PMID: 

J Nerv Ment Dis. 2020 Apr ;208(4):269-276. PMID: 32221179

Abstract Title: 

Safety and Efficacy of Saffron (Crocus sativus L.) for Treating Mild to Moderate Depression: A Systematic Review and Meta-analysis.

Abstract: 

BACKGROUND: Herbal remedies are becoming increasingly popular for the treatment of depression. Recently, accumulating evidences reveal a positive effect of saffron (Crocus sativus L.) in relieving depressive symptoms. The objective of this meta-analysis was to assess the safety and efficacy of saffron in treating mild to moderate depression by synthesizing all available data.MATERIALS AND METHODS: Relevant studies were retrieved from electronic databases and cross-checking of reference lists. Eligible trials were carefully reviewed, and necessary data were extracted. The Hamilton Rating Scale for Depression or Beck Depression Inventory scores, response rate, remission rate, and adverse effects were compared between saffron and placebo or saffron and antidepressants to assess the efficacy of saffron for depression.RESULTS: Twelve studies were included in the meta-analysis. Overall results showed that saffron possessed better efficacy in the improvement of depressive symptoms when compared with placebo, whereas saffron was as effective as synthetic antidepressants. No significant difference was detected in the incidence of adverse effects between saffron and placebo or between saffron and antidepressants.CONCLUSIONS: Saffron could be considered as an alternative to synthetic antidepressants in the treatment of mild to moderate depression. However, multicenter trials with larger sample size, longer treatment duration, and different ethnic groups are required to verify our results.

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PMID: 

Iran J Basic Med Sci. 2019 Dec ;22(12):1476-1482. PMID: 32133067

Abstract Title: 

Effect of safranal, a constituent of saffron, on olanzapine (an atypical antipsychotic) induced metabolic disorders in rat.

Abstract: 

Objectives: Olanzapine, an atypical antipsychotic, causes weight gain and metabolic disorders in humans. Safranal, one of the active components of(saffron), has been shown to have anti-obesity, lipid and blood pressure lowering and anti-diabetes effects. In this investigation, the effect of safranal on metabolic disorders induced by olanzapine was studied.Materials and Methods: Fourty-two female Wistar rats were divided into 7 groups of 6 animals. The two groups were selected as controls, which received olanzapine and safranal solvents, respectively. The third group treated by olanzapine 5 mg/kg. Groups 4, 5 and 6 treated by olanzapine 5 mg/kg plus safranal (2.5, 5 and 10 mg/kg) and the last group received safranal 10 mg/kg. The injections were performed intraperitoneally for 14 days and on the 15day the rats were killed and their serum were collected to measure metabolic factors including glucose, insulin, triglyceride, total cholesterol and HDL cholesterol. Leptin level in plasma was also measured. Mean systolic blood pressure was measured using tail cuff method at the end of study. The rats were weighed every other day and amount of food consumed was measured daily.Results: Olanzapine significantly elevated body weight, food intake, fasting blood glucose, TG, leptin, and mean systolic blood pressure (MSBP). It also significantly decreased HDL cholesterol blood level. Safranal significantly improved all these complications at three doses.Conclusion: Based on the results of this study, safranal is thought to be used as an effective combination in controlling metabolic complications caused by olanzapine.

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PMID: 

Nutr Neurosci. 2020 Apr 7:1-15. Epub 2020 Apr 7. PMID: 32264788

Abstract Title: 

N-Acetylcysteine and Safranal prevented the brain damage induced by hyperthyroidism in adult male rats.

Abstract: 

Hyperthyroidism is associated with impairment in the neurotransmission and severe tissue damage in the brain. The present study explored the potential deleterious effects of experimentally-induced hyperthyroidism on the neurotransmitters, oxidative homeostasis, apoptosis and DNA fragmentation in cerebral cortex, thalamus&hypothalamus, and hippocampus in rats.The ameliorative effects of N-acetylcysteine (NAC; 50 mg/kg, oral) and safranal (50 mg/kg, intraperitoneal) against hyperthyroidism (L-T4 500µg/kg, subcutaneous) were investigated. All treatments continued daily over three weeks. Hyperthyroidism was manifested by significant elevations in serum fT3 and fT4 levels and a decline in serum TSH level and body weight. It was also characterized by significant elevations in the levels of dopamine, serotonin, and 5-hydroxyindole acetic acid, and monoamine oxidase activity to varying degrees in the brain regions examined and a significant reduction in norepinephrine in hippocampus only. Hyperthyroidism resulted in a significant oxidative stress in brain typified by elevations in malondialdehyde and nitric oxide content and reductions in glutathione level and SOD and catalase activities. This led to elevations in Caspases 9 and 3 and a reduction in Bcl2 resulting in DNA damage and confirmed by the histopathology of brain tissue. The administration of NAC or safranal with L-T4 preventedthese deleterious effects by reducing the oxidative load and improving the brain antioxidant status.Hyperthyroidism disrupted the neurotransmitters in the brain which aggravated the oxidative stress and resulted in apoptosis. N-Acetylcysteine and safranal prevented these deleterious effects by enhancing the poor antioxidant milieu of the brain.

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PMID: 

Am J Transl Res. 2020 ;12(3):731-742. Epub 2020 Mar 15. PMID: 32269708

Abstract Title: 

Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice.

Abstract: 

Oxidative stress can trigger DNA damage response and activation of cellular senescence. Accumulating studies have demonstrated that senescent cells can produce senescence-associated secretory phenotype that leads to increased bone resorption and decreased bone formation. And elimination of senescent cells or inhibition of SASP secretion has been shown to prevent bone loss in mice. N-acetylcysteine (NAC) is a strong antioxidant. However, it is unclear whether reversed estrogen deficiency-induced bone loss by antioxidant NAC was associated with the inhibition of oxidative stress, DNA damage, osteocyte senescence and SASP. In this study, OVX mice were supplemented with/without E2 or NAC, and were compared with each other. Our results showed that oxidative stress, DNA damage, osteocyte senescence and the secretion of senescence-associated inflammatory cytokines were increased in OVX mice compared with sham-operated mice. However, these parameters were obviously rescued in OVX mice supplemented with E2 or NAC. Data from this study suggest that NAC can prevent OVX-induced bone loss by inhibiting oxidative stress, DNA damage, cell senescence and the secretion of the senescence-associated secretory phenotype.

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PMID: 

BMC Mol Cell Biol. 2020 Mar 27 ;21(1):20. Epub 2020 Mar 27. PMID: 32220226

Abstract Title: 

Tanshinone IIA alleviates hypoxia/reoxygenation induced cardiomyocyte injury via lncRNA AK003290/miR-124-5p signaling.

Abstract: 

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death globally and has thus placed a heavy burden on healthcare. Tanshinone IIA (TSA) is a major active compound, extracted from Salvia miltiorrhiza Bunge, that possesses various pharmacological activities. The aim of the present study was to investigate the role of TSA in AMI and its underlying mechanism of action.RESULTS: We have shown that TSA decreased the apoptosis rate, the amount of LDH, MDA as well as ROS of cardiomyocytes. Meantime, it elevated mitochondrial membrane potential (MMP) which was decreased by H/R treatment. It was also determined that miR-124-5p targets AK003290 directly. TSA up-regulated the expression of AK003290 and its function can be reversed by knock down of AK003290 as well as miR-124-5p overexpression.CONCLUSION: TSA exerts the protective role against H/R induced apoptosis, oxidative and MMP loss of cardiomyocytes via regulating AK003290 and miR-124-5p signaling.

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PMID: 

Biosci Rep. 2020 Apr 30 ;40(4). PMID: 32232409

Abstract Title: 

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway.

Abstract: 

Cervical cancer is the fourth most common cancer in women globally. Lack of effective pharmacotherapies for cervical cancer mainly attributed to an elusive understanding of the mechanism underlying its pathogenesis. Pyroptosis plays a key role in inflammation and cancer. Our study identified microRNA (miR) 145 (miR-145)/gasdermin D (GSDMD) signaling pathway as critical mediators in the effect of tanshinone II A on HeLa cells. In the present study, we found that treatment of tanshinone II A led to an obvious repression of cell proliferation and an increase in apoptosis on HeLa cells, especially in high concentration. Compared with the controlled group, tanshinone II A enhanced the activity of caspase3 and caspase9. Notably, the results demonstrated that tanshinone II A regulated cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway. Treatment of tanshinone II A significantly up-regulated the expression of GSDMD and miR-145. After transfection of si-miR-145 plasmids, the effects of tanshinone II A on HeLa cells were converted, including cell proliferation, apoptosis and pyroptosis. In addition, the results showed that tanshinone II A treatment altered the expression level of PI3K, p-Akt, NF-kB p65 and Lc3-I. Collectively, our findings demonstrate that tanshinone II A exerts anticancer activity on HeLa cells by regulating miR-145/GSDMD signaling. The present study is the first time to identify miR-145 as a candidate target in cervical cancer and show an association between miR-145 and pyroptosis, which provides a novel therapy for the treatment of cervical cancer.

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PMID: 

Oncol Rep. 2020 Feb 12. Epub 2020 Feb 12. PMID: 32323837

Abstract Title: 

Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colorectal cancer.

Abstract: 

Tumor angiogenesis is an important factor which precipitates recurrence and metastasis of colorectal cancer (CRC). Angiogenesis is also a significant feature which accompanies invasion and metastasis of CRC. Tumor hypoxia activates hypoxia inducible factor (HIF), which promotes angiogenesis in CRC. HIF significantly promotes cell proliferation and angiogenesis in CRC, facilitating invasion and metastasis. Tanshinone IIA (Tan IIA) has been revealed to effectively inhibit angiogenesis in CRC, although the underlying mechanism remains to be determined. The aim of the present study was to determine the effects of HIF‑1α on hypoxia induced angiogenesis in CRC cells, the effects of Tan IIA on the expression of pro‑angiogenic factors in CRC cells, and on human umbilical vein endothelial cell (HUVEC) tube formation in normal and hypoxic conditions. The results of the present study revealed that Tan IIA not only decreased HIF‑1α expression and inhibited the secretion level of vascular endothelial growth factor and basic fibroblast growth factor, but also efficiently decreased proliferation, tube formation and metastasis of HUVECs. The results highlight the potential of Tan IIA‑mediated targeting of HIF‑1α as a potential therapeutic option for treatment of patients with CRC.

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PMID: 

Oxid Med Cell Longev. 2020 ;2020:5390482. Epub 2020 Apr 8. PMID: 32322336

Abstract Title: 

Tanshinone IIA Protects against Acute Pancreatitis in Mice by Inhibiting Oxidative Stress via the Nrf2/ROS Pathway.

Abstract: 

Background: Danshen (Bunge) and its main active component Tanshinone IIA (TSA) are clinically used in China. However, the effects of TSA on acute pancreatitis (AP) and its potential mechanism have not been investigated. In this study, our objective was to investigate the protective effects of TSA against AP via three classic mouse models.Methods: Mouse models of AP were established by caerulein, sodium taurocholate, and L-arginine, separately. Pancreatic and pulmonary histopathological characteristics and serum amylase and lipase levels were evaluated, and changes in oxidative stress injury and the ultrastructure of acinar cells were observed. The reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice were applied to clarify the protective mechanism of the drug.Results: In the caerulein-induced AP model, TSA administration reduced serum amylase and lipase levels and ameliorated the histopathological manifestations of AP in pancreatic tissue. Additionally, TSA appreciably decreased ROS release, protected the structures of mitochondria and the endoplasmic reticulum, and increased the protein expression of Nrf2 and heme oxygenase 1 of pancreatic tissue. In addition, the protective effects of TSA against AP were counteracted by blocking the oxidative stress (NAC administration and Nrf2 knockout in mice). Furthermore, we found that TSA protects pancreatic tissue from damage and pancreatitis-associated lung injury in two additional mouse models induced by sodium taurocholate and by L-arginine.Conclusion: Our data confirmed the protective effects of TSA against AP in mice by inhibiting oxidative stress via the Nrf2/ROS pathway.

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PMID: 

Pain Pract. 2020 Apr 19. Epub 2020 Apr 19. PMID: 32306462

Abstract Title: 

Reduction in Migraine and Headache Frequency and Intensity with Combined Antioxidant Prophylaxis (N-acetylcysteine, Vitamin E and Vitamin C: NEC): A Randomized Sham-Controlled Pilot Study.

Abstract: 

OBJECTIVE: To investigate the preventive effects of a combined antioxidant drug known as NEC (N-acetylcysteine, Vitamin E and C) on migraine outcomes. Migraine is characterised by increased oxidative stress and neurogenic inflammation in the brain; therefore antioxidants may have a migraine preventive effect.DESIGN: Randomized, double-blind, sham-controlled pilot study.SETTING: Australian community.SUBJECTS: Adults reporting 2-8 migraines per month for at least a year. Methods After a 1 month baseline period, 35 subjects completed 3 months treatment with NEC (n = 19) or sham (n = 16) capsules. The primary outcome was the difference in mean number of headaches per month between baseline and final month of the trial, for NEC and sham groups; secondary outcomes are listed below.RESULTS: For NEC there was a significant decrease in mean number of headaches by 3.0 per month (p = .004) compared with 1.4 for sham (p = .073); there was no significant difference in these changes between the two groups (p = .052). Average monthly headache (p = .041) and migraine frequency (p = .018) were significantly less for NEC versus sham. In NEC subjects, there was a significant decrease in average monthly migraine days (-3.1), moderate/severe headache days (-3.2), migraine duration, headache pain scores and acute headache medication use.CONCLUSIONS: This is the first RCT to find that combined antioxidant therapy with NEC reduces headaches and migraines in adult migraineurs. Given the limitations of this pilot study, an adequately powered RCT is planned to further investigate antioxidant prophylaxis in migraine.

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PMID: 

Int J Oncol. 2020 Feb 25. Epub 2020 Feb 25. PMID: 32319585

Abstract Title: 

PHLPP2 is a novel biomarker and epigenetic target for the treatment of vitamin C in pancreatic cancer.

Abstract: 

Epigenetic dysregulations are closely associated with the development of pancreatic ductal adenocarcinoma (PDAC), which is one of the most aggressive malignancies and currently has limited treatment options. Vitamin C (VC), an epigenetic mediator, exerts antitumor effects on several types of cancer. However, the clinical application of VC is limited, particularly in PDAC. Thus, to investigate the antitumor effects and explore the potential clinical application of VC in PDAC, the survival of patients from The Cancer Genome Atlas database were analyzed, and proliferation, apoptosis and migration assays were performed in the present study. It was first established that high expression levels of the sodium‑dependent VC transporter 2, a critical VC transporter, predicted a good prognosis in patients with pancreatic adenocarcinoma. It was further confirmed that VC directly inhibited proliferation, induced apoptosis and suppressed migration of human pancreatic cancer cells. Global 5‑hydroxymethylcytosine (5hmC) content was significantly upregulated in pancreatic cancer cells following VC treatment, predominantly relying on ten‑eleven translocation 2. Furthermore, VC could specifically increase 5hmC levels at the promotor region on PH domain leucine‑rich repeat protein phosphatase 2 (PHLPP2) and enhance PHLPP2 expression levels. When PHLPP2 expression levels were knocked down, VC was able to partially overcome the inhibition of pancreatic cancer cells. These results illustrated a novel and precise mechanism of action of epigenetic alterations that underly the inhibition of VC in pancreatic cancer, and emphasized that PHLPP2 may be a new biomarker and epigenetic target for the clinical treatment of VC in PDAC.

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