bluuebunny/crossref_metadata_2025 huggingface dataset:
Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics
Authors: Scarpini Sara , Dondi Arianna , Totaro Camilla , Biagi Carlotta , Melchionda Fraia , Zama Daniele , Pierantoni Luca , Gennari Monia , Campagna Cinzia , Prete Arcangelo , Lanari Marcello
Published: September 2022

Visceral Leishmaniasis (VL) is a vector-borne disease caused by an intracellular protozoa of the genus Leishmania that can be lethal if not treated. VL is caused by Leishmania donovani in Asia and in Eastern Africa, where the pathogens’ reservoir is represented by humans, and by Leishmania infantum in Latin America and in the Mediterranean area, where VL is a zoonotic disease and dog is the main reservoir. A part of the infected individuals become symptomatic, with irregular fever, splenomegaly, anemia or pancytopenia, and weakness, whereas others are asymptomatic. VL treatment has made progress in the last decades with the use of new drugs such as liposomal amphotericin B, and with new therapeutic regimens including monotherapy or a combination of drugs, aiming at shorter treatment duration and avoiding the development of resistance. However, the same treatment protocol may not be effective all over the world, due to differences in the infecting Leishmania species, so depending on the geographical area. This narrative review presents a comprehensive description of the clinical picture of VL, especially in children, the diagnostic approach, and some insight into the most used pharmacological therapies available worldwide.
Proline Transport and Growth Changes in Proline Transport Mutants of Staphylococcus aureus
Authors: Schwan William R.
Published: September 2022

Staphylococcus aureus is a major cause of skin/soft tissue infections and more serious infections in humans. The species usually requires the importation of proline to be able to survive. Previous work has shown that single mutations in genes that encode for proline transporters affect the ability of S. aureus to survive in vitro and in vivo. To better understand proline transport in S. aureus, double and triple gene mutant strains were created that targeted the opuD, proP, and putP genes. Single gene mutants had some effect on proline transport, whereas double mutants exhibited significantly lower proline transport. An opuD prop putP triple gene mutant displayed the lowest proline transport under low- and high-affinity conditions. To assess growth differences caused by the mutations, the same mutants were grown in brain heart infusion (BHI) broth and defined staphylococcal medium (DSM) with various concentrations of proline. The triple mutant did not grow in DSM with a low concentration of proline and grew poorly in both DSM with a high proline concentration and BHI broth. These results show that S. aureus has multiple mechanisms to import proline into the cell and knocking out three of the main proline transporters significantly hinders S. aureus growth.
Effects of Enzymatically Induced Carbonate Precipitation on Capillary Pressure–Saturation Relations
Authors: Hommel Johannes , Gehring Luca , Weinhardt Felix , Ruf Matthias , Steeb Holger
Published: September 2022

Leakage mitigation methods are an important part of reservoir engineering and subsurface fluid storage, in particular. In the context of multi-phase systems of subsurface storage, e.g., subsurface CO2 storage, a reduction in the intrinsic permeability is not the only parameter to influence the potential flow or leakage; multi-phase flow parameters, such as relative permeability and capillary pressure, are key parameters that are likely to be influenced by pore-space reduction due to leakage mitigation methods, such as induced precipitation. In this study, we investigate the effects of enzymatically induced carbonate precipitation on capillary pressure–saturation relations as the first step in accounting for the effects of induced precipitation on multi-phase flow parameters. This is, to our knowledge, the first exploration of the effect of enzymatically induced carbonate precipitation on capillary pressure–saturation relations thus far. First, pore-scale resolved microfluidic experiments in 2D glass cells and 3D sintered glass-bead columns were conducted, and the change in the pore geometry was observed by light microscopy and micro X-ray computed tomography, respectively. Second, the effects of the geometric change on the capillary pressure–saturation curves were evaluated by numerical drainage experiments using pore-network modeling on the pore networks extracted from the observed geometries. Finally, parameters of both the Brooks–Corey and Van Genuchten relations were fitted to the capillary pressure–saturation curves determined by pore-network modeling and compared with the reduction in porosity as an average measure of the pore geometry’s change due to induced precipitation. The capillary pressures increased with increasing precipitation and reduced porosity. For the 2D setups, the change in the parameters of the capillary pressure–saturation relation was parameterized. However, for more realistic initial geometries of the 3D samples, while the general patterns of increasing capillary pressure may be observed, such a parameterization was not possible using only porosity or porosity reduction, likely due to the much higher variability in the pore-scale distribution of the precipitates between the experiments. Likely, additional parameters other than porosity will need to be considered to accurately describe the effects of induced carbonate precipitation on the capillary pressure–saturation relation of porous media.
Multifunctional Plasmon-Induced Transparency Devices Based on Hybrid Metamaterial-Waveguide Systems
Authors: Chen Hongting , Zhang Zhaojian , Zhang Xiao , Han Yunxin , Zhou Zigang , Yang Junbo
Published: September 2022

In this paper, we design a multifunctional micro-nano device with a hybrid metamaterial-waveguide system, which leads to a triple plasmon-induced transparency (PIT). The formation mechanisms of the three transparent peaks have their own unique characteristics. First, PIT-I can be switched into the BIC (Friedrich–Wintge bound state in continuum), and the quality factors (Q-factors) of the transparency window of PIT-I are increased during the process. Second, PIT-II comes from near-field coupling between two bright modes. Third, PIT-III is generated by the near-field coupling between a low-Q broadband bright mode and a high-Q narrowband guide mode, which also has a high-Q transparent window due to the guide mode. The triple-PIT described above can be dynamically tuned by the gate voltage of the graphene, particularly for the dynamic tuning of the Q values of PIT-I and PIT-III. Based on the high Q value of the transparent window, our proposed structure can be used for highly sensitive refractive index sensors or devices with prominent slow light effects.
Application of Magnonic Crystals in Magnetic Bead Detection
Authors: Manzin Alessandra , Ferrero Riccardo , Vicentini Marta
Published: September 2022

This paper aims at studying a sensor concept for possible integration in magnetic field-based lab-on-chip devices that exploit ferromagnetic resonance (FMR) phenomena in magnonic crystals. The focus is on 2D magnetic antidot arrays, i.e., magnetic thin films with periodic non-magnetic inclusions (holes), recently proposed as magnetic field sensor elements operating in the gigahertz (GHz) range. The sensing mechanism is here demonstrated for magnetic nano/microbeads adsorbed on the surface of permalloy (Ni80Fe20) antidot arrays with a rhomboid lattice structure and variable hole size. Through extensive micromagnetic modelling analysis, it is shown that the antidot arrays can be used as both bead traps and high-sensitivity detectors, with performance that can be tuned as a function of bead size and magnetic moment. A key parameter for the detection mechanism is the antidot array hole size, which affects the FMR frequency shifts associated with the interaction between the magnetization configuration in the nanostructured film and the bead stray field. Possible applications of the proposed device concept include magnetic immunoassays, using magnetic nano/microbeads as probes for biomarker detection, and biomaterial manipulation.
Capturing the Long-Sought Dy@C2v(5)-C80 via Benzyl Radical Stabilization
Authors: Han Xinyi , Xin Jinpeng , Yao Yangrong , Liang Zhihui , Qiu Yongfu , Chen Muqing , Yang Shangfeng
Published: September 2022

Endohedral metallofullerenes (EMFs) are one type of intriguing metal/carbon hybrid molecule with the molecule configuration of sphere cavity-encapsulating metal ions/metal clusters due to their unique physicochemical properties and corresponding application in the fields of biological materials, single molecule magnet materials and energy conversion materials. Although the EMF family is growing, and versatile EMFs have been successfully synthesized and confirmed using crystal structures, some expected EMF members have not been observed using the conventional fullerene separation and purify strategy. These missing EMFs raise an interesting scientific issue as to whether this is due to the difficulty in separating them from the in situ formed carbon soot. Herein, we successfully captured a long-sought dysprosium-based EMF bearing a C2v(5)-C80 cage (Dy@C2v(5)-C80) in the form of Dy@C2v(5)-C80(CH2Ph)(Ph = −C6H5) from carbon soot containing versatile EMFs using simple benzyl radical functionalization and unambiguously confirmed the molecule structure using single crystal X-ray diffraction characterization. Meanwhile, the crystal structure of Dy@C2v(5)-C80(CH2Ph) showed that a single benzyl group was grafted onto the (5,6,6)-carbon, suggesting the open-shell electronic configuration of Dy@C2v(5)-C80. The theoretical calculations unveiled that the benzyl radical addition enables the modulation of the electronic configuration of Dy@C2v(5)-C80 and the corresponding stabilization of Dy@C2v(5)-C80 in conventional organic solvents. This facile stabilization strategy via benzyl radical addition exhibits the considerable capability to capture these missing EMFs, with the benefit of enriching the endohedral fullerene family.
Effect of Green Tea Extract Ingestion on Fat Oxidation during Exercise in the Menstrual Cycle: A Pilot Study
Authors: Ishikawa Akira , Matsuda Tomoka , Gam Hyunjun , Kanno Moe , Yamada Mizuki , Ikegami Nodoka , Funaki Akiko , Ogata Hazuki , Kamemoto Kayoko , Ichihara Takashi , Sakamaki-Sunaga Mikako
Published: September 2022

In women, fat oxidation during exercise changes with the menstrual cycle. This study aimed to investigate the effect of green tea extract (GTE) ingestion on fat oxidation during exercise depending on the menstrual cycle phase. Ten women with regular menstrual cycles participated in this randomized, double-blind, crossover study. GTE or placebo was administered during the menstrual cycle’s follicular phase (FP) and luteal phase (LP). Participants cycled for 30 min at 50% maximal workload, and a respiratory gas analysis was performed. Serum estradiol, progesterone, free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were assessed before, during, and after the exercise. Fat oxidation, carbohydrate oxidation, and the respiratory exchange ratio (RER) were calculated using respiratory gas. Fat oxidation during the exercise was significantly higher in the FP than in the LP with the placebo (p < 0.05) but did not differ between the phases with GTE. Carbohydrate oxidation, serum-free fatty acid, plasma noradrenaline, blood glucose, and lactate concentrations were not significantly different between the phases in either trial. Our results suggest that GTE ingestion improves the decrease in fat oxidation in the LP.
Possible Measures to Improve Both Participation and Response Quality in Japan’s National Health and Nutrition Survey: Results from a Workshop by Local Government Personnel in Charge of the Survey
Authors: Ishikawa Midori , Yokoyama Tetsuji , Takimoto Hidemi
Published: September 2022

Increasing participation rates are crucial to ensure the representativeness of national survey results of the population. This study aimed to identify measures that could be taken by local government personnel in charge of the National Health and Nutrition Survey (NHNS), Japan, to improve participation rates. The subjects were twenty-one health personnel who worked in 19 local governments and participated in the training course at the National Institute of Public Health. Qualitative data were collected through a workshop. They discussed the problems that seem to affect participation rates and identified possible solutions. The contents were coded and grouped to create categories, using the Jiro Kawakita (KJ) method. For data analysis, researchers combined and reviewed all codes and categories. The measures that could improve participation rates were divided into the following 12 categories: 1. standardization of survey methods, 2. investigator skills, 3. survey organization, 4. venue setting, 5. accessing target households, 6. time of survey, 7. responses during the investigation, 8. confirming meal contents reported in the nutritional intake status survey, 9. rewards/incentives, 10. possible rewards, 11. feedback on survey results, and 12. survey practices during the COVID-19 pandemic. These findings represent viable initiatives for local health personnel to increase participation rates for the NHNS.
Healthy Lifestyle, Genetic Risk and Brain Health: A Gene-Environment Interaction Study in the UK Biobank
Authors: Mulugeta Anwar , Navale Shreeya S. , Lumsden Amanda L. , Llewellyn David J. , Hyppönen Elina
Published: September 2022

Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI < 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippocampal volume (beta −0.16 cm3, 95% CI −0.22, −0.11) and total brain volume (−4.34 cm3, 95% CI −7.68, −1.01) in participants aged ≥60 years but not <60 years. Healthy lifestyle was associated with higher total brain, grey matter and hippocampal volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.
Adherence to Mediterranean Diet and Soluble Klotho Level: The Value of Food Synergy in Aging
Authors: Wu Shou-En , Chen Ying-Jen , Chen Wei-Liang
Published: September 2022

Diets for healthy aging have long been an intriguing issue. The current study makes a head-to-head comparison of four dietary patterns and their associations with soluble Klotho (s-Klotho) levels, an aging-related marker. The dietary data of 7906 subjects were obtained from the National Health and Nutrition Examination Survey 2007–2016. Each participant was given a score or was grouped according to four dietary patterns, namely the Mediterranean adherence diet score (MDS), the low-carbohydrate-diet score, a low-fat diet, and a low-carbohydrate diet. Subsequently, the associations with s-Klotho were examined using linear regression analyses. In addition, we calculated the odds ratio (OR) for aging in different dietary patterns, taking the lowest quartile of s-Klotho as a reference for aging. The MDS was the only dietary pattern that revealed a relationship with s-Klotho levels. The positive association (β coefficient: 9.41, p < 0.001) remained significant when dividing the MDS into tertiles (Tertile 2: β coefficient: 36.87, p < 0.001; Tertile 3: β coefficient: 45.92, p < 0.001) and grouping participants into subsets by sex, age, and BMI. A lower OR for aging was observed in higher MDS groups (Tertile 2: OR = 0.86, p = 0.026; Tertile 3: OR = 0.77, p < 0.001). However, when analyzed separately, merely three out of nine components of the MDS, namely alcohol consumption (β coefficient: 42.54, p < 0.001), fruit (β coefficient: 11.59, p = 0.029), and dairy products (β coefficient: 8.55, p = 0.032), showed a significant association with s-Klotho. The Mediterranean diet adopts a food-based approach, which has the merit of valuing the complex interactions between foods and their constituents, and further brings benefits to healthy aging.
Predictive Roles of Basal Metabolic Rate and Body Water Distribution in Sarcopenia and Sarcopenic Obesity: The link to Carbohydrates
Authors: Guan Lizheng , Li Tiantian , Wang Xuan , Yu Kang , Xiao Rong , Xi Yuandi
Published: September 2022

Sarcopenic obesity is a new category of obesity and is a specific condition of sarcopenia. This study aimed to find the relationship of the basal metabolic rate (BMR) and body water distribution with muscle health and their prospective roles in screening for sarcopenic obesity and sarcopenia. The role of nutrients such as carbohydrates in the relationship was further detected. A total of 402 elderly subjects were recruited. Body composition was estimated by bioelectrical impedance analysis. Sarcopenia was defined by the Asian Working Group for Sarcopenia 2019. The cutoff values were determined by the receiver operating characteristic curve. Mediation analyses were performed using SPSS PROCESS. Higher BMR and BMR/body surface area (BSA) were protective factors against sarcopenic obesity (OR = 0.047, p = 0.004; OR = 0.035, p = 0.002) and sarcopenia (OR = 0.085, p = 0.001; OR = 0.100, p = 0.003) in elderly people. Low extracellular water (ECW)/intracellular water (ICW) and ECW/total body water (TBW) were negatively correlated with the skeletal muscle index (SMI). The intake of dietary carbohydrates in people with sarcopenic obesity was the lowest, but in subjects with obesity, it was the highest (p = 0.023). The results of the moderated mediation model showed that BMR fully mediated the positive relationship between carbohydrates and SMI, which was more obvious in the population with an abnormal body water distribution. BMR or BMR/BSA had the potential role of predicting a higher risk of sarcopenic obesity and sarcopenia. Higher BMR and lower ECW/ICW and ECW/TBW may benefit muscle health. The overconsumption of carbohydrates (especially > AMDR) might be a risk factor for obesity. Moderate dietary carbohydrate intake might promote SMI by regulating BMR and body water distribution in the elderly.
Trace Element Interactions, Inflammatory Signaling, and Male Sex Implicated in Reduced Growth Following Excess Oral Iron Supplementation in Pre-Weanling Rats
Authors: McMillen Shasta A. , Nonnecke Eric B. , Lönnerdal Bo
Published: September 2022

Iron supplements are frequently provided to infants in high-income countries despite low incidence of iron deficiency. There is growing concern regarding adverse health and development outcomes of excess iron provision in early life. Excess iron may directly damage developing organs through the formation of reactive oxygen species, alter systemic inflammatory signaling, and/or dysregulate trace mineral metabolism. To better characterize the in vivo effects of excess iron on development, we utilized a pre-weanling rat pup model. Lewis rat litters were culled to eight pups (four males and four females) and randomly assigned to daily supplementation groups receiving either vehicle control (CON; 10% w/v sucrose solution) or ferrous sulfate (FS) iron at one of the following doses: 10, 30, or 90 mg iron/kg body weight—FS-10, FS-30, and FS-90, respectively—from postnatal day (PD) 2 through 9. FS-90 litters, but not FS-30 or FS-10, failed to thrive compared to CON litters and had smaller brains on PD 10. Among the groups, FS-90 liver iron levels were highest, as were white blood cell counts. Compared to CON, circulating MCP-1 and liver zinc were increased in FS-90 pups, whereas liver copper was decreased. Growth defects due to excess FS provision in pre-weanling rats may be related to liver injury, inflammation, and altered trace mineral metabolism.
Effects of Branched-Chain Amino Acids on Skeletal Muscle, Glycemic Control, and Neuropsychological Performance in Elderly Persons with Type 2 Diabetes Mellitus: An Exploratory Randomized Controlled Trial
Authors: Matsuda Takaaki , Suzuki Hiroaki , Sugano Yoko , Suzuki Yasuhiro , Yamanaka Daisuke , Araki Risa , Yahagi Naoya , Sekiya Motohiro , Kawakami Yasushi , Osaki Yoshinori , Iwasaki Hitoshi , Hashimoto Koichi , Takahashi Shin-Ichiro , Hada Yasushi , Shimano Hitoshi
Published: September 2022

Although branched-chain amino acids (BCAA) are known to stimulate myofibrillar protein synthesis and affect insulin signaling and kynurenine metabolism (the latter being a metabolite of tryptophan associated with depression and dementia), the effects of BCAA supplementation on type 2 diabetes (T2D) are not clear. Therefore, a 24-week, prospective randomized open blinded-endpoint trial was conducted to evaluate the effects of supplementation of 8 g of BCAA or 7.5 g of soy protein on skeletal muscle and glycemic control as well as adverse events in elderly individuals with T2D. Thirty-six participants were randomly assigned to the BCAA group (n = 21) and the soy protein group (n = 15). Skeletal muscle mass and HbA1c, which were primary endpoints, did not change over time or differ between groups. However, knee extension muscle strength was significantly increased in the soy protein group and showed a tendency to increase in the BCAA group. Homeostasis model assessment for insulin resistance did not significantly change during the trial. Depressive symptoms were significantly improved in the BCAA group but the difference between groups was not significant. Results suggested that BCAA supplementation may not affect skeletal muscle mass and glycemic control and may improve depressive symptoms in elderly individuals with T2D.
Wogonin, a Compound in Scutellaria baicalensis, Activates ATF4–FGF21 Signaling in Mouse Hepatocyte AML12 Cells
Authors: Yamada Yasunari , Saito Hodaka , Araki Masaya , Tsuchimoto Yuhei , Muroi Shin-ichi , Suzuki Kyohei , Toume Kazufumi , Kim Jun-Dal , Matsuzaka Takashi , Sone Hirohito , Shimano Hitoshi , Nakagawa Yoshimi
Published: September 2022

Fibroblast growth factor 21 (FGF21), which is mainly synthesized and secreted by the liver, plays a crucial role in systemic glucose and lipid metabolism, ameliorating metabolic diseases. In this study, we screened the WAKANYAKU library derived from medicinal herbs to identify compounds that can activate Fgf21 expression in mouse hepatocyte AML12 cells. We identified Scutellaria baicalensis root extract and one of its components, wogonin, as an activator of Fgf21 expression. Wogonin also enhanced the expression of activating transcription factor 4 (ATF4) by a mechanism other than ER stress. Knockdown of ATF4 by siRNA suppressed wogonin-induced Fgf21 expression, highlighting its essential role in wogonin’s mode of action. Thus, our results indicate that wogonin would be a strong candidate for a therapeutic to improve metabolic diseases by enhancing hepatic FGF21 production.
Alterations in Intestinal Brush Border Membrane Functionality and Bacterial Populations Following Intra-Amniotic Administration (Gallus gallus) of Catechin and Its Derivatives
Authors: Kolba Nikolai , Zarei Amin , Cheng Jacquelyn , Agarwal Nikita , Dadmohammadi Younas , Khazdooz Leila , Abbaspourrad Alireza , Tako Elad
Published: September 2022

Catechin is a flavonoid naturally present in numerous dietary products and fruits (e.g., apples, berries, grape seeds, kiwis, green tea, red wine, etc.) and has previously been shown to be an antioxidant and beneficial for the gut microbiome. To further enhance the health benefits, bioavailability, and stability of catechin, we synthesized and characterized catechin pentaacetate and catechin pentabutanoate as two new ester derivatives of catechin. Catechin and its derivatives were assessed in vivo via intra-amniotic administration (Gallus gallus), with the following treatment groups: (1) non-injected (control); (2) deionized H2O (control); (3) Tween (0.004 mg/mL dose); (4) inulin (50 mg/mL dose); (5) Catechin (6.2 mg/mL dose); (6) Catechin pentaacetate (10 mg/mL dose); and (7) Catechin pentabutanoate (12.8 mg/mL dose). The effects on physiological markers associated with brush border membrane morphology, intestinal bacterial populations, and duodenal gene expression of key proteins were investigated. Compared to the controls, our results demonstrated a significant (p < 0.05) decrease in Clostridium genera and E. coli species density with catechin and its synthetic derivative exposure. Furthermore, catechin and its derivatives decreased iron and zinc transporter (Ferroportin and ZnT1, respectively) gene expression in the duodenum compared to the controls. In conclusion, catechin and its synthetic derivatives have the potential to improve intestinal morphology and functionality and positively modulate the microbiome.
“Doctor, Can I Drink an Alcohol-Free Beer?” Low-Alcohol and Alcohol-Free Drinks in People with Heavy Drinking or Alcohol Use Disorders: Systematic Review of the Literature
Authors: Caballeria Elsa , Pons-Cabrera Maria Teresa , Balcells-Oliveró Mercedes , Braddick Fleur , Gordon Rebecca , Gual Antoni , Matrai Silvia , López-Pelayo Hugo
Published: September 2022

No- and low-alcohol drinks (NoLo) have been proposed as a potential way forward for the reduction in the alcohol burden of disease. So far, there is scarce synthesized evidence on the effects of these products on people with alcohol use disorder (AUD), or with a heavy or high-risk drinking pattern. The aim of the present study is to systematically review the evidence of the use of NoLo drinks in these populations. A total of 4045 records were screened and 10 studies were included in the review. Craving and desire to drink have been found to increase after the consumption of NoLo drinks in patients with AUD. The increase in craving correlates with the severity of alcohol dependence. In addition, in this population, alcohol-related cues might trigger physiological responses similar to those experienced when using alcohol. Furthermore, as mentioned, in some of the studies, consumption was shown to increase as the %ABV or verbal descriptors indicate lower alcohol. Last, according to the epidemiological data, heavy drinkers tend to use NoLo drinks on top of their usual alcohol consumption rather than as part of regular drinking patterns. Further studies should be conducted in people with AUD or people with a high-risk drinking pattern to provide new insight to guide clinicians, patients, and other stakeholders to make evidence-based informed decisions.
Isinglass Polysaccharides Regulate Intestinal-Barrier Function and Alleviate Obesity in High-Fat Diet Mice through the HO-1/Nrf2 Pathway and Intestinal Microbiome Environment
Authors: Li Guopeng , Li Shugang , Liu Huanhuan , Zhang Lihua , Gao Jingzhu , Zhang Siteng , Zou Yue , Xia Xiaodong , Ren Xiaomeng
Published: September 2022

Plant polysaccharide intervention has shown significant potential to combat obesity. However, studies on animal polysaccharides are indeed rare. The aim of this study was to investigate the potential functions of CIP (IL) on obesity, intestinal microflora dysbiosis, and the possible protection of intestinal barrier in mice fed with high-fat diet (HFD). Our results revealed that after 13 weeks, the HFD+L (high-fat diet + 25 mg/kg CIP) group showed significantly more weight loss and fat accumulation relative to the HFD+H (high-fat diet + 50 mg/kg CIP) group. Furthermore, CIP intervention modulated lipid metabolism and mRNA levels of inflammatory mediators in liver. Overall, CIP clearly improved the intestinal barrier in HFD-fed mice. Additionally, we observed that CIP intervention improved intestinal microbiota community richness and diversity in HFD-fed mice. The CIP intervention mice group showed a relatively low Firmicutes to Bacteroidetes ratio compared to the HFD group. This study concluded that CIP could be used as a functional food to prevent adipocyte accumulation, reduce systemic inflammation, and protect the intestinal barrier.
Efficient Production of the PET Radionuclide 133La for Theranostic Purposes in Targeted Alpha Therapy Using the 134Ba(p,2n)133La Reaction
Authors: Brühlmann Santiago , Kreller Martin , Pietzsch Hans-Jürgen , Kopka Klaus , Mamat Constantin , Walther Martin , Reissig Falco
Published: September 2022

Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, 225Ac provides all necessary physical and chemical properties for a successful clinical application, which has already been shown by [225Ac]Ac-PSMA-617. While PSMA-617 carries the DOTA moiety as the complexing agent, the chelator macropa as a macrocyclic alternative provides even more beneficial properties regarding labeling and complex stability in vivo. Lanthanum-133 is an excellent positron-emitting diagnostic lanthanide to radiolabel macropa-functionalized therapeutics since 133La forms a perfectly matched theranostic pair of radionuclides with the therapeutic radionuclide 225Ac, which itself can optimally be complexed by macropa as well. 133La was thus produced by cyclotron-based proton irradiation of an enriched 134Ba target. The target (30 mg of [134Ba]BaCO3) was irradiated for 60 min at 22 MeV and 10–15 µA beam current. Irradiation side products in the raw target solution were identified and quantified: 135La (0.4%), 135mBa (0.03%), 133mBa (0.01%), and 133Ba (0.0004%). The subsequent workup and anion-exchange-based product purification process took approx. 30 min and led to a total amount of (1.2–1.8) GBq (decay-corrected to end of bombardment) of 133La, formulated as [133La]LaCl3. After the complete decay of 133La, a remainder of ca. 4 kBq of long-lived 133Ba per 100 MBq of 133La was detected and rated as uncritical regarding personal dose and waste management. Subsequent radiolabeling was successfully performed with previously published macropa-derived PSMA inhibitors at a micromolar range (quantitative labeling at 1 µM) and evaluated by radio-TLC and radio-HPLC analyses. The scale-up to radioactivity amounts that are needed for clinical application purposes would be easy to achieve by increasing target mass, beam current, and irradiation time to produce 133La of high radionuclide purity (>99.5%) regarding labeling properties and side products.
Design and Synthesis of Aminopyrimidinyl Pyrazole Analogs as PLK1 Inhibitors Using Hybrid 3D-QSAR and Molecular Docking
Authors: Bhujbal Swapnil P. , Kim Hyejin , Bae Hyunah , Hah Jung-Mi
Published: September 2022

Cancer continues to be one of the world’s most severe public health issues. Polo-like kinase 1 (PLK1) is one of the most studied members of the polo-like kinase subfamily of serine/threonine protein kinases. PLK1 is a key mitotic regulator responsible for cell cycle processes, such as mitosis initiation, bipolar mitotic spindle formation, centrosome maturation, the metaphase to anaphase transition, and mitotic exit, whose overexpression is often associated with oncogenesis. Moreover, it is also involved in DNA damage response, autophagy, cytokine signaling, and apoptosis. Due to its fundamental role in cell cycle regulation, PLK1 has been linked to various types of cancer onset and progression, such as lung, colon, prostate, ovary, breast cancer, melanoma, and AML. Hence, PLK1 is recognized as a critical therapeutic target in the treatment of various proliferative diseases. PLK1 inhibitors developed in recent years have been researched and studied through clinical trials; however, most of them have failed because of their toxicity and poor therapeutic response. To design more potent and selective PLK1 inhibitors, we performed a receptor-based hybrid 3D-QSAR study of two datasets, possessing similar common scaffolds. The developed hybrid CoMFA (q2 = 0.628, r2 = 0.905) and CoMSIA (q2 = 0.580, r2 = 0.895) models showed admissible statistical results. Comprehensive, molecular docking of one of the most active compounds from the dataset and hybrid 3D-QSAR studies revealed important active site residues of PLK1 and requisite structural characteristics of ligand to design potent PLK1 inhibitors. Based on this information, we have proposed approximately 38 PLK1 inhibitors. The newly designed PLK1 inhibitors showed higher activity (predicted pIC50) than the most active compounds of all the derivatives selected for this study. We selected and synthesized two compounds, which were ultimately found to possess good IC50 values. Our design strategy provides insight into development of potent and selective PLK1 inhibitors.
The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blockers
Authors: Dierks Anne , Vanucci-Bacqué Corinne , Schäfer Anne-Marie , Lehrich Tina , Ruhe Frederike , Schadzek Patrik , Bedos-Belval Florence , Ngezahayo Anaclet
Published: September 2022

Inflammation mediators enhance the activity of connexin (Cx) hemichannels, especially in the epithelial and endothelial tissues. As potential release routes for injury signals, such as (oligo)nucleotides, Cx hemichannels may contribute to long-lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long-lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells, using dye uptake as functional assay. Moreover, the possible impacts of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (>5 µM) and Cx46 (>20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversibly inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to the stimulation of adenosine signalling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversibly block Cx hemichannels. Deciphering the mechanisms of the interactions of these agents with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for better and safer treatment of pathologies that involve Cx hemichannels.
Selective Spectrofluorimetric Approach for the Assessment of Two Antipsychotic Drugs through Derivatization with O-Phthalaldehyde
Authors: Hassan Hassan M. A. , Alsohaimi Ibrahim H. , El-Sayed Mohamed Y. , Ali Ismail I. , El-Didamony Akram M. , Altaleb Hamud A. , Alshammari Mutairah S.
Published: September 2022

A facile and sensible spectrofluorimetric approach for the measurement of two antipsychotic medications, aripiperazole (ARP) and clozapine (CLZ), was devised and validated. The approach involves reacting the examined medicines with o-phthalaldehyde in the presence of β-mercaptoethanol in a borate buffer of pH 9.0 and pH 10 for ARP and CLZ, respectively, to produce a robustly fluorescent compound that is detected at 450 nm following excitation at 340 nm. The experimental variables influencing the performance and product stability were thoroughly investigated and optimized. Under optimal conditions, the intensity of the fluorescence was linear during a concentration range of 0.1–0.5 μg/mL, with a limit of detection (0.0391 and 0.0400 μg/mL) and limit of quantitation (0.1035 and 0.1332 μg/mL), respectively, for ARP and CLZ. The suggested approach was successful in analyzing commercialized tablets. A statistical investigation of the results produced by the suggested and standard methods showed no remarkable variation in the precision and accuracy of the two approaches. A chemical mechanism using o-phthalaldehyde was proposed.
Bactericidal Activity of Carvacrol against Streptococcus pyogenes Involves Alteration of Membrane Fluidity and Integrity through Interaction with Membrane Phospholipids
Authors: Wijesundara Niluni M. , Lee Song F. , Cheng Zhenyu , Davidson Ross , Langelaan David N. , Rupasinghe H. P. Vasantha
Published: September 2022

Background: Carvacrol, a mono-terpenoid phenol found in herbs, such as oregano and thyme, has excellent antibacterial properties against Streptococcus pyogenes. However, its mechanism of bactericidal activity on S. pyogenes has not been elucidated. Objectives: This study investigated the bactericidal mechanism of carvacrol using three strains of S. pyogenes. Methods: Flow cytometry (FCM) experiments were conducted to determine carvacrol’s membrane permeabilization and cytoplasmic membrane depolarization activities. Protoplasts of S. pyogenes were used to investigate carvacrol’s effects on the membrane, followed by gel electrophoresis. The carvacrol-treated protoplasts were examined by transmission electron microscopy (TEM) to observe ultrastructural morphological changes. The fluidity of the cell membrane was measured by steady-state fluorescence anisotropy. Thin-layer chromatographic (TLC) profiling was conducted to study the affinity of carvacrol for membrane phospholipids. Results: Increased membrane permeability and decreased membrane potential from FCM and electron microscopy observations revealed that carvacrol killed the bacteria primarily by disrupting membrane integrity, leading to whole-cell lysis. Ultra-structural morphological changes in the membrane induced by carvacrol over a short period were confirmed using the S. pyogenes protoplast and membrane isolate models in vitro. In addition, changes in the other biophysical properties of the bacterial membrane, including concentration- and time-dependent increased fluidity, were observed. TLC experiments showed that carvacrol preferentially interacts with membrane phosphatidylglycerol (P.G.), phosphatidylethanolamine (P.E.), and cardiolipins (CL). Conclusions: Carvacrol exhibited rapid bactericidal action against S. pyogenes by disrupting the bacterial membrane and increasing permeability, possibly due to affinity with specific membrane phospholipids, such as P.E., P.G., and CL. Therefore, the bactericidal concentration of carvacrol (250 µg/mL) could be used to develop safe and efficacious natural health products for managing streptococcal pharyngitis or therapeutic applications.
The Fabrication of Docetaxel-Containing Emulsion for Drug Release Kinetics and Lipid Peroxidation
Authors: Wu Yifang , Wang Mengmeng , Li Yufan , Xia Hongmei , Cheng Yongfeng , Liu Chang , Xia Ying , Wang Yu , Yue Yan , Cheng Xiaoman , Xie Zili
Published: September 2022

Docetaxel (DTX)-based formulation development is still confronted with significant challenges, due to its refractory solubility and side effects on normal tissues. Inspired by the application of the transdermal drug delivery model to topical treatment, we developed a biocompatible and slow-release DTX-containing emulsion via self-assembly prepared by a high-speed electric stirring method and optimized the formulation. The results of accelerated the emulsion stability experiment showed that the emulsion prepared at 10,000 rpm/min had a stability of 89.15 ± 2.05%. The ADME, skin irritation, skin toxicity and molecular interaction between DTX and excipients were predicted via Discovery Studio 2016 software. In addition, DTX addition in oil or water phases of the emulsion showed different release rates in vitro and ex vivo. The DTX release ex vivo of the DTX/O-containing emulsion and the DTX/W-containing emulsion were 45.07 ± 5.41% and 96.48 ± 4.54%, respectively. In vitro antioxidant assays and anti-lipid peroxidation models revealed the antioxidant potential of DTX. However, DTX-containing emulsions could maintain and even enhance the antioxidant effect, both scavenging free radicals in vitro and inhibiting the process of lipid peroxidation.
In Vitro Studies of Graphene for Management of Dental Caries and Periodontal Disease: A Concise Review
Authors: Nizami Mohammed Zahedul Islam , Yin Iris Xiaoxue , Lung Christie Ying Kei , Niu John Yun , Mei May Lei , Chu Chun Hung
Published: September 2022

Graphene is a single-layer two-dimensional carbon-based nanomaterial. It presents as a thin and strong material that has attracted many researchers’ attention. This study provides a concise review of the potential application of graphene materials in caries and periodontal disease management. Pristine or functionalized graphene and its derivatives exhibit favorable physicochemical, mechanical, and morphological properties applicable to biomedical applications. They can be activated and functionalized with metal and metal nanoparticles, polymers, and other small molecules to exhibit multi-differentiation activities, antimicrobial activities, and biocompatibility. They were investigated in preventive dentistry and regenerative dentistry. Graphene materials such as graphene oxide inhibit cariogenic microbes such as Streptococcus mutans. They also inhibit periodontal pathogens that are responsible for periodontitis and root canal infection. Graphene-fluorine promotes enamel and dentin mineralization. These materials were also broadly studied in regenerative dental research, such as dental hard and soft tissue regeneration, as well as periodontal tissue and bone regeneration. Graphene oxide-based materials, such as graphene oxide-fibroin, were reported as promising in tissue engineering for their biocompatibility, bioactivity, and ability to enhance cell proliferation properties in periodontal ligament stem cells. Laboratory research showed that graphene can be used exclusively or by incorporating it into existing dental materials. The success of laboratory studies can translate the application of graphene into clinical use.
Development and Evaluation of a Novel Diammonium Glycyrrhizinate Phytosome for Nasal Vaccination
Authors: Chen Xiaojin , Fan Xudong , Li Fanzhu
Published: September 2022

The objective of the present research was to formulate diammonium glycyrrhizinate (DG) into phytosomes (DG-P) to induce nasal immune responses and enhance absorption. Plackett- Burman design was used for process optimization, incorporating specific formulation and process variables to obtain the optimal parameters. Fourier transform infrared spectroscopy (FTIR), X-ray power diffraction (P-XRD), and transmission electron microscopy (TEM) were used for characterization. The adjuvant activity of the DG-P was evaluated by using bone marrow dendritic cells. In vitro nasal mucosal permeation and in situ nasal perfusion were also investigated to evaluate nasal absorption. The DG phytosomes were in the size range of 20~30 nm and zeta-potential range of −30~−40 mV. DG-P demonstrated 4.2-fold increased solubility in n-octanol. Coculturing bone marrow dendritic cells with DG-P led to enhanced dendritic cell maturation. Apparent permeability coefficient of the phytosomal formulation was almost four times higher than that of free DG determined by ex vivo permeation studies on excised porcine mucosa. In situ nasal perfusion studies in rats demonstrated that the nasal absorption of DG-P was significantly higher than that of free DG. Conclusively, the results confirmed that DG-P have potential for use as an adjuvant for nasal vaccine.
Mechanical Activation by Ball Milling as a Strategy to Prepare Highly Soluble Pharmaceutical Formulations in the Form of Co-Amorphous, Co-Crystals, or Polymorphs
Authors: Martínez Luz María , Cruz-Angeles Jorge , Vázquez-Dávila Mónica , Martínez Eduardo , Cabada Paulina , Navarrete-Bernal Columba , Cortez Flor
Published: September 2022

Almost half of orally administered active pharmaceutical ingredients (APIs) have low solubility, which affects their bioavailability. In the last two decades, several alternatives have been proposed to modify the crystalline structure of APIs to improve their solubility; these strategies consist of inducing supramolecular structural changes in the active pharmaceutical ingredients, such as the amorphization and preparation of co-crystals or polymorphs. Since many APIs are thermosensitive, non-thermal emerging alternative techniques, such as mechanical activation by milling, have become increasingly common as a preparation method for drug formulations. This review summarizes the recent research in preparing pharmaceutical formulations (co-amorphous, co-crystals, and polymorphs) through ball milling to enhance the physicochemical properties of active pharmaceutical ingredients. This report includes detailed experimental milling conditions (instrumentation, temperature, time, solvent, etc.), as well as solubility, bioavailability, structural, and thermal stability data. The results and description of characterization techniques to determine the structural modifications resulting from transforming a pure crystalline API into a co-crystal, polymorph, or co-amorphous system are presented. Additionally, the characterization methodologies and results of intermolecular interactions induced by mechanical activation are discussed to explain the properties of the pharmaceutical formulations obtained after the ball milling process.
Development and Evaluation of Novel Leflunomide SPION Bioemulsomes for the Intra-Articular Treatment of Arthritis
Authors: Abbas Haidy , Gad Heba A. , El Sayed Nesrine S , Rashed Laila Ahmed , Khattab Mohamed A. , Noor Ahmad O. , Zewail Mariam
Published: September 2022

Systemic treatments for rheumatoid arthritis are associated with many side effects. This study aimed to minimize the side effects associated with the systemic administration of leflunomide (LEF) by formulating LEF-loaded emulsomes (EMLs) for intra-articular administration. Additionally, EMLs were loaded with supramagnetic nanoparticles (SPIONs) to enhance joint localization, where a magnet was placed on the joint area after intra-articular administration. Full in vitro characterization, including colloidal characteristics, entrapment efficiency, and in vitro release were conducted besides the in vivo evaluation in rats with adjuvant-induced arthritis. In vivo study included joint diameter measurement, X-ray radiographic analysis, RT-PCR analysis, Western blotting, ELISA for inflammatory markers, and histopathological examination of dissected joints. The particle size and entrapment efficiency of the selected LEF SPION EMLs were 198.2 nm and 83.7%, respectively. The EMLs exhibited sustained release for 24 h. Moreover, in vivo evaluation revealed LEF SPION EMLs to be superior to the LEF suspension, likely due to the increase in LEF solubility by nanoencapsulation that improved the pharmacological effects and the use of SPION that ensured the localization of EMLs in the intra-articular cavity upon administration.
Interface Edge Mode Confinement in Dielectric-Based Quasi-Periodic Photonic Crystal Structure
Authors: Goyal Amit Kumar , Massoud Yehia
Published: September 2022

In this paper, the localization of optical interface edge-states is analyzed for a dielectric material-based quasi-periodic photonic crystal (QPhC) structure. The design comprises a bilayer PhC structure, where layers are arranged in a Fibonacci configuration to introduce quasi-periodicity. The impact of local symmetric sub-structures on Eigenstate coupling is considered over a wider wavelength range. This confirms the localization of interface edge modes for different wavelengths at the structural local resonators, where the number of local resonators depends on the length of the QPhC. The proposed seven-element QPhC structure shows a strong Tamm-like top interface edge mode localization for a 45.04° incident angle at 750 nm operating wavelength, whereas a bulk interface guided mode is also excited for a higher incident angle of around 79°. The investigation facilitates the development of reconfigurable devices to excite both bulk interface and surface interface edge modes with improved field intensities for spectroscopy and sensing applications.