bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Hemorrhagic Shock Severity Using the Second Heart Sound Determined from Phonocardiogram: A Novel Approach
Authors: Chen Yan , Hou Aisheng , Wu Xiaodong , Cong Ting , Zhou Zhikang , Jiao Youyou , Luo Yungen , Wang Yuheng , Mi Weidong , Cao Jiangbei
Published: June 2022

Introduction: Hemorrhagic shock (HS) is a severe medical emergency. Early diagnosis of HS is important for clinical treatment. In this paper, we report a flexible material-based heart sound monitoring device which can evaluate the degree of HS through a phonocardiogram (PCG) change. Methods: Progressive hemorrhage treatments (H1, H2, and H3 stage) were used in swine to build animal models. The PCG sensor was mounted on the chest of the swine. Routine monitoring was used at the same time. Results: This study showed that arterial blood pressure decreased significantly from the H1 phase, while second heart sound amplitude (S2A) and energy (S2E) decreased significantly from the H2 phase. Both S2A and S2E correlated well with BP (p < 0.001). The heart rate, pulse pressure variation and serum hemoglobin level significantly changed in the H3 stage (p < 0.05). Discussion: The change of second heart sound (S2) was at the H2 stage and was earlier than routine monitoring methods. Therefore, PCG change may be a new indicator for the early detection of HS severity.
A New Approach Determining a Phase Transition Boundary Strictly Following a Definition of Phase Equilibrium: An Example of the Post-Spinel Transition in Mg2SiO4 System
Authors: Ishii Takayuki , Chanyshev Artem , Katsura Tomoo
Published: June 2022

The Clapeyron slope is the slope of a phase boundary in P–T space and is essential for understanding mantle dynamics and evolution. The phase boundary is delineating instead of balancing a phase transition’s normal and reverse reactions. Many previous high pressure–temperature experiments determining the phase boundaries of major mantle minerals experienced severe problems due to instantaneous pressure increase by thermal pressure, pressure drop during heating, and sluggish transition kinetics. These complex pressure changes underestimate the transition pressure, while the sluggish kinetics require excess pressures to initiate or proceed with the transition, misinterpreting the phase stability and preventing tight bracketing of the phase boundary. Our recent study developed a novel approach to strictly determine phase stability based on the phase equilibrium definition. Here, we explain the details of this technique, using the post-spinel transition in Mg2SiO4 determined by our recent work as an example. An essential technique is to observe the change in X-ray diffraction intensity between ringwoodite and bridgmanite + periclase during the spontaneous pressure drop at a constant temperature and press load with the coexistence of both phases. This observation removes the complicated pressure change upon heating and kinetic problem, providing an accurate and precise phase boundary.
Fast-Curing Geopolymer Foams with an Enhanced Pore Homogeneity Derived by Hydrogen Peroxide and Sodium Dodecyl Sulfate Surfactant
Authors: Kim Kyung Won , Lim Hyung Mi , Yoon Seog-Young , Ko Hyunseok
Published: June 2022

The properties of porous and lightweight ceramic foam that can be cured at room temperature using metakaolin-based geopolymers were studied. A geopolymer slurry was prepared using metakaolin and a potassium-based alkaline medium at room temperature, and the obtained viscous paste was expanded via gaseous methods, by means of the decomposition of peroxide at room temperature. Therefore, geopolymer (GP) foam developed in this study through multivariate geopolymer, foaming agents, and surfactants can be cured at room temperature (within 5 days) without a separate heat treatment process. The homogeneous micropores were obtained through the stabilization of the interface between geopolymer slurry and oxygen gas bubbles generated through the base-catalyzed decomposition of hydrogen peroxide. The porosity was confirmed to be 29% and 54% before and after using sodium dodecyl sulfate (SDS). The compressive strengths and densities were 1.57 MPa and 0.75 g/cm3 for GP foam without SDS, and 3.63 MPa and 0.48 g/cm3 for GP foam with SDS. Through the mercury intrusion porosimetry analysis, the pores were further refined from 100 µm to 30 µm when SDS was used, and at the same time, the variation of pore size was minimized, so that a relatively uniform pore size was maintained. In addition, the thermal conductivity is 0.0803 W/m·K and the pore size is 33.2 μm, which is smaller in pore diameter than the geopolymer containing only hydrogen peroxide. As a result, although the hydrogen peroxide alone sample has excellent thermal conductivity, the use of a surfactant is recommended for fine micropore size control. While reducing the non-uniform distribution of pores and the size of micropores generated through the direct foaming method as an inorganic binder, the possibility of an insulation finish was also confirmed by reducing the weight.
Mineralogy, Geochemistry, and Stable Isotopes (C, O, S) of Hot Spring Waters and Associated Travertines near Tamiahua Lagoon, Veracruz, Gulf of Mexico (Mexico)
Authors: Porras-Toribio Israel , Pi-Puig Teresa , Villanueva-Estrada Ruth Esther , Rubio-Ramos Marco Antonio , Solé Jesús
Published: June 2022

Laminated travertine forms in and around an active hot spring on the west coast of Tamiahua Lagoon, north of the state of Veracruz, Mexico. Fluid chemistry is characterized by discharging slightly acidic pH hot water and gas at a constant flow rate. Moreover, finely interbedded mineralogical products from discharging waters at 70 °C host scattered hydrocarbons. The mineralogy and geochemistry of the travertine formations were characterized to determine their origin. Rock samples were collected and further studied by transmitted light petrography, X-ray diffraction, and EDS-coupled scanning electron microprobe. Identified mineralogy from outcrop samples includes aragonite, gypsum, anhydrite, and elemental sulfur as essential minerals, with calcite, celestine, barite, jarosite, opal, and fluorite as accessory minerals. Isotopic analyses for C and O were determined in carbonates, S isotope ratios on both elemental sulfur and sulfates, whereas measurements for trace elements and lanthanides were performed on carbonates. A suit of brines and condensates from gas samples was collected for H and O isotopic analyses and concentration determinations of the main ions and major and trace elements. Isotopic values of δ13C and δ18O of aragonite are in the range of +1.75‰ to +2.37‰ and −1.70‰ to −0.78‰, respectively. The δ34S isotopic values of native sulfur and sulfates ranged from −4.0‰ to +1.2‰. The isotopic values of δ2H (−5.50‰) and δ18O (+7.77‰) of hot water samples collected in terraces where aragonite precipitates suggest a mixture between meteoric water and the Gulf of Mexico oil-field related waters. It was concluded that the aragonitic formations near Tamiahua Lagoon are hypogenic and were generated by CO2 and H2S emanations of deep origin and by oxidation-reduction reactions that can be linked to surficial bacterial activity.
A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus
Authors: Costa Renato A. da , Rocha João A. P. da , Pinheiro Alan S. , Costa Andréia do S. S. da , Rocha Elaine C. M. da , Silva Rai. C. , Gonçalves Arlan da S. , Santos Cleydson B. R. , Brasil Davi do S. B.
Published: June 2022

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.
Study on Quality Control of Compound Anoectochilus roxburghii (Wall.) Lindl. by Liquid Chromatography–Tandem Mass Spectrometry
Authors: Zhang Qiuhua , Huang Lingyi , Wu Youjia , Huang Liying , Xu Xiaowen , Lin Renyi
Published: June 2022

Compound Anoectochilus roxburghii (Wall.) Lindl. (A. roxburghii) oral liquid (CAROL) is a hospital preparation of A. roxburghii and Ganoderma lucidum (G. lucidum), which have hepatoprotective effects. Eight active components (five nucleosides/nucleobases and three triterpenoid acids) in CAROL, A. roxburghii, and G. lucidum were simultaneously detected by high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS). The multiple reaction monitoring (MRM) mode was applied for the detection of analytes. These eight compounds were separated well within 12 min and quantified using the internal standard working curve method. The method showed good linearity (R2 > 0.9935) and high sensitivity (limit of detection = 0.29 ng/mL). The analyte recovery ranged from 85.07% to 97.50% (relative standard deviation < 3.31%). The content of the target analytes in four batches of CAROL, and the raw materials of G. lucidum and A. roxburghii from the five regions was determined using this method. The contents of guanosine and ganoderic acid A in four batches of oral liquid were high and stabilized and could be recommended as quality markers (Q-marker) for CAROL. Simultaneous qualitative and quantitative analysis of nucleosides and triterpenoid acids in CAROL, A. roxburghii, and G. lucidum by LC–MS/MS based on the MRM model was reported for the first time. The proposed method provides a sensitive, rapid, and reliable approach for the quality control of Chinese medicinal products.
The Genus Miconia Ruiz & Pav. (Melastomataceae): Ethnomedicinal Uses, Pharmacology, and Phytochemistry
Authors: da Silva Viviane Bezerra , Almeida-Bezerra José Weverton , Costa Adrielle Rodrigues , Morais-Braga Maria Flaviana Bezerra , de Oliveira Maraiza Gregorio , Pinheiro Anderson Angel Vieira , Sampaio Raimundo Samuel Leite , Castro José Walber Gonçalves , dos Santos Marcos Aurélio Figueiredo , Ulisses Valdilia Ribeiro de Alencar , Pereira Maria Edilania da Silva Serafim , Souza Dieferson Leandro de , Alcântara Bruno Melo de , Generino Maria Elizete Machado , Silva José Thyálisson da Costa , Filho Ademar Maia , Silva Sabrina Bezerra da , Moon Myunghan , Kim Bonglee , Costa José Galberto Martins da
Published: June 2022

Species of the genus Miconia are used in traditional medicine for the treatment of diseases, such as pain, throat infections, fever, and cold, and they used as depuratives, diuretics, and sedatives. This work reviewed studies carried out with Miconia species, highlighting its ethnomedicinal uses and pharmacological and phytochemical potential. This information was collected in the main platforms of scientific research (PubMed, Scopus, and Web of Science). Our findings show that some of the traditional uses of Miconia are corroborated by biological and/or pharmacological assays, which demonstrated, among other properties, anti-inflammatory, analgesic, antimutagenic, antiparasitic, antioxidant, cytotoxic, and antimicrobial activities. A total of 148 chemical compounds were identified in Miconia species, with phenolic compounds being the main constituents found in the species of this genus. Such phytochemical investigations have demonstrated the potential of species belonging to this genus as a source of bioactive substances, thus reinforcing their medicinal and pharmacological importance.
Impact of Thermally Reducing Temperature on Graphene Oxide Thin Films and Microsupercapacitor Performance
Authors: Maphiri Vusani , Bakhoum Daba , Sarr Samba , Sylla Ndeye , Rutavi Gift , Manyala Ncholu
Published: June 2022

In this work, a thermally reduced graphene oxide (TRGO) thin film on microscopic glass was prepared using spray coating and atmospheric pressure chemical vapour deposition. The structure of TRGO was analysed using X-ray diffraction (XRD) spectroscopy, scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), Fourier transform infrared (FTIR) spectroscopy, and ultraviolet–visible spectroscopy (UV-Vis) suggesting a decrease in oxygen functional groups (OFGs), leading to the restacking, change in colour, and transparency of the graphene sheets. Raman spectrum deconvolution detailed the film’s parameters, such as the crystallite size, degree of defect, degree of amorphousness, and type of defect. The electrochemical performance of the microsupercapacitor (µ-SC) showed a rectangular cyclic voltammetry shape, which was maintained at a high scan rate, revealing phenomenal electric double-layer capacitor (EDLC) behaviour. The power law and Trasatti’s analysis indicated that low-temperature TRGO µ-SC is dominated by diffusion-controlled behaviour, while higher temperature TRGO µ-SC is dominated by surface-controlled behaviour.
Surveying the Synthesis, Optical Properties and Photocatalytic Activity of Cu3N Nanomaterials
Authors: Paredes Patricio , Rauwel Erwan , Rauwel Protima
Published: June 2022

This review addresses the most recent advances in the synthesis approaches, fundamental properties and photocatalytic activity of Cu3N nanostructures. Herein, the effect of synthesis conditions, such as solvent, temperature, time and precursor on the precipitation of Cu3N and the formation of secondary phases of Cu and Cu2O are surveyed, with emphasis on shape and size control. Furthermore, Cu3N nanostructures possess excellent optical properties, including a narrow bandgap in the range of 0.2 eV–2 eV for visible light absorption. In that regard, understanding the effect of the electronic structure on the bandgap and on the optical properties of Cu3N is therefore of interest. In fact, the density of states in the d-band of Cu has an influence on the band gap of Cu3N. Moreover, the potential of Cu3N nanomaterials for photocatalytic dye-degradation originates from the presence of active sites, i.e., Cu and N vacancies on the surface of the nanoparticles. Plasmonic nanoparticles tend to enhance the efficiency of photocatalytic dye degradation of Cu3N. Nevertheless, combining them with other potent photocatalysts, such as TiO2 and MoS2, augments the efficiency to 99%. Finally, the review concludes with perspectives and future research opportunities for Cu3N-based nanostructures.
Exercise: A Possibly Effective Way to Improve Vitamin D Nutritional Status
Authors: Zhang Jinghua , Cao Zhen-Bo
Published: June 2022

Vitamin D deficiency has become a widespread public health problem owing to its potential adverse health effects. Generally, the nutritional status of vitamin D depends on sunlight exposure and dietary or supplementary intake. However, recent studies have found that exercise can influence circulating 25(OH)D levels; although, the results have been inconclusive. In this review, we focused on the effect of exercise on circulating vitamin D metabolites and their possible mechanisms. We found that endurance exercise can significantly increase serum 25(OH)D levels in vitamin D-deficient people but has no significant effect on vitamin D-sufficient people. This benefit has not been observed with resistance training. Only chronic endurance exercise training can significantly increase serum 1,25(OH)2D, and the effect may be sex-dependent. Exercise may influence 25(OH)D levels in the circulation by regulating either the vitamin D metabolites stored in tissues or the utilization by target tissues. The effects of exercise on 25(OH)D levels in the circulation may be dependent on many factors, such as the vitamin D nutritional status, exercise type and intensity, and sex. Therefore, further research on the effects and mechanisms of exercise on vitamin D metabolites is required.
Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies
Authors: Sanchez-Gimenez Raul , Ahmed-Khodja Wahiba , Molina Yesica , Peiró Oscar M. , Bonet Gil , Carrasquer Anna , Fragkiadakis George A. , Bulló Mònica , Bardaji Alfredo , Papandreou Christopher
Published: June 2022

Gut microbiota-derived metabolites have recently attracted considerable attention due to their role in host-microbial crosstalk and their link with cardiovascular health. The MEDLINE-PubMed and Elsevier’s Scopus databases were searched up to June 2022 for studies evaluating the association of baseline circulating levels of trimethylamine N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), tryptophan and indole derivatives, with risk of cardiovascular disease (CVD). A total of twenty-one studies were included in the systematic review after evaluating 1210 non-duplicate records. There were nineteen of the twenty-one studies that were cohort studies and two studies had a nested case–control design. All of the included studies were of high quality according to the “Newcastle–Ottawa Scale”. TMAO was positively associated with adverse cardiovascular events and CVD/all-cause mortality in some, but not all of the included studies. Bile acids were associated with atrial fibrillation and CVD/all-cause mortality, but not with CVD. Positive associations were found between BCAAs and CVD, and between indole derivatives and major adverse cardiovascular events, while a negative association was reported between tryptophan and all-cause mortality. No studies examining the relationship between SCFAs and CVD risk were identified. Evidence from prospective studies included in the systematic review supports a role of microbial metabolites in CVD.
Relevance of Early Introduction of Cow’s Milk Proteins for Prevention of Cow’s Milk Allergy
Authors: Ulfman Laurien , Tsuang Angela , Sprikkelman Aline B. , Goh Anne , van Neerven R. J. Joost
Published: June 2022

Food allergy incidence has increased worldwide over the last 20 years. For prevention of food allergy, current guidelines do not recommend delaying the introduction of allergenic foods. Several groundbreaking studies, such as the Learning Early About Peanut Allergy study, showed that the relatively early introduction of this allergenic food between 4–6 months of age reduces the risk of peanut allergy. However, less is known about the introduction of cow’s milk, as many children already receive cow’s-milk-based formula much earlier in life. This can be regular cow’s milk formula with intact milk proteins or hydrolyzed formulas. Several recent studies have investigated the effects of early introduction of cow’s-milk-based formulas with intact milk proteins on the development of cow’s milk allergy while breastfeeding. These studies suggest that depending on the time of introduction and the duration of administration of cow’s milk, the risk of cow’s milk allergy can be reduced (early introduction) or increased (very early introduction followed by discontinuation). The aim of this narrative review is to summarize these studies and to discuss the impact of early introduction of intact cow’s milk protein—as well as hydrolyzed milk protein formulas—and the development of tolerance versus allergy towards cow’s milk proteins.
Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases
Authors: Eicher Tanja Patricia , Mohajeri M. Hasan
Published: June 2022

The involvement of the gut microbiota and the metabolites of colon-residing bacteria in brain disease pathogenesis has been covered in a growing number of studies, but comparative literature is scarce. To fill this gap, we explored the contribution of the microbiota–gut–brain axis to the pathophysiology of seven brain-related diseases (attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, major depressive disorder, and bipolar disorder). In this article, we discussed changes in bacterial abundance and the metabolic implications of these changes on disease development and progression. Our central findings indicate that, mechanistically, all seven diseases are associated with a leaky gut, neuroinflammation, and over-activated microglial cells, to which gut-residing bacteria and their metabolites are important contributors. Patients show a pro-inflammatory shift in their colon microbiota, harbouring more Gram-negative bacteria containing immune-triggering lipopolysaccharides (LPS) in their cell walls. In addition, bacteria with pro-inflammatory properties (Alistipes, Eggerthella, Flavonifractor) are found in higher abundances, whereas lower abundances of anti-inflammatory bacteria (Bifidobacterium, Coprococcus, Eucbacterium, Eubacterium rectale, Faecalibacterium, Faecalibacterium prasunitzii, Lactobacillus, Prevotella, Roseburia) are reported, when compared to healthy controls. On the metabolite level, aberrant levels of short-chain fatty acids (SCFAs) are involved in disease pathogenesis and are mostly found in lower quantities. Moreover, bacterial metabolites such as neurotransmitters (acetylcholine, dopamine, noradrenaline, GABA, glutamate, serotonin) or amino acids (phenylalanine, tryptophan) also play an important role. In the future, defined aberrations in the abundance of bacteria strains and altered bacterial metabolite levels could likely be possible markers for disease diagnostics and follow-ups. Moreover, they could help to identify novel treatment options, underlining the necessity for a deeper understanding of the microbiota–gut–brain axis.
Association between the Dietary Inflammatory Index and Gastric Disease Risk: Findings from a Korean Population-Based Cohort Study
Authors: Sreeja Sundara Raj , Le Trong-Dat , Eom Bang Wool , Oh Seung Hyun , Shivappa Nitin , Hebert James R. , Kim Mi Kyung
Published: June 2022

Evidence suggests that diets with high pro-inflammatory potential may play a substantial role in the origin of gastric inflammation. This study aimed to examine the association between the energy-adjusted dietary inflammatory index (E-DIITM) and gastric diseases at baseline and after a mean follow-up of 7.4 years in a Korean population. A total of 144,196 participants from the Korean Genome and Epidemiology Study_Health Examination (KoGES_HEXA) cohort were included. E-DII scores were computed using a validated semi-quantitative food frequency questionnaire. Multivariate logistic regression and Cox proportional hazards regression were used to assess the association between the E-DII and gastric disease risk. In the prospective analysis, the risk of developing gastric disease was significantly increased among individuals in the highest quartile of E-DII compared to those in the lowest quartile (HRquartile4vs1 = 1.22; 95% CI = 1.08–1.38). Prospective analysis also showed an increased risk in the incidence of gastritis (HRquartile4vs1 = 1.19; 95% CI = 1.04–1.37), gastric ulcers (HRquartile4vs1 = 1.47; 95% CI = 1.16–1.85), and gastric and duodenal ulcers (HRquartile4vs1 = 1.46; 95% CI = 1.17–1.81) in the highest E-DII quartile compared to the lowest quartile. In the cross-sectional analysis, the E-DII score was not associated with the risk of gastric disease. Our results suggest that a pro-inflammatory diet, indicated by high E-DII scores, is prospectively associated with an increased risk of gastric diseases. These results highlight the significance of an anti-inflammatory diet in lowering the risk of gastric disease risk in the general population.
Tea (Camellia sinensis) Ameliorates Hyperuricemia via Uric Acid Metabolic Pathways and Gut Microbiota
Authors: Wu Dan , Chen Ruohong , Li Qiuhua , Lai Xingfei , Sun Lingli , Zhang Zhenbiao , Wen Shuai , Sun Shili , Cao Fanrong
Published: June 2022

Hyperuricemia (HUA) is a metabolic disease that threatens human health. Tea is a healthy beverage with an abundance of benefits. This study revealed the uric acid-lowering efficacy of six types of tea water extracts (TWEs) on HUA in mice. The results revealed that under the intervention of TWEs, the expression of XDH, a key enzyme that produces uric acid, was significantly downregulated in the liver. TWE treatment significantly upregulated the expression of uric acid secretion transporters ABCG2, OAT1, and OAT3, and downregulated the expression of uric acid reabsorption transporter URAT1 in the kidney. Furthermore, HUA-induced oxidative stress could be alleviated by upregulating the Nrf2/HO-1 pathway. The intervention of TWEs also significantly upregulated the expression of the intestinal ABCG2 protein. On the other hand, TWE intervention could significantly upregulate the expression of intestinal ABCG2 and alleviate HUA by modulating the gut microbiota. Taken together, tea can comprehensively regulate uric acid metabolism in HUA mice. Interestingly, we found that the degree of fermentation of tea was negatively correlated with the uric acid-lowering effect. The current study indicated that tea consumption may have a mitigating effect on the HUA population and provided a basis for further research on the efficacy of tea on the dosage and mechanism of uric acid-lowering effects in humans.
An Infancy-Onset 20-Year Dietary Counselling Intervention and Gut Microbiota Composition in Adulthood
Authors: Keskitalo Anniina , Munukka Eveliina , Aatsinki Anna , Saleem Wisam , Kartiosuo Noora , Lahti Leo , Huovinen Pentti , Elo Laura L. , Pietilä Sami , Rovio Suvi P. , Niinikoski Harri , Viikari Jorma , Rönnemaa Tapani , Lagström Hanna , Jula Antti , Raitakari Olli , Pahkala Katja
Published: June 2022

The randomized controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) has completed a 20-year infancy-onset dietary counselling intervention to reduce exposure to atherosclerotic cardiovascular disease risk factors via promotion of a heart-healthy diet. The counselling on, e.g., low intake of saturated fat and cholesterol and promotion of fruit, vegetable, and whole-grain consumption has affected the dietary characteristics of the intervention participants. By leveraging this unique cohort, we further investigated whether this long-term dietary intervention affected the gut microbiota bacterial profile six years after the intervention ceased. Our sub-study comprised 357 individuals aged 26 years (intervention n = 174, control n = 183), whose gut microbiota were profiled using 16S rRNA amplicon sequencing. We observed no differences in microbiota profiles between the intervention and control groups. However, out of the 77 detected microbial genera, the Veillonella genus was more abundant in the intervention group compared to the controls (log2 fold-change 1.58, p < 0.001) after adjusting for multiple comparison. In addition, an association between the study group and overall gut microbiota profile was found only in males. The subtle differences in gut microbiota abundances observed in this unique intervention setting suggest that long-term dietary counselling reflecting dietary guidelines may be associated with alterations in gut microbiota.
A Slight Adjustment of the Nutri-Score Nutrient Profiling System Could Help to Better Reflect the European Dietary Guidelines Regarding Nuts
Authors: Braesco Véronique , Ros Emilio , Govindji Azmina , Bianchi Clélia , Becqueriaux Lise , Quick Belinda
Published: June 2022

The consumption of nuts remains low among European populations despite widespread inclusion as a recommended food group across European dietary guidelines. Front-of-Pack nutrition labelling systems are designed to support consumers make healthier choices and to stimulate product improvement, thus representing a pivotal opportunity to reduce the gap between intakes and recommendations. This study examined how the Nutri-Score algorithm treats nuts and nut-containing products and tested whether slight adjustments could better recognise and motivate nut inclusion in foods and diets. The nutritional score (ScN) and corresponding Nutri-Score letter of 68 nuts and nut-containing products were calculated, using the initial algorithm and slight adjustments, where nut weight was doubled (S1), saturated fats (S2) or energy (S3) from nuts were discounted, or saturated fats were replaced by the saturated fats/lipid ratio (S4). The correlation between the nuts’ content and the ScN was moderate for the initial algorithm (R2 = 0.34) and S1 (R2 = 0.36), but improved for S2, S3 and S4 (R2 = 0.54, 0.55 and 0.52, respectively). Four plain nuts, initially labelled as “B” or “C” obtained a Nutri-Score “A” with S2, S3 and S4. Slight adjustments could better align the Nutri-Score with food-based dietary guidelines, reassure consumers on healthfulness of nuts and nut-containing products, whilst incentivising the inclusion of nuts in diverse foods.
Hydroxycitric Acid Inhibits Chronic Myelogenous Leukemia Growth through Activation of AMPK and mTOR Pathway
Authors: Verrelli Doriana , Dallera Luca , Stendardo Massimo , Monzani Silvia , Pasqualato Sebastiano , Giorgio Marco , Pallavi Rani
Published: June 2022

Metabolic regulation of cancer cell growth via AMP-activated protein kinase (AMPK) activation is a widely studied strategy for cancer treatment, including leukemias. Recent notions that naturally occurring compounds might have AMPK activity led to the search for nutraceuticals with potential AMPK-stimulating activity. We found that hydroxycitric acid (HCA), a natural, safe bioactive from the plant Garcinia gummi-gutta (cambogia), has potent AMPK activity in chronic myelogenous leukemia (CML) cell line K562. HCA is a known competitive inhibitor of ATP citrate lyase (ACLY) and is widely used as a weight loss inducer. We found that HCA was able to inhibit the growth of K562 cells in in vitro and in vivo xenograft models. At the mechanistic level, we identified a direct interaction between AMPK and ACLY that seems to be sensitive to HCA treatment. Additionally, HCA treatment resulted in the co-activation of AMPK and the mammalian target of rapamycin (mTOR) pathways. Moreover, we found an enhanced unfolded protein response as observed by activation of the eIF2α/ATF4 pathway that could explain the induction of cell cycle arrest at the G2/M phase and DNA fragmentation upon HCA treatment in K562 cells. Overall, these findings suggest HCA as a nutraceutical approach for the treatment of CMLs.
Dietary Protein Restriction Improves Metabolic Dysfunction in Patients with Metabolic Syndrome in a Randomized, Controlled Trial
Authors: Ferraz-Bannitz Rafael , Beraldo Rebeca A. , Peluso A. Augusto , Dall Morten , Babaei Parizad , Foglietti Rayana Cardoso , Martins Larissa Marfori , Gomes Patricia Moreira , Marchini Julio Sergio , Suen Vivian Marques Miguel , de Freitas Luiz C. Conti , Navegantes Luiz Carlos , Pretti Marco Antônio M. , Boroni Mariana , Treebak Jonas T. , Mori Marcelo A. , Foss Milton Cesar , Foss-Freitas Maria Cristina
Published: June 2022

Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to determine whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. Twenty-one individuals diagnosed with metabolic syndrome were randomly assigned for caloric restriction (CR; n = 11, diet of 5941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, diet of 8409 ± 2360 KJ per day) and followed for 27 days. Like CR, PR promoted weight loss due to a reduction in adiposity, which was associated with reductions in blood glucose, lipid levels, and blood pressure. More strikingly, both CR and PR improved insulin sensitivity by 62.3% and 93.2%, respectively, after treatment. Fecal microbiome diversity was not affected by the interventions. Adipose tissue bulk RNA-Seq data revealed minor changes elicited by the interventions. After PR, terms related to leukocyte proliferation were enriched among the upregulated genes. Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has more significant potential to be used as adjuvant therapy for people with metabolic syndrome.
Valproate and Short-Chain Fatty Acids Activate Transcription of the Human Vitamin D Receptor Gene through a Proximal GC-Rich DNA Region Containing Two Putative Sp1 Binding Sites
Authors: Moreno-Torres Marta , Guzmán Carla , Petrov Petar D. , Jover Ramiro
Published: June 2022

The vitamin D receptor (VDR) mediates 1,25-dihydroxyvitamin D3 pleiotropic biological actions through transcription regulation of target genes. The expression levels of this ligand-activated nuclear receptor are regulated by multiple mechanisms both at transcriptional and post-transcriptional levels. Vitamin D3 is the natural VDR activator, but other molecules and signaling pathways have also been reported to regulate VDR expression and activity. In this study, we identify valproic acid (VPA) and natural short-chain fatty acids (SCFAs) as novel transcriptional activators of the human VDR (hVDR) gene. We further report a comprehensive characterization of VPA/SCFA-responsive elements in the 5′ regulatory region of the hVDR gene. Two alternative promoter DNA regions (of 2.4 and 3.8 kb), as well as subsequent deletion fragments, were cloned in pGL4-LUC reporter vector. Transfection of these constructs in HepG2 and human Upcyte hepatocytes followed by reporter assays demonstrated that a region of 107 bp (from −107 to −1) upstream of the transcription start site in exon 1a is responsible for most of the increase in transcriptional activity in response to VPA/SCFAs. This short DNA region is GC-rich, does not contain an apparent TATA box, and includes two bona fide binding sites for the transcription factor Sp1. Our results substantiate the hypothesis that VPA and SCFAs facilitate the activity of Sp1 on novel Sp1 responsive elements in the hVDR gene, thus promoting VDR upregulation and signaling. Elevated hepatic VDR levels have been associated with liver steatosis and, therefore, our results may have clinical relevance in epileptic pediatric patients on VPA therapy. Our results could also be suggestive of VDR upregulation by SCFAs produced by gut microbiota.
Calcific Shoulder Tendinopathy (CT): Influence of the Biochemical Process of Hydrolysis of HA (Hydroxyapatite) on the Choice of Ultrasound-Guided Percutaneous Treatment (with the Three-Needle Technique)
Authors: Galletti Stefano , Miceli Marco , Stella Salvatore Massimo , Vita Fabio , Bigliardi Davide , Donati Danilo , Creta Domenico , Frizziero Antonio
Published: June 2022

Calcific shoulder tendinopathy (CT) is a common condition involving the central part or insertion of the rotator cuff tendons (RC) or the subacromial-subdeltoid bursa (SASD). The calcific deposits consist of poorly crystallized calcium hydroxyapatite but the mechanism of their formation still remains unclear. CT can be divided into three distinct stages, as reported by Uthhoff et al. Clinically, this condition varies with the extent of the calcification and the phase of the condition. In particular, the disorder is asymptomatic or may cause mild discomfort during the deposition of calcium, while it becomes acutely painful during the resorptive phase. US-PICT (ultrasound-guided percutaneous irrigation of calcific tendinopathy) is indicated in the acute phase (resorptive phase) of CT with significant pain relief and a very low rate of minor complications. The aim of this manuscript is to define the rationale of the ultrasound-guided percutaneous irrigation of calcific tendinopathy, correlating it with the sequence of biochemical processes that lead to the hydrolysis of hydroxyapatite. Furthermore, we will explain the reasons why we prefer using the three-needle technique for the dissolution of calcifications.
Activation of Cellular Players in Adaptive Immunity via Exogenous Delivery of Tumor Cell Lysates
Authors: Seong Jihyun , Kim Kyobum
Published: June 2022

Tumor cell lysates (TCLs) are a good immunogenic source of tumor-associated antigens. Since whole necrotic TCLs can enhance the maturation and antigen-presenting ability of dendritic cells (DCs), multiple strategies for the exogenous delivery of TCLs have been investigated as novel cancer immunotherapeutic solutions. The TCL-mediated induction of DC maturation and the subsequent immunological response could be improved by utilizing various material-based carriers. Enhanced antitumor immunity and cancer vaccination efficacy could be eventually achieved through the in vivo administration of TCLs. Therefore, (1) important engineering methodologies to prepare antigen-containing TCLs, (2) current therapeutic approaches using TCL-mediated DC activation, and (3) the significant sequential mechanism of DC-based signaling and stimulation in adaptive immunity are summarized in this review. More importantly, the recently reported developments in biomaterial-based exogenous TCL delivery platforms and co-delivery strategies with adjuvants for effective cancer vaccination and antitumor effects are emphasized.
The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil
Authors: Markovic Milica , Zur Moran , Garsiani Sapir , Porat Daniel , Cvijić Sandra , Amidon Gordon L. , Dahan Arik
Published: June 2022

The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.
Glucose-Modified Zein Nanoparticles Enhance Oral Delivery of Docetaxel
Authors: Xing Yabing , Li Xiao , Cui Weiwei , Xue Meng , Quan Yanan , Guo Xinhong
Published: June 2022

Based on glucose (G) transporters (GLUTs), structuring nanoparticles with G as a target are an effective strategy to enhance oral bioavailability and anti-tumor effects of drugs. A novel drug delivery system using G-modified zein (GZ) nanoparticles loaded with docetaxel (DTX) (DTX-GNPs) was prepared and characterized in vitro and in vivo via assessment of cellular uptake, absorption site, pharmacokinetics, ex vivo distribution, and anti-tumor effects. The DTX-GNPs were approximately 120 nm in size. Compared with DTX-NPs, G modification significantly enhanced cellular uptake of DTX-GNPs by 1.22 times in CaCo-2 cells, which was related to GLUT mediation and the enhancement of endocytosis pathways via clathrin, micropinocytosis, and caveolin. Compared to DTX-NPs, G modification significantly enhanced DTX-NP absorption in the jejunum and ileum, delayed plasma concentration peak time, prolonged the average residence time in vivo, and increased oral bioavailability (from 43.82% to 96.04%). Cellular uptake and oral bioavailability of DTX were significantly affected by the G modification ratio. Compared with DTX-NPs, G modification significantly reduced drug distribution in the liver, lungs, and kidneys and increased tumor distribution and tumor growth inhibition rate without obvious systemic toxicity. This study demonstrated the potential of GZ-NPs as nanocarriers for DTX to enhance oral bioavailability and anti-tumor effects.
Intravitreal Application: Physicochemical Properties of Drugs Dissolved in Silicone Oils of Different Density in Comparison to the Porcine Vitreous Body
Authors: Hammer Maximilian , Schickhardt Sonja K. , Merz Patrick R. , Khoramnia Ramin , Scheuerle Alexander F. , Mier Walter , Uhl Philipp , Auffarth Gerd U.
Published: June 2022

Silicone oil endotamponades provide a reservoir for drugs in the eye. Following vitrectomy surgery to treat retinal detachments, extensive diabetic retinopathy or endophthalmitis, they can be used as long-term lipophilic depots. This study aimed to investigate the physicochemical properties of intravitreally applied drugs of different lipophilicity, namely vancomycin, ceftazidime and voriconazole. For this purpose, an in vitro model of the silicone-oil-filled eye compared to porcine vitreous bodies (PVBs) was used. In a glass container, either light or heavy silicone oil or PVB was set into equilibrium with an aqueous fluid. Vancomycin, voriconazole and ceftazidime were added in concentrations commonly applied in clinical practice. The time course of the concentration of the drugs was determined in the hydrophilic phase for up to 24 h. With silicone oil present, the concentrations of vancomycin, voriconazole and ceftazidime were elevated in the aqueous humor when compared to the vitreous body (p < 0.001 for all drugs). With increasing lipophilicity, higher concentrations of the drug dissolved in silicone oil after 24 h (52.7%, 49.1% and 34.3% for vancomycin, ceftazidime and voriconazole, respectively). While no difference between lighter- and heavier-than-water silicone oil was apparent for vancomycin and ceftazidime (p = 0.17 and p = 0.72), voriconazole dissolved significantly better in the heavier-than-water silicone oil (p = 0.002). A higher-than-expected percentage of the glycopeptide vancomycin dissolved in the porcine vitreous body, possibly due to protein binding. In conclusion, silicone oils influence the drug concentration and distribution of intravitreally applied drugs depending on their lipophilicity. The addition of F6H8 used to create heavy silicone oils attenuates these effects for lipophilic drugs. Knowledge of the distribution of these intravitreally applied drugs is crucial to ensure the desired anti-infectious effect.
Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide
Authors: Guo Shi , Song Zhengmei , Ji Ding-Kun , Reina Giacomo , Fauny Jean-Daniel , Nishina Yuta , Ménard-Moyon Cécilia , Bianco Alberto
Published: June 2022

Graphene oxide (GO) is one of the most studied nanomaterials in many fields, including the biomedical field. Most of the nanomaterials developed for drug delivery and phototherapies are based on noncovalent approaches that lead to an unspecific release of physisorbed molecules in complex biological environments. Therefore, preparing covalently functionalized GO using straightforward and versatile methods is highly valuable. Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), have shown great potential as effective therapeutic approaches against cancer. To overcome the limits of a single method, the combination of PTT and PDT can lead to a combined effect with a higher therapeutic efficiency. In this work, we prepare a folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO for combined targeted PTT/PDT. This conjugate can penetrate rapidly into cancer cells and macrophages. A combined effect of PTT and PDT is observed, leading to a higher killing efficiency toward different types of cells involved in cancer and other diseases. Our work provides a simple protocol to prepare multifunctional platforms for the treatment of various diseases.
A Mathematical Approach Using Strat-M® to Predict the Percutaneous Absorption of Chemicals under Finite Dose Conditions
Authors: Kunita Ryoki , Nishijima Takafumi , Todo Hiroaki , Sugibayashi Kenji , Sakaguchi Hitoshi
Published: June 2022

Estimation of the percutaneous absorption is essential for the safety assessment of cosmetic and dermopharmaceutical products. Currently, an artificial membrane, Strat-M®, has been focused on as the tool which could obtain the permeation parameters close to the skin-derived values. Nevertheless, few practical methodologies using the permeation parameters for assessing percutaneous absorption under in-use conditions are available. In the present study, based on Fick’s first law of diffusion, a novel mathematical model incorporating the permeation parameters as well as considering the water evaporation (Teva) was constructed. Then, to evaluate the applicability domain of our model in the case where Strat-M®-derived parameters were used, the permeation parameters were compared between the skin from edible porcine and Strat-M®. Regarding chemicals (−0.2 ≤ Log Kow ≤ 2.0), their permeation profiles were equivalent between Strat-M® and porcine skin. Therefore, for these chemicals, the percutaneous absorption was calculated using our model with the permeation parameters obtained using Strat-M® and the Teva determined by measuring the solution weight. The calculated values revealed a good correlation to the values obtained using porcine skin in finite dose experiments, suggesting that our mathematical approach with Strat-M® would be useful for the future safety assessment of cosmetic and dermopharmaceutical products.