuclear factor erythroid 2 related factor 2 ( Nrf2 ) , heme oxygenase-1 ( HO-1 ) , and NADP ( H ) : quinone oxidoreductase 1 ( NQO1 ) .
Conclusion : These findings suggest that crocetin ameliorates ATO-induced hepatic injury in rats .
In addition , the effect of crocetin might be related to its role in antioxidant stress , as an anti-inflammatory agent , and in regulating the Nrf2 signaling pathway .

Purpose: Arsenic trioxide (ATO) has been shown to induce hepatic injury. Crocetin is a primary constituent of saffron, which has been verified to have antioxidant and anti-inflammatory effects. In the current experiment, we evaluated the efficacy of crocetin against ATO-induced hepatic injury and explored the potential molecular mechanisms in rats.
Methods: Rats were pretreated with 25 or 50 mg/kg crocetin 6 h prior to treating with 5 mg/kg ATO to induce hepatic injury daily for 7 days.
Results: Treatment with crocetin attenuated ATO-induced body weight loss, decreases in food and water consumption, and improved ATO-induced hepatic pathological damage. Crocetin significantly inhibited ATO-induced alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) increases. Crocetin prevented ATO-induced liver malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Crocetin abrogated the ATO-induced decrease of catalase (CAT) and superoxide dismutase (SOD) activity. Crocetin was found to significantly restore the protein levels of interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Furthermore, crocetin promoted the expression of nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADP(H): quinone oxidoreductase 1 (NQO1).
Conclusion: These findings suggest that crocetin ameliorates ATO-induced hepatic injury in rats. In addition, the effect of crocetin might be related to its role in antioxidant stress, as an anti-inflammatory agent, and in regulating the Nrf2 signaling pathway.


greenmedinfo--2020-08-27--Crocetin attenuates sepsis-induced cardiac dysfunction.

Sepsis-induced systemic inflammation can induce cardiac dysfunction , which can result in heart failure and death .
Recently , natural @ @ @ @ @ as therapeutic agents to prevent sepsis-induced cardiac dysfunction .
Crocetin ( CRO ) is a @ @ @ @ @ shown to reduce inflammation and cytotoxicity in cardiac ischemia/reperfusion injury .
However , the effects @ @ @ @ @ dysfunction have not been evaluated .
In this study , we used lipopolysaccharide ( LPS @ @ @ @ @ anmodel to mimic cardiac sepsis .
Crocetin significantly alleviated LPS-induced cytotoxicity , cellular apoptosis , @ @ @ @ @ Bcl-2 activity and PI3K-Akt signaling and suppression of caspase 3 and caspase 9 activities .
@ @ @ @ @ the mRNA levels of TNF-α , IL-1 , IL-6 , and IL-8 via suppression of @ @ @ @ @ Nrf2/HO-1/NQO1 signaling .
In addition , CRO protected mitochondrial respiration , free fatty acid β-oxidation @ @ @ @ @ LPS-induced H9c2 cells .
This study showed that CRO attenuated LPS-induced cardiac dysfunction via regulation @ @ @ @ @ mitochondrial function and potentially had an effect on sepsis-induced cardiac dysfunction .

Sepsis-induced systemic inflammation can induce cardiac dysfunction, which can result in heart failure and death. Recently, natural drugs/compounds have received increased attention as therapeutic agents to prevent sepsis-induced cardiac dysfunction. Crocetin (CRO) is a natural compound that has been shown to reduce inflammation and cytotoxicity in cardiac ischemia/reperfusion injury. However, the effects of CRO on sepsis-induced cardiac dysfunction have not been evaluated. In this study, we used lipopolysaccharide (LPS)-induced H9c2 cells as anmodel to mimic cardiac sepsis. Crocetin significantly alleviated LPS-induced cytotoxicity, cellular apoptosis, and oxidative stress through increased Bcl-2 activity and PI3K-Akt signaling and suppression of caspase 3 and caspase 9 activities. Furthermore, CRO dramatically decreased the mRNA levels of TNF-α, IL-1, IL-6, and IL-8 via suppression of p65/Keap1 signaling and activation of Nrf2/HO-1/NQO1 signaling. In addition, CRO protected mitochondrial respiration, free fatty acid β-oxidation, and mitochondrial morphology in LPS-induced H9c2 cells. This study showed that CRO attenuated LPS-induced cardiac dysfunction via regulation of the inflammatory response and mitochondrial function and potentially had an effect on sepsis-induced cardiac dysfunction.


greenmedinfo--2020-08-27--Crocetin improves dengue virus-induced liver injury.

Dengue virus ( DENV ) infection is one of the most widespread mosquito-borne viral infections .
Liver injury is commonly observed in severe DENV infection , and the present study aimed to examine the efficacy of crocetin treatment in an immunocompetent mouse model of DENV infection exhibiting liver injury .
The efficacy of crocetin treatment in DENV-induced liver injury was assessed via both transaminase levels and histopathology analysis .
A real-time polymerase chain reaction array was then used to describe the expression of 84 apoptosis-related genes .
Using real-time RT-PCR and Western blot analysis , the gene expressions of host @ @ @ @ @ @ @ effect of crocetin in NF-kB signaling during DENV infection was studied .
We did not observe any significant reduction in virus production when DENV-infected mice were treated with crocetin .
However , DENV-infected mice treated with crocetin showed reduced DENV-induced apoptosis .
The real-time polymerase chain reaction array revealed pro-inflammatory cytokine expressions to be significantly reduced in the crocetin-treated DENV-infected mice .
We also found that crocetin could effectively modulate antioxidant status in DENV-infected mice .
Moreover , crocetin demonstrated the ability to reduce the nuclear translocation of NF-kB in DENV-infected mice .
@ @ @ @ @ @ @ not inhibit DENV replication in the liver of DENV-infected mice ; however , we did find that crocetin improves host responses that reduce liver injury .

Dengue virus (DENV) infection is one of the most widespread mosquito-borne viral infections. Liver injury is commonly observed in severe DENV infection, and the present study aimed to examine the efficacy of crocetin treatment in an immunocompetent mouse model of DENV infection exhibiting liver injury. The efficacy of crocetin treatment in DENV-induced liver injury was assessed via both transaminase levels and histopathology analysis. A real-time polymerase chain reaction array was then used to describe the expression of 84 apoptosis-related genes. Using real-time RT-PCR and Western blot analysis, the gene expressions of host factors were investigated. Additionally, the effect of crocetin in NF-kB signaling during DENV infection was studied. We did not observe any significant reduction in virus production when DENV-infected mice were treated with crocetin. However, DENV-infected mice treated with crocetin showed reduced DENV-induced apoptosis. The real-time polymerase chain reaction array revealed pro-inflammatory cytokine expressions to be significantly reduced in the crocetin-treated DENV-infected mice. We also found that crocetin could effectively modulate antioxidant status in DENV-infected mice. Moreover, crocetin demonstrated the ability to reduce the nuclear translocation of NF-kB in DENV-infected mice. Our results suggest that crocetin treatment does not inhibit DENV replication in the liver of DENV-infected mice; however, we did find that crocetin improves host responses that reduce liver injury.


greenmedinfo--2020-08-27--Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy.

OBJECTIVE : Resting-state ( rs ) network dysfunction is a contributing factor to treatment resistance in epilepsy .
In treatment-resistant epilepsy ( TRE ) , pharmacological and nonpharmacological therapies have been shown to improve such dysfunction .
In this study , our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol ( CBD ; Epidiolex® ) on rs functional magnetic resonance imaging ( fMRI ) functional connectivity ( rs-FC ) .
We hypothesized that CBD would change and potentially normalize the rs-FC in TRE .
METHODS : Twenty-two of 27 participants with TRE completed all study procedures @ @ @ @ @ @ @ mean age = 36.2 ± 15.9 years , TRE duration = 18.3 ± 12.6 years ) ; there were no differences in age ( p = 0.99 ) or sex ( p = 0.15 ) between groups .
Assessments collected included seizure frequency ( SF ) , Chalfont Seizure Severity Scale ( CSSS ) , Columbia Suicide Severity Rating Scale ( C-SSRS ) , Adverse Events Profile ( AEP ) , and Profile of Mood States ( POMS ) .
Twenty-three healthy controls ( HCs ) received rs-fMRI and POMS once .
RESULTS @ @ @ @ @ @ @ of 71.7 % in SF ( p SIGNIFICANCE : This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain .
This effect may underlie its efficacy .
This study provides Class III evidence for CBD 's normalizing effect on rs-FC in TRE .

OBJECTIVE: Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE.
METHODS: Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean age = 36.2 ± 15.9 years, TRE duration = 18.3 ± 12.6 years); there were no differences in age (p = 0.99) or sex (p = 0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once.
RESULTS: Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences inrs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs.
SIGNIFICANCE: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.


greenmedinfo--2020-08-27--Insights on cannabidiol's antiallodynic and anxiolytic mechanisms of action in a model of neuropathi

Insights on cannabidiol's antiallodynic and anxiolytic mechanisms of action in a model of neuropathic pain.

Recent studies have shown that cannabidiol ( CBD ) could have a great therapeutic potential for treating disorders such as @ @ @ @ @ In the target article , the authors propose that CBD modulates serotonergic transmission and reverses @ @ @ @ @ a rat model of neuropathic pain .
Furthermore , this study shows an antinociceptive effect @ @ @ @ @ 5-HTreceptors , as well as an anxiolytic effect mediated by 5-HTreceptors.De Gregorio D , McLaughlin @ @ @ @ @ Ochoa-Sanchez R , Enns J , Lopez-Canul M , Aboud M , Maione S , @ @ @ @ @ G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model @ @ @ @ @ 2019 ; 160:36-150 .

Recent studies have shown that cannabidiol (CBD) could have a great therapeutic potential for treating disorders such as chronic pain and anxiety. In the target article, the authors propose that CBD modulates serotonergic transmission and reverses allodynia and anxiety-like behaviour in a rat model of neuropathic pain. Furthermore, this study shows an antinociceptive effect mediated by TRPVand partially by 5-HTreceptors, as well as an anxiolytic effect mediated by 5-HTreceptors.De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comai S, and Gobbi G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. PAIN 2019;160:36-150.


greenmedinfo--2020-08-27--Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics.

Cannabidiol ( CBD ) is a major phytocannabinoid in Cannabis sativa .
CBD is being increasingly reported as a clinical treatment for neurological diseases .
Febrile seizure is one of the most common diseases in children with limited therapeutic options .
We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism .
Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures .
Hippocampal neuronal excitability was significantly decreased by CBD .
Further , CBD significantly reduced theα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ( AMPAR ) mediated evoked excitatory @ @ @ @ @ @ @ amplitude and frequency of miniature EPSCs ( mEPSCs ) .
Furthermore , CBD significantly accelerated deactivation in GluA1 and GluA2 subunits .
Interestingly , CBD slowedreceptor recovery from desensitization of GluA1 , but not GluA2 .
These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8 , the high expression isoform 8 of transmembrane AMPAR regulated protein ( TARPγ8 ) in the hippocampus .
The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2 .
CBD inhibited AMPAR activity and reduced @ @ @ @ @ @ @ symptoms of febrile seizure in mice .
The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR .

Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced theα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowedreceptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.


greenmedinfo--2020-08-27--The results show that cannabidiol exerts a markedly different effect on the viability of the human H

The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line.

OBJECTIVE : Cannabinoids are able to reduce tumor growth in xenograft models , but their therapeutic potential as anti-cancer drugs in humans is unclear yet .
In vitro studies of the effect of cannabinoids on cancer cells are often carried out in absence of serum or in low serum concentration ( i.e .
0.5 % serum ) , conditions that limit cellular growth and therefore can increase the response of cells to additional challenges such as the presence of cannabinoids .
However , the tumor microenvironment can be teaming with growth factors .
In this study we assessed the viability @ @ @ @ @ @ @ cannabidiol in presence of a serum concentration that commonly sustains cell growth ( 10 % serum ) .
RESULTS : The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line when cultured in presence of 0.5 % serum in comparison to 10 % serum , displaying a cytotoxic effect only in the former situation .
In presence of 10 % serum , no inhibitory effect of cannabidiol on DNA replication of HT-29 cells was detected , and a weak inhibition was observed for @ @ @ @ @ @ @ indicate that the effect of cannabidiol is cell context-dependent being modulated by the presence of growth factors .

OBJECTIVE: Cannabinoids are able to reduce tumor growth in xenograft models, but their therapeutic potential as anti-cancer drugs in humans is unclear yet. In vitro studies of the effect of cannabinoids on cancer cells are often carried out in absence of serum or in low serum concentration (i.e. 0.5% serum), conditions that limit cellular growth and therefore can increase the response of cells to additional challenges such as the presence of cannabinoids. However, the tumor microenvironment can be teaming with growth factors. In this study we assessed the viability and proliferation of cancer cells treated with cannabidiol in presence of a serum concentration that commonly sustains cell growth (10% serum).
RESULTS: The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line when cultured in presence of 0.5% serum in comparison to 10% serum, displaying a cytotoxic effect only in the former situation. In presence of 10% serum, no inhibitory effect of cannabidiol on DNA replication of HT-29 cells was detected, and a weak inhibition was observed for other cancer cell lines. These results indicate that the effect of cannabidiol is cell context-dependent being modulated by the presence of growth factors.


greenmedinfo--2020-08-27--The anti-tumourigenic effect of ellagic acid in SKOV-3 ovarian cancer cells entails activation of au

The anti-tumourigenic effect of ellagic acid in SKOV-3 ovarian cancer cells entails activation of autophagy mediated by inhibiting Akt and activating AMPK.

This study investigated the effect of ellagic acid ( EA ) on SKOV-3 cell growth and invasiveness and tested if the underlying mechanism involves modulating autophagy .
Cells were treated with EA in the presence or absence of chloroquine ( CQ ) , an autophagy inhibitor , compound C ( CC ) , an AMPK inhibitor , or an insulin-like growth factor-1 ( IGF-1 ) , a PI3K/Akt activator .
EA , at an ICof 36.6 µmol/L , inhibited cell proliferation , migration , and invasion and induced cell apoptosis in SKOV-3 cells .
These events were prevented by CQ @ @ @ @ @ @ @ Beclin-1 , ATG-5 , LC3I/II , Bax , cleaved caspase-3/8 and reduced those of p62 and Bcl-2 in these cancer cells .
Mechanistically , EA decreased levels of p-S6K1 ( Thr ) and 4EBP-1 ( Thr ) , two downstream targets of mTORC1 , and p-Akt ( Thr ) but increased levels of AMPK ( Thr ) and p-raptor ( Ser ) , a natural inhibitor of mTORC1 .
CC or IGF-1 alone partially prevented the effect of EA on cell survival , cell invasions , and levels of LDH , Beclin-1 , @ @ @ @ @ @ @ EA can inhibit SKOV-3 growth , migration , and invasion by activating cytotoxic autophagy mediated by inhibition of mTORC1 and Akt and activation of AMPK .

This study investigated the effect of ellagic acid (EA) on SKOV-3 cell growth and invasiveness and tested if the underlying mechanism involves modulating autophagy. Cells were treated with EA in the presence or absence of chloroquine (CQ), an autophagy inhibitor, compound C (CC), an AMPK inhibitor, or an insulin-like growth factor-1 (IGF-1), a PI3K/Akt activator. EA, at an ICof 36.6 µmol/L, inhibited cell proliferation, migration, and invasion and induced cell apoptosis in SKOV-3 cells. These events were prevented by CQ. Also, EA increased levels of Beclin-1, ATG-5, LC3I/II, Bax, cleaved caspase-3/8 and reduced those of p62 and Bcl-2 in these cancer cells. Mechanistically, EA decreased levels of p-S6K1 (Thr) and 4EBP-1 (Thr), two downstream targets of mTORC1, and p-Akt (Thr) but increased levels of AMPK (Thr) and p-raptor (Ser), a natural inhibitor of mTORC1. CC or IGF-1 alone partially prevented the effect of EA on cell survival, cell invasions, and levels of LDH, Beclin-1, and cleaved caspase-3. In conclusion, EA can inhibit SKOV-3 growth, migration, and invasion by activating cytotoxic autophagy mediated by inhibition of mTORC1 and Akt and activation of AMPK.


greenmedinfo--2020-08-27--Ellagic acid protects mice against sleep deprivation-induced memory impairment and anxiety.

Sleep disorder has become a prevalent issue in current society and is connected with the deterioration of neurobehaviors such as mood , cognition and memory .
Ellagic acid ( EA ) is a phenolic phytoconstituent extracted from grains and fruits that has potent neuroprotective properties .
This research aimed to study the alleviative effect and mechanism of EA on memory impairment and anxiety caused by sleep deprivation ( SD ) .
EA ameliorated behavioral abnormalities in SD mice , associated with increased dendritic spine density , and reduced shrinkage and loss of hippocampal neurons .
EA reduced the inflammatory response @ @ @ @ @ @ @ , which may be related to activation of the Nrf2/HO-1 pathway and mitigation of the TLR4-induced inflammatory response .
In addition , EA significantly reduced the mortality and ROS levels in glutamate ( Glu ) -induced hippocampal neuron injury , and these effects of EA were enhanced in TLR4 siRNA-transfected neurons .
However , knockdown of Nrf2 dramatically restrained the protective impact of EA on Glu-induced toxicity .
Taken together , EA alleviated memory impairment and anxiety in sleep-deprived mice potentially by inhibiting TLR4 and activating Nrf2 .
Our findings suggested that EA @ @ @ @ @ @ @ prevent cognitive impairment and anxiety caused by sleep loss .

Sleep disorder has become a prevalent issue in current society and is connected with the deterioration of neurobehaviors such as mood, cognition and memory. Ellagic acid (EA) is a phenolic phytoconstituent extracted from grains and fruits that has potent neuroprotective properties. This research aimed to study the alleviative effect and mechanism of EA on memory impairment and anxiety caused by sleep deprivation (SD). EA ameliorated behavioral abnormalities in SD mice, associated with increased dendritic spine density, and reduced shrinkage and loss of hippocampal neurons. EA reduced the inflammatory response and oxidative stress injury caused by SD, which may be related to activation of the Nrf2/HO-1 pathway and mitigation of the TLR4-induced inflammatory response. In addition, EA significantly reduced the mortality and ROS levels in glutamate (Glu)-induced hippocampal neuron injury, and these effects of EA were enhanced in TLR4 siRNA-transfected neurons. However, knockdown of Nrf2 dramatically restrained the protective impact of EA on Glu-induced toxicity. Taken together, EA alleviated memory impairment and anxiety in sleep-deprived mice potentially by inhibiting TLR4 and activating Nrf2. Our findings suggested that EA may be a promising nutraceutical ingredient to prevent cognitive impairment and anxiety caused by sleep loss.


greenmedinfo--2020-08-27--Oral ellagic acid micro-dispersion is beneficial to aging and represents a nutraceutical ingredient

Oral ellagic acid micro-dispersion is beneficial to aging and represents a nutraceutical ingredient for elders.

The immune system and the central nervous system message each other to preserving central homeostasis .
Both systems undergo changes during aging that determine central age-related defects .
Ellagic acid ( EA ) is a natural product which is beneficial in both peripheral and central diseases , including aging .
We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion ( EAm ) , that largely increased the EA solubility , in young and old mice .
Oral EAm did not modify animal weight and behavioral skills in young and old mice , but significantly @ @ @ @ @ @ @ vitro '' parameters in old animals .
Cortical noradrenaline exocytosis decreased in aged mice .
EAm administration did not modify noradrenaline overflow in young animals , but recovered it in old mice .
Furthermore , GFAP staining was increased in the cortex of aged mice , while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones .
EAm treatment significantly reduced CD45 signal in both young and old cortical lysates ; it diminished GFAP immunopositivity in young mice , but failed to affect IBA-1 expression in both young and old animals @ @ @ @ @ @ @ IL1beta expression in old mice .
These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders .

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in"ex-vivo, in vitro"parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.


greenmedinfo--2020-08-27--Ellagic acid induces cell cycle arrest and apoptosis in human colon cancer HCT 116 cells.

Colorectal carcinoma ( CRC ) is a major type of malignancy worldwide .
Ellagic acid ( EA ) , a natural phenolic constituent , has been shown to exhibit anticancer effects .
In our previous study , it was shown that EA inhibited proliferation of CRC cells .
Additionally , microarray analysis revealed 4,738 differentially expressed genes ( DEGs ) which were associated with multiple cellular events , including cell growth , apoptosis and angiogenesis .
However , the associated pathways had not been validated .
In the present study , it was shown that EA induced G0/G1 cell cycle @ @ @ @ @ @ @ apoptosis .
Furthermore , DEGs identified by cDNA microarray analysis were investigated , and showed changes in five genes which were associated with the TGF‑β1/Smad3 signaling pathway .
TGF‑β1 small interfering RNA and SIS3 , a Smad3 inhibitor , were used to assess the role of TGF‑β1 and Smad3 , respectively , and it was shown that the they reduced the effects of EA on HCT‑116 CRC cells .
In addition , the expression patterns of downstream DEGs of the TGF‑β1/Smad3 pathway were altered .
Thus , this pathway may underlie the molecular @ @ @ @ @ @ @ vitro in CRC cells .
Accordingly , targeting the TGF‑β1/Smad3 pathway with anticancer agents such as EA may be potentially used to treat CRC .

Colorectal carcinoma (CRC) is a major type of malignancy worldwide. Ellagic acid (EA), a natural phenolic constituent, has been shown to exhibit anticancer effects. In our previous study, it was shown that EA inhibited proliferation of CRC cells. Additionally, microarray analysis revealed 4,738 differentially expressed genes (DEGs) which were associated with multiple cellular events, including cell growth, apoptosis and angiogenesis. However, the associated pathways had not been validated. In the present study, it was shown that EA induced G0/G1 cell cycle arrest in HCT‑116 cells, and increased apoptosis. Furthermore, DEGs identified by cDNA microarray analysis were investigated, and showed changes in five genes which were associated with the TGF‑β1/Smad3 signaling pathway. TGF‑β1 small interfering RNA and SIS3, a Smad3 inhibitor, were used to assess the role of TGF‑β1 and Smad3, respectively, and it was shown that the they reduced the effects of EA on HCT‑116 CRC cells. In addition, the expression patterns of downstream DEGs of the TGF‑β1/Smad3 pathway were altered. Thus, this pathway may underlie the molecular mechanism by which EA exhibitsits effects in vitro in CRC cells. Accordingly, targeting the TGF‑β1/Smad3 pathway with anticancer agents such as EA may be potentially used to treat CRC.


greenmedinfo--2020-08-27--Phenolic compound ellagic acid inhibits mitochondrial respiration and tumor growth in lung cancer.

Ellagic acid ( EA ) , a natural polyphenol compound that exists in a variety of fruits and vegetables , @ @ @ @ @ tumor growth by reducing cell growth , inducing apoptosis , and damaging mitochondria .
Recent @ @ @ @ @ cancer cell death through energy metabolism and that different types of cell death coexist in @ @ @ @ @ EA inhibited lung cancer cell proliferation , markedly decreased ATP levels , decreased the potential @ @ @ @ @ and decreased oxygen consumption in vitro .
In addition , EA activated AMP-activated protein kinase @ @ @ @ @ HIF-1α in lung cancer cells .
Moreover , the treatment of tumor-bearing mice with EA @ @ @ @ @ increased p-AMPK and suppressed HIF-1α levels .
These findings suggest that EA could be a @ @ @ @ @ mitochondrial metabolism in lung cancer .

Ellagic acid (EA), a natural polyphenol compound that exists in a variety of fruits and vegetables, has been reported to inhibit tumor growth by reducing cell growth, inducing apoptosis, and damaging mitochondria. Recent reports demonstrate that mitochondria regulate cancer cell death through energy metabolism and that different types of cell death coexist in vivo. We showed that EA inhibited lung cancer cell proliferation, markedly decreased ATP levels, decreased the potential of the inner mitochondrial membrane and decreased oxygen consumption in vitro. In addition, EA activated AMP-activated protein kinase (AMPK) and reduced HIF-1α in lung cancer cells. Moreover, the treatment of tumor-bearing mice with EA dramatically inhibited tumor growth, increased p-AMPK and suppressed HIF-1α levels. These findings suggest that EA could be a promising chemotherapeutic agent that targets mitochondrial metabolism in lung cancer.


greenmedinfo--2020-08-27--Nano ellagic acid counteracts cisplatin-induced upregulation in OAT1 and OAT3.

Cisplatin is an anticancer drug commonly used for solid tumors .
However , it causes nephrotoxicity .
OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells .
The present study was designed to examine the protective role of ellagic acid nanoformulation ( ellagic acid nano ) on cisplatin-induced nephrotoxicity in rats , and the role of OAT1/OAT3 in this effect .
Four groups of male Wistar rats were used ( n = 6 ) : ( 1 ) control , ( 2 ) cisplatin ( 7.5 mg/kg single dose , @ @ @ @ @ @ @ + ellagic acid nano ( 1 mg/kg ) , and ( 4 ) cisplatin + ellagic acid nano ( 2 mg/kg ) .
Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine , urea , and oxidative stress marker , malondialdehyde ( MDA ) .
Additionally , ellagic acid nano restored renal glutathione ( GSH ) , superoxide dismutase ( SOD ) , catalase ( CAT ) , and glutathione peroxidase ( GPx ) .
Ellagic acid nano improved the histopathological changes induced by cisplatin , such @ @ @ @ @ @ @ degeneration .
Interestingly , OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group .
These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity .

Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.


greenmedinfo--2020-08-27--Ellagic acid attenuates post-cerebral ischemia and reperfusion behavioral deficits.

Objectives : Cerebral ischemia/reperfusion ( I/R ) causes brain inflammation that ultimately causes long time brain function disturbances .
We aimed to evaluate the effect of ellagic acid ( EA ) on anxiety , depression , locomotion behaviors , blood-brain barrier ( BBB ) permeability , brain edema , and inflammation in male rats with cerebral I/R .
Materials and Methods : Sixty male Wistar rats ( 250-300 g ) divided into 6 groups randomly with 10 in each : 1 ) Sham+Veh ; rats submitted to the surgery without any I/R and received vehicle ( 10 % DMSO in @ @ @ @ @ @ @ .
2 ) I/R+Veh ; 3-5 ) I/R+EA ; I/R rats received 50 , 75 and 100 EA mg/kg , by gavages 3 times daily for one week .
The cerebral I/R injury was induced by clamping the bilateral common carotid arteries for 20 minutes followed by reperfusion .
Behaviors were tested one week after treatment , and brain tissue cytokines were measured by special ELISA kits .
Results : Cerebral I/R disrupted BBB function ( < 0.001 ) , increased brain water content ( < 0.01 ) , anxiety-like ( < 0.001 @ @ @ @ @ @ @ behaviors and cytokines in the brain tissue ( < 0.001 ) , while decreased locomotion and exploratory behaviors significantly ( < 0.01 and < 0.001 , respectively ) .
Administration of EA ( 100 mg/kg but not other doses ) could improve post-ischemic complications such as clinical signs ( < 0.01 ) , BBB function ( < 0.001 ) , brain edema ( < 0.01 ) , brain tissue cytokines ( < 0.001 ) , locomotion and exploratory behaviors significantly ( < 0.05 and < 0.001 , respectively ) .
Conclusion : The @ @ @ @ @ @ @ potential therapeutic agent against cerebral I/R , possibly through its intertwined anti-inflammatory effects .
Further research is required to investigate the involved mechanisms in details .

Objectives: Cerebral ischemia/reperfusion (I/R) causes brain inflammation that ultimately causes long time brain function disturbances. We aimed to evaluate the effect of ellagic acid (EA) on anxiety, depression, locomotion behaviors, blood-brain barrier (BBB) permeability, brain edema, and inflammation in male rats with cerebral I/R.
Materials and Methods: Sixty male Wistar rats (250-300 g) divided into 6 groups randomly with 10 in each: 1) Sham+Veh; rats submitted to the surgery without any I/R and received vehicle (10% DMSO in normal saline 5 ml/kg, gavages). 2) I/R+Veh; 3-5) I/R+EA; I/R rats received 50, 75 and 100 EA mg/kg, by gavages 3 times daily for one week. The cerebral I/R injury was induced by clamping the bilateral common carotid arteries for 20 minutes followed by reperfusion. Behaviors were tested one week after treatment, and brain tissue cytokines were measured by special ELISA kits.
Results: Cerebral I/R disrupted BBB function (<0.001), increased brain water content (<0.01), anxiety-like (<0.001), depression-like (<0.001) behaviors and cytokines in the brain tissue (<0.001), while decreased locomotion and exploratory behaviors significantly (<0.01 and<0.001, respectively). Administration of EA (100 mg/kg but not other doses) could improve post-ischemic complications such as clinical signs (<0.01), BBB function (<0.001), brain edema (<0.01), brain tissue cytokines (<0.001), locomotion and exploratory behaviors significantly (<0.05 and<0.001, respectively).
Conclusion: The results suggest that EA could be a potential therapeutic agent against cerebral I/R, possibly through its intertwined anti-inflammatory effects. Further research is required to investigate the involved mechanisms in details.


greenmedinfo--2020-08-27--Ellagic acid-derived urolithins as modulators of oxidative stress.

Oxidative stress is a state of excess of prooxidative species relative to the antioxidant defenses ( enzymatic and nonenzymatic ) in a living organism .
The consequence of this imbalance is damage of the major cellular macromolecules ( carbohydrates , lipids , proteins , and DNA ) , which further leads to a gradual loss of tissue and organ function .
It has been shown that oxidative stress plays an important role in the pathogenesis of many chronic diseases ( cardiovascular , metabolic , and neurodegenerative diseases and cancer ) and in the process of aging .
Thus , many @ @ @ @ @ @ @ proposed and tested .
In this context , food rich in antioxidants has received great attention .
Pomegranate , berries , and walnuts have been recognized as '' superfood '' particularly for their cardioprotective effects .
The common characteristic of these foods is the high content of ellagitannins .
Since tannins are not bioavailable , they have been neglected in nutrition science and even considered antinutrients for a long time .
However , this view has changed dramatically once it was recognized that ellagic acid , released from ellagitannins in the gastrointestinal system @ @ @ @ @ @ @ to bioavailable compounds-known as urolithins .
Thus , urolithins ( 3,4-benzocoumarin derivatives ) have emerged as novel natural bioactive compounds and are now the focus of extensive investigations .
So far , urolithins were shown to be powerful modulators of oxidative stress and agents with potential anti-inflammatory , antiproliferative , and antiaging properties .
Furthermore , a few synthetic derivatives of urolithins were recognized as lead compounds for new drug development .
Available data on urolithin synthesis , physicochemical and pharmacokinetic characteristics , biological activity , and safety will be presented in this @ @

Oxidative stress is a state of excess of prooxidative species relative to the antioxidant defenses (enzymatic and nonenzymatic) in a living organism. The consequence of this imbalance is damage of the major cellular macromolecules (carbohydrates, lipids, proteins, and DNA), which further leads to a gradual loss of tissue and organ function. It has been shown that oxidative stress plays an important role in the pathogenesis of many chronic diseases (cardiovascular, metabolic, and neurodegenerative diseases and cancer) and in the process of aging. Thus, many strategies to combat oxidative stress have been proposed and tested. In this context, food rich in antioxidants has received great attention. Pomegranate, berries, and walnuts have been recognized as"superfood"particularly for their cardioprotective effects. The common characteristic of these foods is the high content of ellagitannins. Since tannins are not bioavailable, they have been neglected in nutrition science and even considered antinutrients for a long time. However, this view has changed dramatically once it was recognized that ellagic acid, released from ellagitannins in the gastrointestinal system, is further metabolized by colonic microbiota to bioavailable compounds-known as urolithins. Thus, urolithins (3,4-benzocoumarin derivatives) have emerged as novel natural bioactive compounds and are now the focus of extensive investigations. So far, urolithins were shown to be powerful modulators of oxidative stress and agents with potential anti-inflammatory, antiproliferative, and antiaging properties. Furthermore, a few synthetic derivatives of urolithins were recognized as lead compounds for new drug development. Available data on urolithin synthesis, physicochemical and pharmacokinetic characteristics, biological activity, and safety will be presented in this review.


greenmedinfo--2020-08-27--Ellagic acid inhibits neuroinflammation and cognitive impairment induced by lipopolysaccharides.

Neuroinflammation is a predisposing factor for the development of cognitive impairment and dementia .
Among the new molecules that are currently being studied , ellagic acid ( EA ) has stood out for its neuroprotective properties .
The present study investigated the effects of ellagic acid in the object recognition test , oxidative stress , cholinergic neurotransmission , glial cell expression , and phosphorylated Tau protein expression .
For this , 32 male Wistar rats received an intraperitoneal ( IP ) application of lipopolysaccharides ( LPS ) at a dose of 250 µg/kg or 0.9 % saline solution ( SAL @ @ @ @ @ @ @ after the IP injections , the animals received 100 mg/kg of EA or SAL via intragastric gavage .
Behavioral parameters ( open field test and object recognition ) were performed on days 5 , 6 , and 7 of the experimental periods .
The results showed that the treatment with EA in the LPS group was able to inhibit cognitive impairment , modulate the immune system response by significantly reducing glial cell expression , attenuating phosphorylated Tau and oxidative damage with consequent improvement in the antioxidant system , as well as preventing the @ @ @ @ @ @ @ the neuroprotective effects of EA and its therapeutic potential in cognitive disorders secondary to neuroinflammation were demonstrated .

Neuroinflammation is a predisposing factor for the development of cognitive impairment and dementia. Among the new molecules that are currently being studied, ellagic acid (EA) has stood out for its neuroprotective properties. The present study investigated the effects of ellagic acid in the object recognition test, oxidative stress, cholinergic neurotransmission, glial cell expression, and phosphorylated Tau protein expression. For this, 32 male Wistar rats received an intraperitoneal (IP) application of lipopolysaccharides (LPS) at a dose of 250 µg/kg or 0.9% saline solution (SAL) for 8 days. Two hours after the IP injections, the animals received 100 mg/kg of EA or SAL via intragastric gavage. Behavioral parameters (open field test and object recognition) were performed on days 5, 6, and 7 of the experimental periods. The results showed that the treatment with EA in the LPS group was able to inhibit cognitive impairment, modulate the immune system response by significantly reducing glial cell expression, attenuating phosphorylated Tau and oxidative damage with consequent improvement in the antioxidant system, as well as preventing the increase of acetylcholinesterase activity. Thus, the neuroprotective effects of EA and its therapeutic potential in cognitive disorders secondary to neuroinflammation were demonstrated.


greenmedinfo--2020-08-26--Ellagic acid and urolithin A modulate the immune response in LPS-stimulated U937 monocytic cells and

Ellagic acid and urolithin A modulate the immune response in LPS-stimulated U937 monocytic cells and THP-1 differentiated macrophages.

Dietary polyphenols are subjected , following ingestion , to an extensive metabolism , and the molecules that act at the cellular and tissue level will be , most likely , metabolites rather than native polyphenols .
The mechanisms behind the positive effects exerted by polyphenols are not yet completely elucidated , since most in vitro studies use unmetabolised polyphenols rather than the metabolites present in the body .
The aim of this study was to investigate and compare the potential effect of phenolic metabolites on the immune response using U937 monocyte and THP-1 macrophage cell cultures .
Of the 16 @ @ @ @ @ @ @ , and Uro A , in particular were the most potent , showing a modest increase in basal NF-κB activity and a reduction in lipopolysaccaride ( LPS ) -induced NF-κB activity , gene expression and secretion of pro-inflammatory cytokines .
Protocatechuic acid and its sulfate/glucuronide metabolites reduced LPS-induced NF-κB activity , but not IL-6 and TNF-α cytokine secretion .
Interestingly , both ellagic acid and its metabolite Uro A had immunomodulating effects , although they regulated the immune response differently , and both reduced LPS-induced NF-κB activity in U937 cells .
However , @ @ @ @ @ @ @ IL-10 mRNA expression , no effect could be observed with ellagic acid .
In THP-1 cells , treatment with ellagic acid dramatically reduced the expression of Toll-like receptor 4 , while Uro A had no effect .
The dual role observed for Uro A , showing both a modest increase in basal NF-κB activity and a reduction in LPS-induced NF-κB activity , as well as a reduction in LPS-induced pro-inflammatory cytokine secretion , makes this metabolite particularly interesting for further studies in animals and humans .

Dietary polyphenols are subjected, following ingestion, to an extensive metabolism, and the molecules that act at the cellular and tissue level will be, most likely, metabolites rather than native polyphenols. The mechanisms behind the positive effects exerted by polyphenols are not yet completely elucidated, since most in vitro studies use unmetabolised polyphenols rather than the metabolites present in the body. The aim of this study was to investigate and compare the potential effect of phenolic metabolites on the immune response using U937 monocyte and THP-1 macrophage cell cultures. Of the 16 metabolites tested, urolithins (Uro), and Uro A, in particular were the most potent, showing a modest increase in basal NF-κB activity and a reduction in lipopolysaccaride (LPS)-induced NF-κB activity, gene expression and secretion of pro-inflammatory cytokines. Protocatechuic acid and its sulfate/glucuronide metabolites reduced LPS-induced NF-κB activity, but not IL-6 and TNF-α cytokine secretion. Interestingly, both ellagic acid and its metabolite Uro A had immunomodulating effects, although they regulated the immune response differently, and both reduced LPS-induced NF-κB activity in U937 cells. However, while Uro A dramatically reduced IL-6 and IL-10 mRNA expression, no effect could be observed with ellagic acid. In THP-1 cells, treatment with ellagic acid dramatically reduced the expression of Toll-like receptor 4, while Uro A had no effect. The dual role observed for Uro A, showing both a modest increase in basal NF-κB activity and a reduction in LPS-induced NF-κB activity, as well as a reduction in LPS-induced pro-inflammatory cytokine secretion, makes this metabolite particularly interesting for further studies in animals and humans.