PMID: 

Front Neurosci. 2019 ;13:1284. Epub 2019 Nov 28. PMID: 31849592

Abstract Title: 

Folic Acid and Risk of Preterm Birth: A Meta-Analysis.

Abstract: 

The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.

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PMID: 

Environ Epigenet. 2019 Oct ;5(4):dvz024. Epub 2019 Dec 14. PMID: 31853372

Abstract Title: 

Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced byenvironmental contaminant exposure.

Abstract: 

Persistent organic pollutants (POPs) can induce epigenetic changes in the paternal germline. Here, we report that folic acid (FA) supplementation mitigates sperm miRNA profiles transgenerationally followingpaternal exposure to POPs in a rat model. Pregnant founder dams were exposed to an environmentally relevant POPs mixture (or corn oil)± FA supplementation and subsequent F1-F4 male descendants were not exposed to POPs and were fed the FA control diet. Sperm miRNA profiles of intergenerational (F1, F2) and transgenerational (F3, F4) lineages were investigated using miRNA deep sequencing. Across the F1-F4 generations, sperm miRNA profiles were less perturbed with POPs+FA compared to sperm from descendants of dams treated with POPs alone. POPs exposure consistently led to alteration of three sperm miRNAs across two generations, and similarly one sperm miRNA due to POPs+FA; which was in common with one POPs intergenerationallyaltered sperm miRNA. The sperm miRNAs that were affected by POPs alone are known to target genes involved in mammary gland and embryonic organ development in F1, sex differentiation and reproductive system development in F2 and cognition and brain development in F3. When the POPs treatment was combined with FA supplementation, however, these same miRNA-targeted gene pathways were perturbed to a lesser extend and only in F1 sperm. These findings suggest that FA partially mitigates the effect of POPs on paternally derived miRNA in a intergenerational manner.

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PMID: 

Int J Mol Sci. 2019 Dec 20 ;21(1). Epub 2019 Dec 20. PMID: 31861819

Abstract Title: 

Folic Acid Decreases Astrocyte Apoptosis by Preventing Oxidative Stress-Induced Telomere Attrition.

Abstract: 

Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0-40μmol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.

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PMID: 

Pharm Dev Technol. 2020 Jan 2:1-11. Epub 2020 Jan 2. PMID: 31893979

Abstract Title: 

Folic acid receptor-targeted solid lipid nanoparticles to enhance cytotoxicity of letrozole through induction of caspase-3 dependent-apoptosis for breast cancer treatment.

Abstract: 

Chemotherapy using cytotoxic agents, such as letrozole (LTZ), is one of the most effective treatments for hormone-dependent breast cancer. Nevertheless, nonspecific targeting of the drug constructs several remarkable systemic toxicities. In this study, we synthesized solid lipid nanoparticles (SLNs) by solvent emulsification evaporation method as LTZ carriers. Nanoparticles were also modified with a cancer cell-targeting ligand, folic acid (FA), and then characterized. Cell membrane damage and cell viability were investigated by lactate dehydrogenase (LDH) and 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays, respectively. Caspase-3 activity and TUNEL assays were performed to verify induced apoptosis. Scanning electron microscopy (SEM) exhibited uniform and spherical morphology of the SLNs-LTZ and FA-SLNs-LTZ. The X-ray diffraction (XRD) confirmed LTZ was dispersed as amorphous in the SLNs. The cell culture results revealed that FA-SLNs-LTZ was significantly more cytotoxic than SLNs-LTZ and free drug against MCF-7 cancer cells, with a 50% inhibitory concentration (IC50) value of 81 ± 0.89 nM, but both nanoformulations had negligible cytotoxicity toward MCF-10A normal cells and they showed promising biocompatibility. Taken together, these findings indicated the evidence of apoptosis as a mechanism of cell death. This study suggests the potential of FA-SLNs-LTZ for inducing apoptosis in a target-specific manner with minimal systemic side effects.

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PMID: 

Phytother Res. 2019 Dec ;33(12):3163-3176. Epub 2019 Aug 30. PMID: 31468630

Abstract Title: 

Panax notoginseng saponins suppress lipopolysaccharide-induced barrier disruption and monocyte adhesion on bEnd.3 cells via the opposite modulation of Nrf2 antioxidant and NF-κB inflammatory pathways.

Abstract: 

Dysfunction of the blood-brain barrier (BBB) is a prerequisite for the pathogenesis of many cerebral diseases. Oxidative stress and inflammation are well-known factors accounting for BBB injury. Panax notoginseng saponins (PNS), a clinical commonly used drug against cerebrovascular disease, possess efficient antioxidant and anti-inflammatory activity. In the present study, the protective effects of PNS on lipopolysaccharide (LPS)-insulted cerebral microvascular endothelial cells (bEnd.3) were assessed and the underlying mechanisms were investigated. The results showed that PNS mitigated the decrease of Trans-Endothelial Electrical Resistance, increase of paracellular permeability, and loss of tight junction proteins in bEnd.3 BBB model. Meanwhile, PNS suppressed the THP-1 monocytes adhesion on bEnd.3 monolayer. Moreover, PNS prevented the pro-inflammatory cytokines secretion and reactive oxygen species generation in bEnd.3 cells stimulated with LPS. Mechanism investigations suggested that PNS promoted the Akt phosphorylation, activated Nrf2 antioxidant signaling, and inhibited the NF-κB activation. All the effects of PNS could be abolished by PI3K inhibition at different levels. Taken together, these observations suggest that PNS may act as an extrinsic regulator that activates Nrf2 antioxidant defense system depending on PI3K/Akt and inhibits NF-κB inflammatory signaling to attenuate LPS-induced BBB disruption and monocytes adhesion on cerebral endothelial cells in vitro.

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PMID: 

Front Pharmacol. 2019 ;10:1013. Epub 2019 Sep 20. PMID: 31616293

Abstract Title: 

Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis.

Abstract: 

Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Althoughsaponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stress and its associated cell apoptosis along with the related mechanism in cardiac myocytes. PNS compounds were identifiedhigh-performance liquid chromatograph (HPLC) assay. PNS-pretreated H9c2 cells, HL-1 cells, and primary cultured neonatal rat cardiomyocytes were stimulated with thapsigargin (TG) to induce ER stress response and apoptosis. ER stress response was tested by immunofluorescence or immunoblot of the ER protein chaperones-calnexin, binding immunoglobulin protein (BiP) and the C/EBP homologous protein (CHOP). Cell viability was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was detected by immunoblot of Cleaved caspase-3 and flow cytometry analysis of Annexin V/propidium iodide (PI) staining. Cytosolic, mitochondrial, and ER calcium dynamics were investigated by calcium imaging. Moreover, a ryanodine receptor type-2 (RyR) overexpression stable cell line was generated to verify the mechanism of RyRinvolved in PNS in the inhibition of ER stress and cell apoptosis. We demonstrate here that PNS protected cardiac myocytes from ER stress response and associated cell death in a concentration-dependent manner. Importantly, PNS reduced the elevation of cytosolic calcium, mitochondria calcium, as well as ER calcium in response to either TG or histamine treatment. PNS protection in ER stress was regulated by RyRexpression. In summary, PNS protection against TG-induced ER stress response and its associated cell apoptosis in cardiac myocytes is calcium dependent. Through the regulation of ER calcium release mediated by RyR, a novel mechanism for PNS in the prevention of cardiovascular diseases is thereby identified.

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PMID: 

FEBS Open Bio. 2019 Nov 12. Epub 2019 Nov 12. PMID: 31715069

Abstract Title: 

Panax notoginseng saponins ameliorate cisplatin-induced mitochondrial injury via the HIF-1α/mitochondria/ROS pathway.

Abstract: 

Cisplatin is a major antineoplastic drug that is used to treat solid tumors, but its use is restricted by its nephrotoxicity. Such cisplatin-induced nephrotoxicity (CIN) is believed to occur primarily through mitochondrial damage and reactive oxygen species (ROS) generation. Our previous studies have indicated that Panax notoginseng saponins (PNSs) mitigate CIN by enhancing hypoxia-inducible factor 1α (HIF-1α)-induced mitochondrial autophagy. In this study, the role of the HIF-1α/mitochondria/ROS pathway in PNSs protection against CIN was investigated using a rat model. A CIN model was generated by giving rats intraperitoneal injections with cisplatin (a single dose) and then treating them with or without 2-methoxyestradiol (HIF-1α inhibitor) and PNSs. We then measured ROS levels, superoxide dismutase, glutathione, catalase malondialdehyde and nitric oxide (to evaluate oxidative stress) and ATP, mitochondrial membrane potential and mitochondrial permeability transition pore opening (to evaluate mitochondrial function) in kidneys at different time points. We observed that PNSs remarkably reduced the levels of ROS, malondialdehyde and nitric oxide, as well as the opening of mitochondrial permeability transition pore, which is increased by cisplatin and further increased by HIF-1αinhibition. In addition, PNSs increased the levels of superoxide dismutase, catalase and glutathione, as well as ATP and mitochondrial membrane potential in renal tissues; these are all reduced by cisplatin and further reduced by HIF-1α inhibition. In conclusion, we demonstrate here that PNSs protects against mitochondrial damage induced by cisplatin through HIF-1α/mitochondria/ROS.

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PMID: 

Saudi J Biol Sci. 2019 Nov ;26(7):1436-1441. Epub 2018 Jun 5. PMID: 31762606

Abstract Title: 

Panax ginseng improves glucose metabolism in streptozotocin-induced diabetic rats through 5' adenosine monophosphate kinase up-regulation.

Abstract: 

5' AMP-activated protein kinase (AMPK), insulin receptors and transporters are distorted in diabetes mellitus. In this study, the effect ofwas assessed on glucose manipulating enzymes activities and gene expression of AMPK, IRA and GLUT2 in streptozotocin-induced diabetic male rats. Forty male albino rats were randomly divided to four groups 10 rats of each, group I, normal control group (received saline orally); group II, normal rats received 200 mg/kg oforally; group III, Streptozotocin (STZ) -induced diabetic rats and group IV, STZ-induced diabetic rats received 200 mg/kg oforally. The duration of experiment was 30 days. Results showed the ability ofinduce a significant decrease in the blood glucose and increase in the serum insulin levels, hepatic glucokinase (GK), and glycogen synthase (GS) activities with a modulation of lipid profile besides high expression levels of AMPK, insulin receptor A (IRA), glucose transporting protein-2 (GLUT-2) in liver of diabetic rats. In conclusion, the obtained results point to the ability ofto improve the glucose metabolism in diabetic models.

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PMID: 

Int J Mol Sci. 2019 Nov 22 ;20(23). Epub 2019 Nov 22. PMID: 31771121

Abstract Title: 

Enhanced Neuroprotective Effects ofG115andGK501Combinations In Vitro Models of Excitotoxicity.

Abstract: 

Neurological-related disorders are seen as an increasingly important aspect of welfare. While conventional medicine is still the mainstay for the treatment of these diseases, it is becoming apparent that patients are also seeking more natural and preventative interventions.G115andGK501extracts alone or in combination were used in two in vitro experimental models of primary cultures exposed to excitotoxicity: rat organotypic hippocampal slices exposed to either 5µM kainic acid or 10 µM-Methyl-d-aspartate for 24 hours, and mixed cortical cells exposed to 300µM NMDA for 10 min. Cell death in theareas CA3 or CA1 subregions of slices was quantified by measuring propidium iodide fluorescence, whereas in cortical cells, it was assessed by measuring the amount of lactate dehydrogenase. In slices, treatment with extracts alone or in combination significantly attenuated CA3 and CA1 damage induced by exposure to kainic acid or NMDA, respectively. A similar neuroprotective effect was observed in cortical cells exposed to NMDA. Analysis of cell signaling pathways found that the two extracts induced an increase of the phosphorylation and they reversed the decrease of phosphorylation of ERK1/2 and Akt induced by kainic acid and NMDA in organotypic hippocampal slices. These results suggest thatG115andGK501extracts may mediate their effects by activating phosphorylation of ERK1/2 and Akt signaling pathways, protecting against excitotoxicity-induced damage in in vitro models.

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PMID: 

Phytother Res. 2019 Dec 29. Epub 2019 Dec 29. PMID: 31885119

Abstract Title: 

Antimicrobial activities of Asian ginseng, American ginseng, and notoginseng.

Abstract: 

Asian ginseng (Panax ginseng C.A. Meyer), American ginseng (Panax quinquefolius) and notoginseng (Panax notoginseng) are the three most commonly used ginseng botanicals in the world. With the increasing interests on antimicrobial properties of plants, the antimicrobial activities of ginseng species have been investigated by a number of researchers worldwide. This overview interprets our present knowledge of the antimicrobial activities of the three ginseng species and some of their bioactive components against pathogenic bacteria (Pseudomonas aeruginosa, Helicobacter pylori, Staphylococcus aureus, Escherichia coli, Propionibacterium acnes, et al.) and fungi (Candida albicans, Fusarium oxysporum, et al). Ginsenosides, polysaccharides, essential oil, proteins, and panaxytriol are all might responsible for the antimicrobial activities of ginseng. The antimicrobial mechanisms of ginseng components could be summarized to the following points: (a) inhibit the microbial motility and quorum-sensing ability; (b) affect the formation of biofilms and destroy the mature biofilms, which can weaken the infection ability of the microbes; (c) perturb membrane lipid bilayers, thus causing the formation of pores, leakages of cell constituents and eventually cell death; (d) stimulate of the immune system and attenuate microbes induced apoptosis, inflammation, and DNA damages, which can protect or help the host fight against microbial infections; and (e) inhibit the efflux of antibiotics that can descend the drug resistance of the microbial. The collected information might facilitate and guide further studies needed to optimize the use of ginseng and their components to improve microbial food safety and prevent or treat animal and human infections.

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