Pharmacodynamics and Mechanism of Astragali Radix and Anemarrhenae Rhizoma in Treating Chronic Heart Failure by Inhibiting Complement Activation.

Astragali radix (AR) and anemarrhenae rhizoma (AAR) are used clinically in Chinese medicine for the treatment of chronic heart failure (CHF), but the exact therapeutic mechanism is unclear. In this study, a total of 60 male C57BL/6 mice were divided into 5 groups, namely sham, model, AR, AAR, and AR-AAR. In the sham group, the chest was opened without ligation. In the other groups, the chest was opened and the transverse aorta was ligated to construct the transverse aortic constriction model. After 8 weeks of feeding, mice were given medicines by gavage for 4 weeks. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were detected by echocardiography. Heart weight index (HWI) and wheat germ agglutinin staining were used to evaluate cardiac hypertrophy. Hematoxylin-eosin staining was used to observe the pathological morphology of myocardial tissue. Masson staining was used to evaluate myocardial fibrosis. The content of serum brain natriuretic peptide (BNP) was detected by enzyme-linked immunosorbent assay kit. The content of serum immunoglobulin G (IgG) was detected by immunoturbidimetry. The mechanism of AR-AAR in the treatment of CHF was explored by proteomics. Western blot was used to detect the protein expressions of complement component 1s (C1s), complement component 9 (C9), and terminal complement complex 5b-9 (C5b-9). The results show that AR-AAR inhibits the expression of complement proteins C1s, C9, and C5b-9 by inhibiting the production of IgG antibodies from B cell activation, which further inhibits the complement activation, attenuates myocardial fibrosis, reduces HWI and cardiomyocyte cross-sectional area, improves cardiomyocyte injury, reduces serum BNP release, elevates LVEF and LVFS, improves cardiac function, and exerts myocardial protection.

Extraction, rapid preparation and neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir.

Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%. Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM. Compared with the normal group, the expression of Bcl-2 protein in OGD/R-injured PC12 cells was downregulated (p < 0.01), and that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins were upregulated (p < 0.01, p < 0.001). Compared with the OGD/R group, 25 µM texasin could upregulate the expression of Bcl-2 protein (p < 0.01), and downregulate that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins (p < 0.01, p < 0.001). The 7-OH and 1-O of texasin formed H-bonds with residues Cys891 of the hinge ß-strand of PERK, which is crucial for kinase inhibitors. The above results suggest that the method established in the present study achieved rapid preparation of high-purity texasin. Texasin might inhibit neuronal apoptosis via the regulation of endoplasmic reticulum stress PERK/eIF2α/ATF4/CHOP signalling pathway to exert a protective effect on OGD/R-injured PC12 cells. Aiding by molecular docking, texasin was assumed to be a potential PERK inhibitor.

Melatonin in cancer biology: pathways, derivatives, and the promise of targeted delivery.

Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we delved into how melatonin interacts with key signaling pathways, such as the Wnt/ß-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity. Additionally, a comprehensive review of current clinical studies provides a dual perspective. These studies confirm melatonin's potential in cancer management but also underscore its inherent limitations, particularly its limited bioavailability, which often relegates it to a supplementary role in treatments. Despite this limitation, there is an ongoing quest for innovative solutions and current advancements include the development of melatonin derivatives and cutting-edge delivery systems. By synthesizing the past, present, and future, this review provides a detailed overview of melatonin's evolving role in oncology, positioning it as a potential cornerstone in future cancer therapeutics.

A new biphenanthrene with cytotoxic activity from Liparis nervosa (Thunb.) Lindl.

2,7,2'-Trihydroxy-3,4,4'7'-tetramethoxy-1,1'-biphenanthrene (1), a previously undescribed biphenanthrene, and five known phenanthrenes, i.e. 2,5-dihydroxy-4-methoxy-9,10-dihydroxyphenanthrene (2), 2,4-dihydroxy -7-methoxy-9,10-dihydroxyphenanthrene (3), 7-hydroxy-2-methoxy-phenanthrene-1,4-dione (4), 7-hydroxy-2-methoxy-9,10-dihydro-phenanthrene-1,4-dione (5), and 4,4',7,7'-tetrahydroxy-2,2'-dimethoxy-9,9',10,10'-tetrahydro-1,1'-biphenanthrene (6) were isolated from the whole plant (stems, leaves, roots and fruits) of Liparis nervosa (Thunb.) Lindl., which is a medicinal plant of the genus Liparis in the Orchidaceae family. The structures of isolates were identified using spectroscopic methods, including NMR and mass spectrometry. Additionally, the cytotoxic potency of all the isolates against human lung cancer A549 cell line was evaluated by an MTT assay. All the isolated compounds showed cytotoxic activities with IC50 values in the range of 10.20 ± 0.81 to 42.41 ± 2.34 µM. The obtained data highlight the importance of L. nervosa as a source of natural lead compounds for cancer therapy.

Saponin of Aralia taibaiensis promotes angiogenesis through VEGF/VEGFR2 signaling pathway in cerebral ischemic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Aralia taibaiensis is known for its ability to promote blood circulation and dispel blood stasis, activate meridians and remove arthralgia. The saponins of Aralia taibaiensis (sAT) are the main active components that are often used to treat cardiovascular and cerebrovascular diseases. However, it has not been reported whether sAT can improve ischemic stroke (IS) by promoting angiogenesis. AIM OF THE STUDY: In this study, we investigated the potential of sAT to promote post-ischemic angiogenesis in mice and determined the underlying mechanism through in vitro experiments. METHODS: To establish the middle cerebral artery occlusion (MCAO) mice model in vivo. First of all, we examined the neurological function, brain infarct volume, and degree of brain swelling in MCAO mice. We also observed pathological changes in brain tissue, ultrastructural changes in blood vessels and neurons, and the degree of vascular neovascularization. Additionally, we established the oxygen-glucose deprivation/reoxygenation (OGD/R) -human umbilical vein endothelial cells (HUVECs) model in vitro to detect the survival, proliferation, migration and tube formation of OGD/R HUVECs. Finally, we verified the regulatory mechanism of Src and PLCγ1 siRNA on sAT promoting angiogenesis by cell transfection technique. RESULTS: In the cerebral ischemia-reperfusion mice, sAT distinctly improved the cerebral infarct volume, brain swelling degree, neurological dysfunction, and brain histopathological morphology due to cerebral ischemia/reperfusion injury. It also increased the double positive expression of BrdU and CD31 in brain tissue, promoted the release of VEGF and NO and decreased the release of NSE and LDH. In the OGD/R HUVECs, sAT significantly improved cell survival, proliferation, migration and tube formation, promoted the release of VEGF and NO, and increased the expression of VEGF, VEGFR2, PLCγ1, ERK1/2, Src and eNOS. Surprisingly, the effect of sAT on angiogenesis was inhibited by Src siRNA and PLCγ1 siRNA in OGD/R HUVECs. CONCLUSION: The results proved that sAT promotes angiogenesis in cerebral ischemia-reperfusion mice and its mechanism is to regulate VEGF/VEGFR2 and then regulate Src/eNOS and PLCγ1/ERK1/2.

Ca:Mg ratio, medium-chain fatty acids, and the gut microbiome.

BACKGROUND & AIMS: Ketogenic medium-chain fatty acids (MCFAs) with profound health benefits are commonly found in dairy products, palm kernel oil and coconut oil. We hypothesize that magnesium (Mg) supplementation leads to enhanced gut microbial production of MCFAs and, in turn, increased circulating MCFAs levels. METHODS: We tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants. Six 24-h dietary recalls were performed for all participants at the baseline and during the intervention period. Based on the baseline 24-h dietary recalls, the Mg treatment used a personalized dose of Mg supplementation that would reduce the calcium (Ca): Mg intake ratio to around 2.3. We measured plasma MCFAs, sugars, ketone bodies and tricarboxylic acid cycle (TCA cycle) metabolites using the Metabolon's global Precision Metabolomics™ LC-MS platform. Whole-genome shotgun metagenomics (WGS) sequencing was performed to assess microbiota in stool samples, rectal swabs, and rectal biopsies. RESULTS: Personalized Mg treatment (mean dose 205.58 mg/day with a range from 77.25 to 389.55 mg/day) significantly increased the plasma levels of C7:0, C8:0, and combined C7:0 and C8:0 by 18.45%, 25.28%, and 24.20%, respectively, compared to 14.15%, 10.12%, and 12.62% decreases in the placebo arm. The effects remain significant after adjusting for age, sex, race and baseline level (P = 0.0126, P = 0.0162, and P = 0.0031, respectively) and FDR correction at 0.05 (q = 0.0324 for both C7:0 and C8:0). Mg treatment significantly reduced the plasma level of sucrose compared to the placebo arm (P = 0.0036 for multivariable-adjusted and P = 0.0216 for additional FDR correction model) whereas alterations in daily intakes of sucrose, fructose, glucose, maltose and C8:0 from baseline to the end of trial did not differ between two arms. Mediation analysis showed that combined C7:0 and C8:0 partially mediated the effects of Mg treatment on total and individual ketone bodies (P for indirect effect = 0.0045, 0.0043, and 0.03, respectively). The changes in plasma levels of C7:0 and C8:0 were significantly and positively correlated with the alterations in stool microbiome α diversity (r = 0.51, p = 0.0023 and r = 0.34, p = 0.0497, respectively) as well as in stool abundance for the signatures of MCFAs-related microbiota with acyl-ACP thioesterase gene producing C7:0 (r = 0.46, p = 0.0067) and C8:0 (r = 0.49, p = 0.003), respectively, following Mg treatment. CONCLUSIONS: Optimizing Ca:Mg intake ratios to around 2.3 through 12-week personalized Mg supplementation leads to increased circulating levels of MCFAs (i.e. C7:0 and C8:0), which is attributed to enhanced production from gut microbial fermentation and, maybe, sucrose consumption.

Quantitative Evaluation of Chronic Obstructive Pulmonary Disease and Risk Prediction of Acute Exacerbation by High-Resolution Computed Tomography.

Objective: It is imperative to popularize the tertiary prevention of chronic obstructive pulmonary disease (COPD) and to improve the diagnosis and treatment. Methods: COPD patients were divided into mild (n = 18), moderate (n = 20), severe (n = 24), and extremely severe (n = 22) groups for performing high-resolution computed tomography (HRCT) and pulmonary function test. Serum procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP) were detected, and the occurrence rate of acute exacerbation COPD (AECOPD) was recorded during a 12-months follow-up period. Results: With an increase in the severity grade, the HRCT indexes, including emphysema index (EI), 1st and 15th percentile of inspiratory attenuation distribution (Perc1 and Perc15), ratio of expiratory/inspiratory mean lung density (MLDex/in) and lung volume (LVex/in), and ratio of the wall thickness to the outer diameter of the lumen (TDR), as well as percentage of the wall area to the total cross-sectional area (WA%) were increased with a decreased change in relative lung volume with attenuation values between -860 and -950 HU (RVC-860to -950) and lumen area (A i). These were correlated with the ratio of forced expiratory volume in 1 sec (FEV1) over forced vital capacity (FVC) (FEV1/FVC), the percentage of FEV1 the predicted value (FEV1%), and ratio of residual volume to total lung volume (RV/TLC). Body mass index, MLDex/in, FEV1%, FEV1/FVC, and PCT had a predictive value to AECOPD, with the combined AUC of 0.812. Conclusions: HRCT imaging effectively classifies the severity of COPD, which combined with BMI, PFT, and serum PCT can predict the risk of AECOPD.

N-3 Long Chain Fatty Acids Supplementation, Fatty Acids Desaturase Activity, and Colorectal Cancer Risk: A Randomized Controlled Trial.

INTRODUCTION: n-3 long-chain polyunsaturated fatty acids (LCPUFA) have anti-inflammatory effects and may reduce colorectal cancer risk. The purpose of this study was to evaluate the effects of n-3 LCPUFA supplementation on markers of rectal cell proliferation and apoptosis and examine how genetic variation in desaturase enzymes might modify this effect. METHODS: We conducted a randomized, double-blind, control six-month trial of 2.5 grams of n-3 LCPUFA per day compared to olive oil. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1). Our primary outcome was change in markers of rectal epithelial proliferation and apoptosis. RESULTS: A total of 141 subjects were randomized. We found no difference in apoptosis markers between participants randomized to n-3 LCPUFA compared to olive oil (P = 0.41). N-3 LCPUFA supplementation increased cell proliferation in the lower colonic crypt compared to olive oil (P = 0.03) however baseline indexes of proliferation were different between the groups at randomization. We found no evidence that genotype modified the effect. CONCLUSIONS: Our study did not show evidence of a proliferative or pro-apoptotic effect on n-3 LCPUFA supplementation on rectal mucosa regardless of the FADS genotype.ClinicalTrials.gov Identifier: NCT01661764Supplemental data for this article is available online at https://dx.doi.org/10.1080/01635581.2021.1955286.

[Effect of auricular acupuncture on reduction of sertraline hydrochloride in patients with depression: a randomized controlled trial].

OBJECTIVE: To observe the effect of auricular acupuncture on reduction rate of sertraline hydrochloride, and to explore the long-term efficacy of auricular acupuncture in patients with depression. METHODS: Seventy-two patients with depression were randomly divided into an observation group (36 cases, 1 case dropped off) and a control group (36 cases, 2 cases dropped off). The patients in the control group were treated with conventional dosage reduction method, that is, the dosage of sertraline hydrochloride was reduced by 25% every week until the dosage was stopped completely on the premise of no aggravation of depressive symptoms. Based on the conventional dosage reduction method used in the control group, the patients in the observation group were treated with auricular acupuncture at Xin (CO15), Gan (CO12), Shenmen (TF4), Pizhixia (AT4) and Neifenmi (CO18), once every 3 days for 4 weeks. The reduction of dosage was observed before dosage reduction, after 1, 2, 3, 4 weeks of dosage reduction and follow-up 6 months after the end of treatment; the rate of dosage reduction was observed after 4 weeks of dosage reduction and during follow-up; the Hamilton depression scale (HAMD) was used to evaluate the depression severity before dosage reduction, after 4 weeks of dosage reduction and during follow-up; the incidence rate of withdrawal syndrome and clinical efficacy were compared between the two groups. RESULTS: The dosage of sertraline hydrochloride in the observation group was less than that in the control group after 2, 3, 4 weeks of dosage reduction and during follow-up (P<0.05). The dosage reduction rates were 80.6% and 82.2% after 4 weeks of dosage reduction and during follow-up in the observation group, which were higher than 65.8% and 62.2% in the control group (P<0.05). After 4 weeks of dosage reduction, the HAMD scores in the two groups were higher than those before dosage reduction (P<0.05), and the HAMD score in the observation group was lower than that in the control group (P<0.05). During follow-up, HAMD score in the observation group was lower than that in the control group and that after 4 weeks of dosage reduction (P<0.05), while HAMD score in the control group was higher than that before dosage reduction and that after 4 weeks of treatment (P<0.05). The incidence rate of withdrawal syndrome in the observation group was 11.4% (4/35), which was lower than 47.1% (16/34) in the control group (P<0.05). After 4 weeks of dosage reduction and during follow-up, the total effective rate was 97.1% (34/35) in the observation group, which was higher than 79.4% (27/34) in the control group (P<0.05). CONCLUSION: Auricular acupuncture could effectively reduce the dosage of sertraline hydrochloride, improve the dosage reduction rate, reduce the incidence of withdrawal syndrome and reduce the risk of long-term recurrence in patients with depression.

[Clinical observation of acupuncture combined with moxibustion on college students with depression].

OBJECTIVE: To observe the clinical efficacy of acupuncture combined with moxibustion with seed-sized moxa cone in the treatment of depression in college students, and explore its effect on serum 5-hydroxytryptamine (5-HT). METHODS: Sixty undergraduates with depression were divided into acupuncture-moxibustion group and medication group according to the random number table, with 30 patients in each group. The patients in acupuncture-moxibustion group received acupuncture and moxibustion with seed-sized moxa cone at acupoints on Shaoyang meridian according to the method of "rotating the pivot and regulating the qi", one time every other day. The patients in medication group received oral administration of fluoxetine hydrochloride capsule 20 mg once a day, and both groups were treated continuously for 8 weeks. The scores of Hamilton depression (HAMD-17) scale, self-rating depression scale (SDS) and serum 5-HT content before and after treatment were compared between the two groups. RESULTS: Compared with before treatment, the HAMD-17 and SDS scores of the acupuncture-moxibustion group began to decrease after 2 weeks of treatment (P<0.05); while the HAMD-17 and SDS scores of the the medication group began to decrease after 4 weeks of treatment (P<0.05). After 2, 4 and 8 weeks of treatment, the HAMD-17 and SDS scores of the acupuncture-moxibustion group decreased more significantly than the medication group (P<0.05). The 5-HT contents of the two groups were significantly higher than those before treatment (P<0.05)，and there was no significant difference in serum 5-HT content between the two groups (P>0.05). The adverse reaction score of the acupuncture-moxibustion group was lower than that of the medication group (P<0.05). The total effective rate of the acupuncture-moxibustion group was 92.86%（26/28）, better than the medication group 81.48% (22/27,P<0.05). CONCLUSION: Acupuncture combined with seed-sized moxa cone moxibustion is more effective than oral administration of fluoxetine hydrochloride in treating college students' depression, and acupuncture combined with moxibustion has a faster onset and fewer adverse reactions in the treatment of college students' depression.

[Therapeutic effect of acupuncture combined with wheat-grain moxibustion on perimenopausal depression with kidney deficiency and liver depression].

OBJECTIVE: To compare the therapeutic effect of acupuncture combined with wheat-grain moxibustion and oral fluoxetine hydrochloride capsule on perimenopausal depression with kidney deficiency and liver depression. METHODS: A total of 60 patients of perimenopausal depression with kidney deficiency and liver depression were randomized into an observation group and a control group, 30 cases in each one. Acupuncture combined with wheat-grain moxibustion were adopted in the observation group. Acupuncture was applied at Baihui (GV 20), Yintang (GV 29), Fengchi (GB 20), etc. for 30 min. Wheat-grain moxibustion was applied at Ganshu (BL 18), Shenshu (BL 23), Mingmen (GV 4) and Yongquan (KI 1), 3 moxa-cones for each acupoint. The treatment in the observation group was given once every 2 days, 3 times a week. Fluoxetine hydrochloride capsule was given orally in the control group, 20 mg each time, once a day. Treatment for 8 weeks was required in the both groups. The scores of Hamilton depression scale (HAMD) and modified Kupperman scale were observed in the both groups before and after treatment, and at 1, 3, 6-month follow-up. The therapeutic efficacy was evaluated after treatment. RESULTS: Compared before treatment, the scores of HAMD and modified Kupperman scale after treatment and at each time point of follow-up were decreased in the both groups (P<0.01), and the HAMD scores in the observation group were lower than the control group (P<0.01). The total effective rate was 93.3% (28/30) in the observation group, which was superior to 80.0% (24/30) in the control group (P<0.01). CONCLUSION: Acupuncture combined with wheat-grain moxibustion can effectively treat perimenopausal depression with kidney deficiency and liver depression, and have more stable and sustained therapeutic effect compared with oral fluoxetine hydrochloride capsule.

Perspective: Characterization of Dietary Supplements Containing Calcium and Magnesium and Their Respective Ratio-Is a Rising Ratio a Cause for Concern?

Low magnesium intakes coupled with high calcium intakes and high calcium-to-magnesium (Ca:Mg) intake ratios have been associated with increased risk for multiple chronic conditions such as cardiovascular disease and metabolic syndrome, as well as some cancers (colorectal, prostate, esophageal), and total mortality. A high dietary Ca:Mg ratio (>2.60) may affect body magnesium status while, on the other hand, high intakes of magnesium could adversely impact individuals with an exceedingly low dietary Ca:Mg ratio (<1.70). Thus, a Ca:Mg ratio range of 1.70-2.60 (weight to weight) has been proposed as an optimum range. Data from NHANES surveys have shown the mean Ca:Mg intake ratio from foods alone for US adults has been >3.00 since 2000. One-third of Americans consume a magnesium supplement with a mean dose of 146 mg/d, and 35% of Americans consume a calcium supplement with a mean dose of 479 mg/d. Our review of Ca:Mg ratios in dietary supplements sold in the United States and listed in NIH's Dietary Supplement Label Database (DSLD) found a mean ratio of 2.90 across all calcium- and magnesium-containing products, with differences by product form. The ratios ranged from a low of 0.10 in liquid products to a high of 48.5 in powder products. Thirty-one percent of products fell below, 40.5% fell within, and 28.3% fell above the ratio range of 1.70-2.60. Our findings of calculated Ca:Mg ratios from dietary supplements coupled with food-intake data suggest that, in individuals with high calcium intakes from diet and/or supplements, magnesium supplementation may be warranted to establish a more favorable dietary Ca:Mg ratio in their total diet. Additional research may provide greater insight into whether the Ca:Mg ratio is a biomarker of interest for moderating chronic disease and which population groups may derive benefit from moderating that ratio.

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial.

BACKGROUND: Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). OBJECTIVE: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). METHODS: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. RESULTS: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). CONCLUSION: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer's disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483.

[Effects of mild moxibustion on Beclin-1/Bcl-2 expression in spinal cord of rats with cervical spondylotic radiculopathy].

OBJECTIVE: To observe the effects of mild moxibustion on the expression of autophagy and apoptosis factors Beclin-1, Bcl-2 mRNA and protein in spinal cord (including nerve root tissues) of cervical spondylotic radiculopathy (CSR) rats, so as to explore the analgesic mechanism of mild moxibustion at "Dazhui" (GV14) on CSR. METHODS: SD rats were randomly divided into blank group, model group, mild moxibustion group and mild moxibustion+3-methyladenine(3-MA) group, with 10 rats in each group. CSR model was established by inserting the wire into the cervical nerve root. The rats in the blank group were only fed normally without any intervention.The rats in the mild moxibustion group and mild moxibustion+3-MA group were given mild moxibustion at GV14 for 10 min each time,and intraperitoneal injection of 1 mL 0.9% normal saline and 1 mL 3-MA(15 mg/kg)separately. Rats in the model group were given 0.9% normal saline every day. All the three interventions were started from the 3rd day after modeling for 7 days. The rat's behavioral reaction of gait was scored and the pain threshold of rat was measured with a pain analyzer; the expressions of Beclin-1 and Bcl-2 mRNA and protein in the spinal cord (including nerve root) were detected by fluorescence quantitative PCR and immunohistochemistry, separately. The autophagosome and ultrastructure of the spinal nerve root tissue were observed by transmission electron microscope. RESULTS: After modeling, the gait score was significantly increased (P<0.01) and the pain threshold significantly decreased (P<0.01) in the model group in comparison with the blank group. There was no statistical difference in Beclin-1 and Bcl-2 mRNA and protein expression between the blank and the model groups. After intervention, compared with the model group, the gait scores were significantly reduced (P<0.01), the pain threshold and the expressions of Beclin-1 and Bcl-2 mRNA and protein were significantly increased (P<0.01，P<0.05) in the mild moxibustion and mild moxibustion+3-MA groups. The improvement of the above indicators as more significant in the mild moxibustion group than that in the mild moxibustion+3-MA group (P<0.05). After modeling, the organelles in the spinal nerve root tissue cells of the model group were damaged and there were a small amount of autophagosomes. Compared with the model group, the ultrastructure of the spinal nerve root tissue cells in the mild moxibustion group were relatively complete, and the number of autophagosomes increased. CONCLUSION: Mild moxibustion at GV14 has a good analgesic effect on CSR rats, which may be related to its effects in up-regulation of Beclin-1 and Bcl-2 expressions and activation of autophagy and inhibition of apoptosis.

Associations between calcium and magnesium intake and the risk of incident gastric cancer: A prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study.

Gastric cancer remains a leading cause of cancer-related mortality. Identifying dietary and other modifiable disease determinants has important implications for risk attenuation in susceptible individuals. Our primary aim was to estimate the association between dietary and supplemental intakes of calcium and magnesium and the risk of incident gastric cancer. We conducted a prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons Diet and Health Study. We used Cox proportional hazard modeling to estimate the association between calcium and magnesium intakes with risk of incident gastric adenocarcinoma (GA) overall and by anatomic location, noncardia GA (NCGA) and cardia GA (CGA). A total of 536,403 respondents (59% males, 41% females) were included for analysis, among whom 1,518 incident GAs (797 NCGA and 721 CGA) occurred. Increasing calcium intake was associated with lower risk of GA overall (p-trend = 0.05), driven primarily by the association with NCGA, where the above median calcium intakes were associated with a 23% reduction in risk compared to the lowest quartile (p-trend = 0.05). This magnitude of NCGA risk reduction was greater among nonwhite ethnic group and Hispanics (hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.24-1.07, p-trend = 0.04), current/former smokers (HR 0.58, 95% CI: 0.41-0.81), obese individuals (HR 0.54, 95% CI: 0.31-0.96) and those with high NCGA risk scores (HR 0.50, 95% CI: 0.31-0.80). Among men only, increasing magnesium intake was associated with 22-27% reduced risk of NCGA (p-trend = 0.05), while for the cohort, dietary magnesium intake in the highest vs. lowest quartile was associated with a 34% reduced risk of NCGA (HR 0.66, 95% CI: 0.48-0.90). These findings have important implications for risk factor modification. Future investigations are needed not only to confirm our results, but to define mechanisms underlying these associations.

Physical activity, dietary calcium to magnesium intake and mortality in the National Health and Examination Survey 1999-2006 cohort.

Calcium and magnesium affect muscle mass and function. Magnesium and calcium are also important for optimal vitamin D status. Vitamin D status modifies the associations between physical activity and risk of incident cardiovascular disease (CVD) and CVD mortality. However, no study examined whether levels of magnesium and calcium and the ratio of dietary calcium to magnesium (Ca:Mg) intake modify the relationship between physical activity and mortality. We included 20,295 National Health and Nutrition Examination Survey participants (1999-2006) aged >20 years with complete dietary, physical activity and mortality data (2,663 deaths). We assessed physical activity based on public health guidelines and sex-specific tertiles of MET-minutes/week. We used Cox proportional hazards models adjusted for potential confounding factors and stratified by the intakes of magnesium, calcium, Ca:Mg ratio. We found higher physical activity was significantly associated with reduced risk of total mortality and cause-specific mortality, regardless of Ca:Mg ratio, magnesium or calcium intake. In contrast, both moderate and high physical activity were significantly associated with substantially reduced risks of mortality due to cancer when magnesium intake was above the RDA level. We also found higher physical activity was significantly associated with a reduced risk of mortality due to cancer only when Ca:Mg ratios were between 1.7 and 2.6, although the interaction was not significant. Overall, dietary magnesium and, potentially, the Ca:Mg ratio modify the relationship between physical activity and cause-specific mortality. Further study is important to understand the modifying effects of the balance between calcium and magnesium intake on physical activity for chronic disease prevention.

[Raw Materials and End Treatment-based Emission Factors for Volatile Organic Compounds (VOCs) from Typical Solvent Use Sources].

A database of refined raw materials and end treatment-based VOCs emission factors for typical solvent use sources was developed for the Pearl River Delta. For this, the impact of composition and the content of raw materials, production process, and comprehensive end treatment on the emission of VOCs was analyzed. The solvent use sources included printing, furniture manufacturing, and electronic component and equipment manufacturing. The results showed that the main VOCs in the raw materials used in printing were ethyl acetate, propyl acetate, isopropanol, propanol, and ethanol, which contributed 60%-80% to the total amount of VOCs. Ethyl acetate and butyl acetate were the main oxygenated VOCs (OVOCs) from the raw materials used in furniture manufacturing, contributing 45%-65% of the total. The main VOCs from the raw materials used in electronic component and equipment manufacturing were OVOCs such as alcohols, ethers and phenols, BTEX, and halohydrocarbons. The uncontrolled and controlled emission factors for VOCs from printing were 415.2 kg·t-1 and 184.3 kg·t-1, respectively. Of these, solvent-based raw materials accounted for 704.9 kg·t-1 and 200.1 kg·t-1, water-based raw materials accounted for 325.6 kg·t-1 and 230.3 kg·t-1, UV raw materials accounted for 197.0 kg·t-1 and 129.0 kg·t-1, and plant-based raw materials accounted for 89.0 kg·t-1 and 89.0 kg·t-1, respectively. The uncontrolled and controlled emission factors for VOCs from furniture manufacturing were 379.0 kg·t-1 and 290.2 kg·t-1, respectively. Of these, solvent-based raw materials accounted for 603.0 kg·t-1 and 448.5 kg·t-1, water-based raw materials accounted for 80.0 kg·t-1 and 80.0 kg·t-1, and powder raw materials accounted for 230.0 kg·t-1 and 184.0 kg·t-1, respectively. In electronic component and equipment manufacturing, the uncontrolled and controlled emission factors (unit:kg·million-1) for VOCs from AC ceramic capacitors, CC ceramic capacitors, varistors, and aluminum electrolytic capacitors were 59.7 and 40.8, 394.1 and 269.6, 282.4 and 193.2, and 1.2 and 1.0, respectively. The uncontrolled and controlled emission factors for VOCs from the manufacturing of continuous terminals, enameled wire, and printed circuit boards were 56.3 kg·t-1 and 42.8 kg·t-1, 87.2 kg·t-1 and 28.3 kg·t-1, and 26.4 kg·(100 m2)-1 and 11.6 kg·(100 m2)-1, respectively.

Trends in Magnesium Intake among Hispanic Adults, the National Health and Nutrition Examination Survey (NHANES) 1999-2014.

This study aimed at examining trends in magnesium intake among U.S. Hispanic adults stratified by gender, Hispanic origins, age, and poverty income ratio (PIR) level. Data on 9304 Hispanic adults aged ≥20 years from eight National Health and Nutrition Examination Survey (NHANES) cycles (1999-2014) were included in this study. For each cycle, survey-weighted mean dietary and total magnesium intakes were estimated. The prevalence of dietary and total magnesium intake below the Recommended Dietary Allowance (RDA) was further estimated stratified by gender and age groups. Linear regression was used to test trend. Over the survey cycles, both dietary and total magnesium intakes were significantly increased among Hispanic adults. In the study period, magnesium intake tended to be lower in females, adults in other Hispanic-origin group, those aged ≥65 years old, and those with a PIR <1.0. The prevalence of magnesium intake inadequacy decreased among Hispanic adults; however, more than 70% of Hispanic males and females continued to have magnesium intake below the RDA in 2013-2014. From 1999/2000 to 2013/2014, despite several improvements in magnesium intake having been identified, additional findings showed insufficient intake in Hispanic males and females, suggesting the need to improve magnesium intake through diet and dietary supplementation for U.S. Hispanics.

Discovery of Noncancer Drug Effects on Survival in Electronic Health Records of Patients With Cancer: A New Paradigm for Drug Repurposing.

PURPOSE: Drug development is becoming increasingly expensive and time consuming. Drug repurposing is one potential solution to accelerate drug discovery. However, limited research exists on the use of electronic health record (EHR) data for drug repurposing, and most published studies have been conducted in a hypothesis-driven manner that requires a predefined hypothesis about drugs and new indications. Whether EHRs can be used to detect drug repurposing signals is not clear. We want to demonstrate the feasibility of mining large, longitudinal EHRs for drug repurposing by detecting candidate noncancer drugs that can potentially be used for the treatment of cancer. PATIENTS AND METHODS: By linking cancer registry data to EHRs, we identified 43,310 patients with cancer treated at Vanderbilt University Medical Center (VUMC) and 98,366 treated at the Mayo Clinic. We assessed the effect of 146 noncancer drugs on cancer survival using VUMC EHR data and sought to replicate significant associations (false discovery rate < .1) using the identical approach with Mayo Clinic EHR data. To evaluate replicated signals further, we reviewed the biomedical literature and clinical trials on cancers for corroborating evidence. RESULTS: We identified 22 drugs from six drug classes (statins, proton pump inhibitors, angiotensin-converting enzyme inhibitors, ß-blockers, nonsteroidal anti-inflammatory drugs, and α-1 blockers) associated with improved overall cancer survival (false discovery rate < .1) from VUMC; nine of the 22 drug associations were replicated at the Mayo Clinic. Literature and cancer clinical trial evaluations also showed very strong evidence to support the repurposing signals from EHRs. CONCLUSION: Mining of EHRs for drug exposure-mediated survival signals is feasible and identifies potential candidates for antineoplastic repurposing. This study sets up a new model of mining EHRs for drug repurposing signals.

Effects of fish oil supplementation on eicosanoid production in patients at higher risk for colorectal cancer.

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.