Trajectories of Human Milk Gangliosides during the First Four Hundred Days and Maternal-to-Offspring Transfer of Gangliosides: Results from a Chinese Cohort Study.

BACKGROUND: Gangliosides are crucial for early-life cognition and immunity development. However, limited data exist on gangliosides within the Chinese population, and maternal-to-fetal/infant ganglioside transport remains unclear. OBJECTIVES: This study aimed to investigate gangliosides concentrations and trajectories in Chinese human milk during the first 400 d of lactation, and seek to understand gangliosides transmission between mother and offspring. METHODS: This study involved 921 cross-sectional participants providing human milk samples across 0-400 d of lactation and 136 longitudinal participants offering maternal plasma, cord plasma, and human milk samples within the first 45 d postpartum. Ultrahigh-performance liquid chromatography-tandem mass spectrometry was used for the quantification of gangliosides. RESULTS: Human milk GM3 (Neu5Acα2-3Galß1-4GlcßCer) concentration increased from 2.29 ± 1.87 to 13.93 ± 4.82 µg/mL, whereas GD3 (Neu5Acα2-8Neu5Acα2-3Galß1-4GlcßCer) decreased from 17.94 ± 6.41 to 0.30 ± 0.50 µg/mL during the first 400 d postpartum (all P < 0.05). Consistent results were observed in cross-sectional and longitudinal participants. GD3 concentration gradually increased from maternal plasma (1.58 µg/mL) through cord plasma (2.05 µg/mL) to colostrum (21.35 µg/mL). Significant positive correlations were observed between maternal and cord plasma for both GM3 (r = 0.30, P < 0.001) and GD3 (r = 0.35, P < 0.001), and maternal plasma GD3 also correlated positively with colostrum concentrations (r = 0.21, P = 0.015). Additionally, in maternal and cord plasma, gangliosides were mainly linked with 16- and 18-carbon fatty acids. However, human milk GM3 showed a broad spectrum of fatty acid chain lengths, whereas GD3 was primarily tied to very long-chain fatty acids (≥20 carbon). CONCLUSIONS: We identified an increase in GM3 and a decrease in GD3 concentration in human milk, with GD3 notably more concentrated in cord plasma and colostrum. Importantly, ganglioside concentrations in maternal plasma positively correlated with those in cord plasma and colostrum. Our findings contribute to the existing Chinese data on gangliosides and enhance understanding of their transmission patterns from mother to offspring. This trial was registered at chictr.org.cn as ChiCTR1800015387.

Effects of Fermentation with Kombucha Symbiotic Culture of Bacteria and Yeasts on Antioxidant Activities, Bioactive Compounds and Sensory Indicators of Rhodiola rosea and Salvia miltiorrhiza Beverages.

Kombucha is a well-known fermented beverage traditionally made from black tea infusion. Recent studies have focused on finding alternative materials to create novel kombucha beverages with various health benefits. In this study, we prepared and evaluated two novel kombucha beverages using Rhodiola rosea and Salvia miltiorrhiza as materials. The effects of fermentation with the residue of these plants on the kombucha were also investigated. The antioxidant activities, total phenolic contents, and concentrations of the bioactive compounds of the kombucha beverages were determined by the Trolox equivalent antioxidant capacity test, ferric-reducing antioxidant power test, Folin-Ciocalteu method, and high-performance liquid chromatography, respectively. The results revealed that the kombucha beverages made with Rhodiola rosea and Salvia miltiorrhiza had strong antioxidant capacities and abundant phenolic contents. Additionally, the kombucha fermented with Rhodiola rosea residue had higher FRAP, TEAC and TPC values than that fermented without residue. On the other hand, the Salvia miltiorrhiza kombucha fermented with residue had similar FRAP and TEAC values but lower TPC values compared to that fermented without residue. The correlation analysis showed that gallic acid, salidroside, and tyrosol were responsible for the antioxidant abilities and total phenolic contents of the Rhodiola rosea kombucha, and salvianolic acid A and salvianolic acid B contributed to the antioxidant abilities of the Salvia miltiorrhiza kombucha. Furthermore, the kombucha fermented with Rhodiola rosea residue had the highest sensory scores among the kombucha beverages studied. These findings suggest that Rhodiola rosea and Salvia miltiorrhiza are suitable for making novel kombucha beverages with strong antioxidant abilities and abundant phenolic contents, which can be used in preventing and managing oxidative stress-related diseases.

[Progress in Gene Polymorphisms Associated With Osteoporosis Susceptibility in Zhuang Ethnic Group in Guangxi].

The purpose of this paper is to systematically summarize the gene polymorphisms associated with osteoporosis(OP)susceptibility in Zhuang ethnic group in Guangxi.These genes mainly encode vitamin D receptor,estrogen receptor,calcitonin receptor,and adiponectin.The genotype and allele distribution frequency were compared between Zhuang ethnic group and other ethnic groups,which can clarify the existing genes and the potential gene polymorphism associated with OP in Zhuang ethnic group.The findings provide a representative solution for the subsequent research on the genes associated with OP susceptibility in ethnic minorities.

Effects and mechanisms of natural products on Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in elderly people with a high incidence rate and complicated pathogenesis, and causes progressive cognitive deficit and memory impairment. Some natural products and bioactive compounds from natural sources show great potential in the prevention and treatment of AD, such as apple, blueberries, grapes, chili pepper, Monsonia angustifolia, cruciferous vegetables, Herba epimedii, Angelica tenuissima, Embelia ribes, sea cucumber, Cucumaria frondosa, green tea, Puer tea, Amanita caesarea and Inonotus obliquus, via reducing amyloid beta (Aß) deposition, decreasing Tau hyperphosphorylation, regulating cholinergic system, reducing oxidative stress, inhibiting apoptosis and ameliorating inflammation. This review mainly summarizes the effects of some natural products and their bioactive compounds on AD with the potential molecular mechanisms.

Dietary sources, health benefits, and risks of caffeine.

Dietary intake of caffeine has significantly increased in recent years, and beneficial and harmful effects of caffeine have been extensively studied. This paper reviews antioxidant and anti-inflammatory activities of caffeine as well as its protective effects on cardiovascular diseases, obesity, diabetes mellitus, cancers, and neurodegenerative and liver diseases. In addition, we summarize the side effects of long-term or excessive caffeine consumption on sleep, migraine, intraocular pressure, pregnant women, children, and adolescents. The health benefits of caffeine depend on the amount of caffeine intake and the physical condition of consumers. Moderate intake of caffeine helps to prevent and modulate several diseases. However, the long-term or over-consumption of caffeine can lead to addiction, insomnia, migraine, and other side effects. In addition, children, adolescents, pregnant women, and people who are sensitive to caffeine should be recommended to restrict/reduce their intake to avoid potential adverse effects.

Mitigating the impact of bisphenol A exposure on mortality: Is diet the key? A cohort study based on NHANES.

Bisphenol A (BPA) is a widespread environmental pollutant linked to detrimental effects on human health and reduced life expectancy following chronic exposure. This prospective cohort study aimed to examine the association between BPA exposure and mortality in American adults and to explore the potential mitigating effects of dietary quality on BPA-related mortality. This study utilized data from 8761 American adults in the 2003-2016 National Health and Nutrition Examination Survey (NHANES). Urinary BPA levels were employed to assess BPA exposure, and dietary quality was evaluated using the Healthy Eating Index-2015 (HEI-2015). All-cause, cardiovascular disease (CVD), and cancer mortality statuses were determined until December 31, 2019, resulting in a cumulative follow-up of 80,564 person-years. The results showed that the highest tertile of urinary BPA levels corresponded to a 36% increase in all-cause mortality and a 62% increase in CVD mortality compared to the lowest tertile. In contrast, the highest tertile of HEI-2015 scores was associated with a 29% reduction in all-cause mortality relative to the lowest tertile. Although no significant interaction was found between HEI-2015 scores and urinary BPA levels concerning mortality, the association between HEI-2015 scores and both all-cause and CVD mortality was statistically significant at low urinary BPA levels. Continuous monitoring of BPA exposure is crucial for evaluating its long-term adverse health effects. Improving dietary quality can lower all-cause mortality and decrease the risk of all-cause and CVD mortality at low BPA exposure levels. However, due to the limited protective effect of dietary quality against BPA exposure, minimizing BPA exposure remains a vital goal.

Effects and mechanisms of resveratrol for prevention and management of cancers: An updated review.

Cancer is a severe public health problem. Resveratrol is a famous natural compound that has various bioactivities, such as antioxidant, anti-inflammatory, antidiabetic and antiaging activities. Especially, resveratrol could prevent and treat various cancers, such as oral, thyroid, breast, lung, liver, pancreatic, gastric, colorectal, bladder, prostate and ovarian cancers. The underlying mechanisms have been widely studied, such as inhibiting cell proliferation, suppressing metastasis, inducing apoptosis, stimulating autophagy, modulating immune system, attenuating inflammation, regulating gut microbiota and enhancing effects of other anticancer drugs. In this review, we summarize effects and mechanisms of resveratrol on different cancers. This paper is helpful to develop resveratrol, crude extract containing resveratrol, or foods containing resveratrol into functional food, dietary supplements or auxiliary agents for prevention and management of cancers.

Multifunctional Dinuclear Dy-Based Coordination Complex Showing Visible Photoluminescence, Single-Molecule Magnet Behavior, and Proton Conduction.

A new Dy-based complex, [Dy2(phen)4(PAA)4](ClO4)2 (1), was obtained by using 4-hydroxyphenyl acetate (HPAA) as a ligand and 1,10-phenanthroline as an auxiliary ligand. Complex 1 shows a dinuclear structure and a 2D supramolecular layer constructed by π-π stacking interactions. The complex displays a characteristic Dy(III) emission. Moreover, magnetic susceptibility measurements revealed that 1 exhibits a single-molecule magnet (SMM) behavior. In addition, it also shows a proton conductivity of 1.08 × 10-5 S cm-1 under 353 K and 100% relative humidity conditions, which is mainly assigned to H-bonded networks formed by the undeprotonated and uncoordinated phenolic groups of HPAA ligands and guest water molecules. Remarkably, 1 is the first example of a dinuclear complex showing photoluminescence, SMM behavior, and proton conduction.

Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review.

Cancer has been a serious public health problem. Berberine is a famous natural compound from medicinal herbs and shows many bioactivities, such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, and antimicrobial activities. In addition, berberine shows anticancer effects on a variety of cancers, such as breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate cancers. The underlying mechanisms of action include inhibiting cancer cell proliferation, suppressing metastasis, inducing apoptosis, activating autophagy, regulating gut microbiota, and improving the effects of anticancer drugs. This paper summarizes effectiveness and mechanisms of berberine on different cancers and highlights the mechanisms of action. In addition, the nanotechnologies to improve bioavailability of berberine are included. Moreover, the side effects of berberine are also discussed. This paper is helpful for the prevention and treatment of cancers using berberine.

The risks of sulfur addition on cadmium accumulation in paddy rice under different water-management conditions.

Recently, the application of sulfur (S) has been recommended to control the accumulation of cadmium (Cd) in rice in contaminated paddy soil. However, the effects of exogenous S on Cd transfer in paddy rice systems under different water-management practices have not been systematically investigated. Pot experiments were performed to monitor the composition of soil pore water and the Cd accumulation in iron plaque and rice tissue were compared under different S (0 and 200 mg/kg Na2SO4) and water (continuous and discontinuous flooding) treatments. Sulfur application significantly increased Cd concentrations in soil pore water under discontinuous flooding conditions, but slightly reduced them under continuous flooding. Moreover, the oxidation/reduction potential (Eh) was the most critical factor that affected the Cd levels. When the Eh exceeded -42.5 mV, S became the second critical factor, and excessive S application promoted Cd dissolution. In addition, S addition elevated the Cd levels in iron plaque and reduced the Cd transfer from the iron plaque to rice roots. In rice, S addition inhibited Cd transfer from the rice roots to the straw; thus, more Cd was stored in the rice roots. Nevertheless, additional S application increased the Cd content in the rice grains by 72% under discontinuous flooding, although this effect was mitigated by continued flooding. Under simulated practical water management conditions, S addition increased the risk of Cd contamination in rice, suggesting that S application should be reconsidered as a paddy fertilization strategy.

A Nanocluster [Ag307Cl62(SPhtBu)110]: Chloride Intercalation, Specific Electronic State, and Superstability.

The controlling synthesis of novel nanoclusters of noble metals (Au, Ag) and the determination of their atomically precise structures provide opportunities for investigating their specific properties and applications. Here we report a novel silver nanocluster [Ag307Cl62(SPhtBu)110] (Ag307) whose structure is determined by X-ray single crystal diffraction. The structure analysis shows that nanocluster Ag307 contains a Ag167 core, a surface shell of [Ag140Cl2S110], and a Cl60 intermediate layer located between Ag167 and [Ag140Cl2S110]. It is a first example that such many chlorides are intercalated into a Ag nanocluster. Chlorides are released in situ from solvent CHCl3. Nanocluster Ag307 exhibits superstability. Differential pulse voltammetry experiment reveals that Ag307 has continuous charging/discharging behavior with a capacitance value of 1.39 aF, while the Ag307 has a surface plasmonic feature. These characteristics show that Ag307 is of metallic behavior. However, its electron paramagnetic resonance (EPR) spectra display a spin magnetic behavior which could be originated from the unpassivated dangling bonds of surface atoms. The direct capture of EPR signals can be attributed to the Cl- intercalating layer which partly suppresses the electronic interactions between core and surface atoms, resulting in the relatively independent electronic states for core and surface atoms.

Design, synthesis and biological evaluation of novel pleuromutilin derivatives as potent anti-MRSA agents targeting the 50S ribosome.

A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC50 = 3.95 µM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.

No effect of 6-month supplementation with 300 mg/d docosahexaenoic acid on executive functions among healthy school-aged children: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Docosahexaenoic acid (DHA) plays an essential role in brain, and its status is dependent on dietary intakes. School-aged children in rural China, who consume diets low in omega-3 polyunsaturated fatty acids, may benefit from DHA supplementation. Therefore, this trial was performed to examine the effect of 6-month DHA supplementation on executive functions (EFs) among healthy school-aged children in rural China. METHODS: A randomized, double-blind, placebo-controlled trial was conducted among 106 primary school children aged 7-12 years in rural China. Participants were randomized to receive either 300 mg/d DHA or placebo for 6 months. EFs including working memory and cognitive flexibility were evaluated at baseline, at 3 months and at 6 months, using Digit Span Backwards and Wisconsin card sorting test, respectively. Socio-demographic data were collected at baseline, and erythrocyte membrane fatty acids and serum neurotransmitters were measured at baseline and after 6-month intervention. RESULTS: Ninety-four children (88.7%) completed the study according to the protocol. Changes in erythrocyte membrane fatty acids indicated good compliance of the participants. There was no significant intervention effect on serum neurotransmitters. In two-factor ANCOVA, both groups showed a significant improvement in the Digit Span Backwards and the Wisconsin card sorting test from baseline to endpoint. However, no significant intervention effect was found on any EF scores. Linear regression analysis suggested no significant association between changes in erythrocyte DHA level with changes in any EF scores. CONCLUSIONS: Supplementation with 300 mg/d DHA for 6 months had no benefit on EFs including working memory and cognitive flexibility among healthy school-aged children. This trial was registered at clinicaltrials.gov as NCT02308930 on December 5, 2014.

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion.

BACKGROUND: Chronic brain hypoperfusion (CBH) is closely related to Alzheimer's disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear. METHODS: In the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1-43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO). RESULTS: Compared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1-43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2'-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3' untranslated region (3'UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats. CONCLUSIONS: Overexpression of miR-153 controls CBH-induced presynaptic vesicle release impairment by posttranscriptionally regulating the expression of four vesicle release-related proteins by targeting the 3'UTRs of the Stx1a, Snap25, Vamp2 and Syt1 genes. These findings identify a novel mechanism of presynaptic plasticity impairment during CBH, which may be a new drug target for prevention or treatment of AD and VaD. Video Abstract.

Metoprolol prevents neuronal dendrite remodeling in a canine model of chronic obstructive sleep apnea.

Obstructive sleep apnea (OSA) is closely associated with central nervous system diseases and could lead to autonomic nerve dysfunction, which is often seen in neurodegenerative diseases. Previous studies have shown that metoprolol prevents several chronic OSA-induced cardiovascular diseases through inhibiting autonomic nerve hyperactivity. It remains unclear whether chronic OSA can lead to dendritic remodeling in the brain, and whether metoprolol affects the dendritic remodeling. In this study we investigated the effect of metoprolol on dendrite morphology in a canine model of chronic OSA, which was established in beagles through clamping and reopening the endotracheal tube for 4 h every other day for 12 weeks. OSA beagles were administered metoprolol (5 mg· kg-1· d-1). The dendritic number, length, crossings and spine density of neurons in hippocampi and prefrontal cortices were assessed by Golgi staining. And the protein levels of hypoxia-inducible factor-1α (HIF-1α) and brain-derived neurotrophic factor (BDNF) were measured by Western blotting. We showed that chronic OSA successfully induced significant brain hypoxia evidenced by increased HIF-1α levels in CA1 region and dentate gyrus of hippocampi, as well as in prefrontal cortex. Furthermore, OSA led to markedly decreased dendrite number, length and intersections, spine loss as well as reduced BDNF levels. Administration of metoprolol effectively prevented the dendritic remodeling and spine loss induced by chronic OSA. In addition, administration of metoprolol reversed the decreased BDNF, which might be associated with the metoprolol-induced neuronal protection. In conclusion, metoprolol protects against neuronal dendritic remodeling in hippocampi and prefrontal cortices induced by chronic OSA in canine.

Semi-solid extrusion 3D printing ODFs: an individual drug delivery system for small scale pharmacy.

Orodispersible films (ODFs) are promising drug delivery systems for customized medicines as it provide an alternative approach to increase consumer acceptance by advantages of rapid dissolution and administration without water. The aim of this study was to develop a platform to support the realization of tailored treatments suitable for the extemporaneous production of ODFs by semi-solid extrusion (SSE) 3D printing (3DP). Hydroxypropyl methyl cellulose (HPMC) was used as the polymer of ODFs, and levocetirizine hydrochloride was used as the model drug. The optimal formulation was HPMC:API:PS:maltitol:sucralose at a ratio of 64:10:10:15:1. Seventeen percent HPMC solution and optimal formulation were used to prepare film precursors. The impact of dynamic viscosities and fluid mechanics difference on printing applicability was discussed. The ODFs of cube designs with aimed dose of 1.25 mg, 2.5 mg, and 5 mg were printed by SSE 3DP. Good linear relationship between theoretical model volume and drug content (R2 = 0.999) and good dose accuracy indicate that 3DP is a suitable method for preparing individualized ODFs.

Applications of excipients in the field of 3D printed pharmaceuticals.

The aim of this study was to determine the effect of varying excipient content on the formation and physical properties of 3 D printed tablets. Fifteen different excipient preparations were formed into tablets with radii of 5 mm and thickness of 2 mm, using binder jetting (BJ). The tablets were analyzed by assessing visual and microstructural appearance, friability, hardness, and disintegration time. We found that filling agents with high water solubility (e.g. D-sucrose), binding agents with a high viscosity in solution (e.g. polyethylene glycol 4000) and moistening agent with higher water content can increase the bonding strength and hardness of the 3 D printed tablets and prolonged their disintegration time. This work has demonstrated that the type of excipient and its concentration affects the properties of the 3 D printed tablet. This article may be used as a guide for elucidation of the effects of using conventional tablet excipients in the field of 3 D printed pharmaceuticals. The present work should enable the identification of excipients that satisfy requirements, reduce analysis time, and improve efficiency.

Knockdown of MicroRNA-1 in the Hippocampus Ameliorates Myocardial Infarction Induced Impairment of Long-Term Potentiation.

BACKGROUNDS/AIMS: It has been reported that myocardial infarction (MI) is a risk factor for vascular dementia. However, the molecular mechanism remains largely unknown. METHODS: MI mice were generated by ligation of the left coronary artery (LCA) for 4 weeks. Passive and active avoidance tests were performed to evaluate the cognitive ability of MI mice. A theta-burst stimulation (TBS) protocol was applied to elicit long-term potentiation (LTP) of the perforant pathway-dentate gyrus synapse (PP-DG). Western blot analysis was employed to assess protein levels. RESULTS: In this study, we demonstrated that after 4 weeks of MI, C57BL/6 mice had significantly impaired memory. Compared with the sham group, in vivo physiological recording in the MI group revealed significantly decreased amplitude of population spikes (PS) with no effect on the latency and duration of the stimulus-response curve. The amplitude of LTP was markedly decreased in the MI group compared with the sham group. Further examination showed that the expression of the TBS-LTP-related proteins BDNF, GluA1 and phosphorylated GluA1 were all decreased in the MI group compared with those in the sham group. Strikingly, all these changes were prevented by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-1). CONCLUSION: MI induced cognitive decline and TBS-LTP impairment, and decreased BDNF and GluA1 phosphorylation levels from overexpression of miR-1ated were involved in this process.

Overexpression of miR-1 in the heart attenuates hippocampal synaptic vesicle exocytosis by the posttranscriptional regulation of SNAP-25 through the transportation of exosomes.

BACKGROUND: The link between cardiac diseases and cognitive deterioration has been accepted from the concept of "cardiogenic dementia", which was proposed in the late 1970s. However, the molecular mechanism is unclarified. METHODS: The two animal models used in this study were cardiac-specific overexpression of microRNA-1-2 transgenic (Tg) mice and a myocardial infarction mouse model generated by left coronary artery ligation (LCA). First, we observed the microRNA-1 (miR-1) level and synaptic vesicles (SV) distribution in the hippocampus using in situ hybridization and transmission electron microscopy (TEM) and evaluated the expression of vesicle exocytosis related proteins by western blotting. Second, we used dual luciferase reporter assay as well as antagonist and miRNA-masking techniques to identify the posttranscriptional regulatory effect of miR-1 on the Snap25 gene. Third, FM1-43 staining was performed to investigate the effect of miR-1 on synaptic vesicle exocytosis. Lastly, we used GW4869 to inhibit the biogenesis and secretion of exosomes to determine the transportation effect of exosomes for miR-1 from the heart to the brain. RESULTS: Compared with the levels in age-matched WT mice, miR-1 levels were increased in both the hearts and hippocampi of Tg mice, accompanied by the redistribution of SVs and the reduction in SV exocytosis-related protein SNAP-25 expression. In vitro studies showed that SNAP-25 protein expression was down- or upregulated by miR-1 overexpression or inhibition, respectively, however, unchanged by miRNA-masking the 3'UTR of the Snap25 gene. SV exocytosis was inhibited by miR-1 overexpression, which could be prevented by co-transfection with an anti-miR-1 oligonucleotide fragment (AMO-1). The knockdown of miR-1 by hippocampal stereotaxic injection of AMO-1 carried by a lentivirus vector (lenti-pre-AMO-1) led to the upregulation of SNAP-25 expression and prevented SV concentration in the synapses in the hippocampi of Tg mice. The application of GW4869 significantly reversed the increased miR-1 level in the blood and hippocampi as well as reduced the SNAP-25 protein levels in the hippocampi of both Tg and LCA mice. CONCLUSION: The overexpression of miR-1 in the heart attenuated SV exocytosis in the hippocampus by posttranscriptionally regulating SNAP-25 through the transportation of exosomes. This study contributes to the understanding of the relationship between cardiovascular disease and brain dysfunction.

Oral disintegrating patient-tailored tablets of warfarin sodium produced by 3D printing.

Individualized medicine is a new direction in the field of modern pharmacy. In this study, we assessed the feasibility and accuracy of 3D printing techniques for the preparation of individualized doses of mouth-disintegrating tablets of warfarin. Warfarin sodium, D-sucrose, pregelatinized starch, povidone K30, microcrystalline cellulose, and silicon dioxide (at a ratio of 1:42.45:46.15:5.1:4.9:0.4) were mixed and used as the printing powder in the 3D printer; preset parameters were used. The dosage of the tablet was controlled by the number of printing layers. The content, dose uniformity, dose accuracy, hardness, friability, disintegration time, dissolution, and the microstructural and overall appearance were determined to evaluate the printed tablets. For the doses of 3, 2, and 1 mg that were produced in the experiment, the disintegration times were 50.0 ± 5.2, 35.7 ± 4.3, and 11.0 ± 2.2 s, respectively, and the relative errors of the dose were -2.33, -1.50, and 0%, respectively. The other indicators were consistent with the preparation requirements of pharmaceutical tablets. It is possible to prepare tablets with excellent properties and controlled drug doses by using 3D printing techniques. This technology will be an important means to achieve individualized medicine.