bluuebunny/crossref_metadata_2025 huggingface dataset:
Femtosecond Autocorrelation of Localized Surface Plasmons
Authors: Yi Ruizhi , Wu Wenwen , Zhang Xinping
Published: April 2023

Plasmon electronic dephasing lifetime is one of the most important characteristics of localized surface plasmons, which is crucial both for understanding the related photophysics and for their applications in photonic and optoelectronic devices. This lifetime is generally shorter than 100 fs and measured using the femtosecond pump–probe technique, which requires femtosecond laser amplifiers delivering pulses with a duration even as short as 10 fs. This implies a large-scale laser system with complicated pulse compression schemes, introducing high-cost and technological challenges. Meanwhile, the strong optical pulse from an amplifier induces more thermal-related effects, disturbing the precise resolution of the pure electronic dephasing lifetime. In this work, we use a simple autocorrelator design and integrate it with the sample of plasmonic nanostructures, where a femtosecond laser oscillator supplies the incident pulses for autocorrelation measurements. Thus, the measured autocorrelation trace carries the optical modulation on the incident pulses. The dephasing lifetime can be thus determined by a comparison between the theoretical fittings to the autocorrelation traces with and without the plasmonic modulation. The measured timescale for the autocorrelation modulation is an indirect determination of the plasmonic dephasing lifetime. This supplies a simple, rapid, and low-cost method for quantitative characterization of the ultrafast optical response of localized surface plasmons.
Coexistent VO2 (M) and VO2 (B) Polymorphous Thin Films with Multiphase-Driven Insulator–Metal Transition
Authors: Qiu Mengxia , Yang Wanli , Xu Peiran , Huang Tiantian , Chen Xin , Dai Ning
Published: April 2023

Reversible insulator–metal transition (IMT) and structure phase change in vanadium dioxide (VO2) remain vital and challenging with complex polymorphs. It is always essential to understand the polymorphs that coexist in desired VO2 materials and their IMT behaviors. Different electrical properties and lattice alignments in VO2 (M) and VO2 (B) phases have enabled the creation of versatile functional devices. Here, we present polymorphous VO2 thin films with coexistent VO2 (M) and VO2 (B) phases and phase-dependent IMT behaviors. The presence of VO2 (B) phases may induce lattice distortions in VO2 (M). The plane spacing of (011)M in the VO2 (M) phase becomes widened, and the V-V and V-O vibrations shift when more VO2 (B) phase exists in the VO2 (M) matrix. Significantly, the coexisting VO2 (B) phases promote the IMT temperature of the polymorphous VO2 thin films. We expect that such coexistent polymorphs and IMT variations would help us to understand the microstructures and IMT in the desired VO2 materials and contribute to advanced electronic transistors and optoelectronic devices.
Correction: Vičič et al. Assessment of Vitamin D Status in Slovenian Premenopausal and Postmenopausal Women, Using Total, Free, and Bioavailable 25-Hydroxyvitamin D (25(OH)D). Nutrients 2022, 14, 5349
Authors: Vičič Vid , Kukec Andreja , Kugler Saša , Geršak Ksenija , Osredkar Joško , Pandel Mikuš Ruža
Published: April 2023

In the original publication [...]
Plum-Derived Exosome-like Nanovesicles Induce Differentiation of Osteoblasts and Reduction of Osteoclast Activation
Authors: Park Yu-Seong , Kim Hyun-Woo , Hwang Jin-Hyeon , Eom Jung-Young , Kim Dong-Ha , Park Jinho , Tae Hyun-Jin , Lee Seunghoon , Yoo Jae-Gyu , Kim Jee-In , Lim Jae-Hwan , Kwun In-Sook , Baek Moon-Chang , Cho Young-Eun , Kim Do-Kyun
Published: April 2023

Osteoblasts and osteoclasts play crucial roles in bone formation and bone resorption. We found that plum-derived exosome-like nanovesicles (PENVs) suppressed osteoclast activation and modulated osteoblast differentiation. PENVs increased the proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells and osteoblasts from mouse bone marrow cultures. Notably, PENVs elevated the expression of osteoblastic transcription factors and osteoblast differentiation marker proteins in MC3T3-E1 cells. Higher levels of phosphorylated BMP-2, p38, JNK, and smad1 proteins were detected in PENV-treated MC3T3-E1 cells. Additionally, the number of TRAP-positive cells was significantly decreased in PENV-treated osteoclasts isolated from osteoblasts from mouse bone marrow cultures. Importantly, osteoclastogenesis of marker proteins such as PPAR-gamma, NFATc1, and c-Fos were suppressed by treatment with PENVs (50 μg/mL). Taken together, these results demonstrate that PENVs can be used as therapeutic targets for treating bone-related diseases by improving osteoblast differentiation and inhibiting osteoclast activation for the first time.
Toward an Integrated Consideration of 24 h Movement Guidelines and Nutritional Recommendations
Authors: Fournier Elora , Łuszczki Edyta , Isacco Laurie , Chanséaume-Bussiere Emilie , Gryson Céline , Chambrier Claire , Drapeau Vicky , Chaput Jean-Philippe , Thivel David
Published: April 2023

While physical activity, sleep and sedentary behaviors are almost always considered independently, they should be considered as integrated human behaviors. The 24 h Movement approach proposes a concomitant consideration of these behaviors to promote overall health. Not only do these behaviors impact energy expenditure, but they have also been shown to separately impact energy intake, which should be further explored when considering the entire integration of these movement behaviors under the 24 h movement approach. After an evaluation of the prevalence of meeting the 24 h Movement and dietary recommendations, this review summarizes the available evidence (using English publications indexed in PubMed/MEDLINE) regarding the association between the 24 h Movement Guidelines and eating habits. Altogether, the results clearly show the beneficial impact of promoting the 24 h guidelines simultaneously, highlighting that the higher the number of respected movement recommendations, the better eating behaviors in both children and adults. Importantly, our results point out the importance of emphasizing the need to reach sedentary guidelines for better eating habits. Movement and dietary behaviors appear closely related, and giving recommendations on one might impact the other. Combining the 24 h Movement with dietary Guidelines might be more efficient than promoting them separately in public health strategies.
The Role of Vitamin D in Obese Children with Non-Alcoholic Fatty Liver Disease and Associated Metabolic Syndrome
Authors: Stepan Mioara Desdemona , Vintilescu Ștefănița Bianca , Streață Ioana , Podeanu Mihaela Andreea , Florescu Dan Nicolae
Published: April 2023

Non-alcoholic fatty liver disease (NAFLD) represents a complex chronic condition, which in the absence of screening–monitoring markers and effective standardized treatment is one of the most important issues in pediatric pathology. In this study, we analyzed the role of vitamin D supplementation in obese children with/without NAFLD and the impact on the components of the associated metabolic syndrome (MS). The study included 22 children with simple obesity (SO) and 50 with NAFLD, aged between 6 and 14 years, who received regimen-based therapy or vitamin D supplementation in case of deficiency. Anthropometric and paraclinical data associated with MS were statistically compared before and after treatment. It was observed that there was a statistical association of NAFLD with MS components, which were present both in SO and in the 6–9 years group. Vitamin D deficiency was associated with the presence of obesity, NAFLD and MS components, and correction of the deficiency induced a tendency to normalize the associated parameters. In the case of a treatment strictly based on the regimen, we found decreases in vitamin D values and additional alteration of some parameters. Supplementation with vitamin D potentiates the effects of the specific regimen, and the effects seem to be dependent on the MS components.
Resveratrol Alleviates Diabetic Periodontitis-Induced Alveolar Osteocyte Ferroptosis Possibly via Regulation of SLC7A11/GPX4
Authors: Li Yue , Huang Zhijun , Pan Shuaifei , Feng Yuhui , He Haokun , Cheng Shuguang , Wang Lijing , Wang Liping , Pathak Janak Lal
Published: April 2023

The mode and mechanism of diabetic periodontitis-induced alveolar-osteocyte death are still unclear. This study aimed to investigate the occurrence of ferroptosis in alveolar osteocytes during diabetic periodontitis and the therapeutic potential of resveratrol to alleviate osteocyte ferroptosis. Diabetic periodontitis was induced in C57/BL6-male mice and treated with or without resveratrol. Periodontitis pathogenicity was analyzed by micro-CT and histology, and alveolar-osteocyte ferroptosis was analyzed by immunohistochemistry. MLOY4 osteocytes were treated with P. gingivalis-derived lipopolysaccharide (LPS)+advanced glycosylated end products (AGEs) mimicking diabetic periodontitis condition in vitro, with or without resveratrol or ferrostatin-1 (ferroptosis inhibitor). Osteocyte ferroptosis and expression of inflammatory mediators were analyzed. Diabetic periodontitis aggravated periodontitis pathogenicity and inhibited the expression of GPX4 and SLC7A11 in alveolar osteocytes and resveratrol alleviated these effects. LPS+AGEs triggered osteocyte ferroptosis in vitro as indicated by the downregulated GPX4 and SLC7A11, upregulated malondialdehyde, disrupted mitochondrial morphology, and overexpressed pro-inflammatory mediators IL-1β, TNF-α, SOST, RANKL, and IL-6, and ferrostatin-1 or resveratrol treatment reversed these effects. LPS+AGEs upregulated pIKBα and pNF-κB p65 expression in osteocytes, and resveratrol or ferrostatin-1 reversed this effect. In conclusion, diabetic periodontitis triggers alveolar osteocyte ferroptosis possibly via disruption of the SLC7A11/GPX4 axis, and resveratrol has therapeutic potential to correct this biological event.
The Effects of Creatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy: A Systematic Review with Meta-Analysis
Authors: Burke Ryan , Piñero Alec , Coleman Max , Mohan Adam , Sapuppo Max , Augustin Francesca , Aragon Alan A. , Candow Darren G. , Forbes Scott C. , Swinton Paul , Schoenfeld Brad J.
Published: April 2023

The purpose of this paper was to carry out a systematic review with a meta-analysis of randomized controlled trials that examined the combined effects of resistance training (RT) and creatine supplementation on regional changes in muscle mass, with direct imaging measures of hypertrophy. Moreover, we performed regression analyses to determine the potential influence of covariates. We included trials that had a duration of at least 6 weeks and examined the combined effects of creatine supplementation and RT on site-specific direct measures of hypertrophy (magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound) in healthy adults. A total of 44 outcomes were analyzed across 10 studies that met the inclusion criteria. A univariate analysis of all the standardized outcomes showed a pooled mean estimate of 0.11 (95% Credible Interval (CrI): −0.02 to 0.25), providing evidence for a very small effect favoring creatine supplementation when combined with RT compared to RT and a placebo. Multivariate analyses found similar small benefits for the combination of creatine supplementation and RT on changes in the upper and lower body muscle thickness (0.10–0.16 cm). Analyses of the moderating effects indicated a small superior benefit for creatine supplementation in younger compared to older adults (0.17 (95%CrI: −0.09 to 0.45)). In conclusion, the results suggest that creatine supplementation combined with RT promotes a small increase in the direct measures of skeletal muscle hypertrophy in both the upper and lower body.
Dietary Diversity and Inflammatory Diet Associated with All-Cause Mortality and Incidence and Mortality of Type 2 Diabetes: Two Prospective Cohort Studies
Authors: Zheng Guzhengyue , Cai Miao , Liu Huiling , Li Rui , Qian Zhengmin , Howard Steven W. , Keith Amy E. , Zhang Shiyu , Wang Xiaojie , Zhang Junguo , Lin Hualiang , Hua Junjie
Published: April 2023

A higher dietary diversity score (DDS) and a lower energy-adjusted dietary inflammatory index (E-DII) may be associated with lower risks of type 2 diabetes (T2D) and mortality. This cohort study aimed to investigate the associations of DDS and E-DII with all-cause mortality, incidence of T2D, and mortality of T2D, as well as the joint effects of these two dietary factors. A total of 181,360 participants without all types of diabetes at baseline from the UK Biobank and 42,139 participants from the US NHANES were included. Cox proportional hazards models were used to assess the associations of DDS and E-DII with outcomes. In the UK Biobank data, 8338 deaths, 3416 incident T2D cases, and 353 T2D deaths occurred during a median follow-up of 12.5 years. In the US NHANES data, 6803 all-cause deaths and 248 T2D-specific deaths were recorded during a median follow-up of 9.6 years. We observed that higher DDS and lower E-DII were significantly associated with lower risks of total mortality and incident T2D. Compared with low DDS, the hazard ratios (HRs) and 95% confidence intervals (CIs) of high DDS were 0.69 (0.64, 0.74) for all-cause mortality, 0.79 (0.70, 0.88) for incident T2D in the UK Biobank, and 0.69 (0.61, 0.78) for all-cause mortality in the US NHANES. Compared with participants in tertile 3 of E-DII, those in tertile 1 had a lower risk of overall death [HR 0.86 (95% CI: 0.81, 0.91) in UK Biobank; 0.83 (0.77, 0.88) in US NHANES] and incident T2D [0.86 (0.79, 0.94)] in UK Biobank. No evidence was observed of the interactive effects of DDS and E-DII on either all-cause mortality or the incidence and mortality of T2D. There was no significant association found between any exposure and T2D mortality in this study. In conclusion, our results revealed that higher DDS and lower E-DII were associated with both total mortality and incident T2D in UK and US adults.
Maternal High-Fructose Corn Syrup Intake Impairs Corticosterone Clearance by Reducing Renal 11β-Hsd2 Activity via miR-27a-Mediated Mechanism in Rat Offspring
Authors: Nouchi Yuki , Munetsuna Eiji , Yamada Hiroya , Yamazaki Mirai , Ando Yoshitaka , Mizuno Genki , Ikeya Miyuki , Kageyama Itsuki , Wakasugi Takuya , Teshigawara Atsushi , Hattori Yuji , Tsuboi Yoshiki , Ishikawa Hiroaki , Suzuki Koji , Ohashi Koji
Published: April 2023

We previously reported that maternal fructose consumption increases blood corticosterone levels in rat offspring. However, the underlying mechanism of action remains unclear. In the present study, we aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring (GC; corticosterone in rodents and cortisol in humans). Female Sprague Dawley rats received HFCS solution during gestation and lactation. The male offspring were fed distilled water from weaning to 60 days of age. We investigated the activities of GC-metabolizing enzymes (11β-Hsd1 and 11β-Hsd2) in various tissues (i.e., liver, kidney, adrenal glands, muscle, and white adipose tissue) and epigenetic modification. 11β-Hsd2 activity decreased in the kidney of the HFCS-fed dams. Moreover, the epigenetic analysis suggested that miR-27a reduced Hsd11b2 mRNA expression in the kidney of offspring. Maternal HFCS-induced elevation of circulating GC levels in offspring may be explained by a decrease in 11β-Hsd2 activity via renal miR-27a expression. The present study may allow us to determine one of the mechanisms of GC elevation in rat offspring that is often observed in the developmental origins of the health and disease (DOHaD) phenomenon.
Lactobacillus paracasei subsp. paracasei X12 Strain Induces Apoptosis in HT-29 Cells through Activation of the Mitochondrial Pathway
Authors: Wang Shumei , Shan Yi , Zhang Shuang , Zhang Lanwei , Jiao Yuehua , Xue Dijia , Zhang Lili , Yi Huaxi
Published: April 2023

L. paracasei subsp. paracasei X12 was obtained from traditional cheese produced in northwestern China. In this study, we showed that whole peptidoglycan (WPG), extracted from L. paracasei subsp. paracasei X12, inhibited proliferation and induced apoptosis in HT-29 cells in a dose-dependent manner. In addition, WPG-induced apoptosis was associated with the loss of mitochondrial membrane potential (Ψm), the release of cytochrome c (Cyto-C) from mitochondrialto cytosolic spaces, activation of Caspase 3, and accumulation of intracellular reactive oxygen species (ROS). Finally, semi-quantitative RT-PCR showed that these events were accompanied by upregulation of proapoptotic genes (Bax or Bad) and downregulation of antiapoptotic genes (Bcl-xl). Taken together, our results demonstrated that WPG induced apoptosis in HT-29 cells through activation of the mitochondrial pathway. WPG exerted only minor toxicity upon noncancerous cells and therefore might be used as a natural agent in the treatment of cancer in future.
Advanced Raman Spectroscopy Based on Transfer Learning by Using a Convolutional Neural Network for Personalized Colorectal Cancer Diagnosis
Authors: Kalatzis Dimitris , Spyratou Ellas , Karnachoriti Maria , Kouri Maria Anthi , Orfanoudakis Spyros , Koufopoulos Nektarios , Pouliakis Abraham , Danias Nikolaos , Seimenis Ioannis , Kontos Athanassios G. , Efstathopoulos Efstathios P.
Published: April 2023

Advanced Raman spectroscopy (RS) systems have gained new interest in the field of medicine as an emerging tool for in vivo tissue discrimination. The coupling of RS with artificial intelligence (AI) algorithms has given a boost to RS to analyze spectral data in real time with high specificity and sensitivity. However, limitations are still encountered due to the large amount of clinical data which are required for the pre-training process of AI algorithms. In this study, human healthy and cancerous colon specimens were surgically resected from different sites of the ascending colon and analyzed by RS. Two transfer learning models, the one-dimensional convolutional neural network (1D-CNN) and the 1D–ResNet transfer learning (1D-ResNet) network, were developed and evaluated using a Raman open database for the pre-training process which consisted of spectra of pathogen bacteria. According to the results, both models achieved high accuracy of 88% for healthy/cancerous tissue discrimination by overcoming the limitation of the collection of a large number of spectra for the pre-training process. This gives a boost to RS as an adjuvant tool for real-time biopsy and surgery guidance.
Investigation on the Biological Safety and Activity of a Gluconolactone-Based Lotion for Dermocosmetic Application
Authors: Zerbinati Nicola , Di Francesco Serena , Capillo Maria Chiara , Maccario Cristina , Stabile Giorgio , Galadari Hassan , Rauso Raffaele , Sommatis Sabrina , Mocchi Roberto
Published: April 2023

(1) Background: Cosmeceuticals are formulas enriched with active ingredients that exert efficacy on different skin molecular targets. (2) Methods: Cell viability and the absence of potential irritant risk were evaluated on keratinocytes (HaCaT), fibroblasts (NHDF), adipocytes (3T3-L1), sebocytes (PCi-SEB_CAU) and reconstructed human epidermis (RHE), respectively. Several treatments were performed to evaluate the ability of the lotion to stimulate the production of collagen and elastin, stimulate the differentiation of keratinocytes and reduce the number of senescent cells following UVB stimulation. In addition, the modulation of genes involved in the production, storage and accumulation of sebum were investigated. (3) Results: The results obtained demonstrated the biosafety of the formula in all cell lines tested. The 24-h treatment with non-cytotoxic concentrations determined an increase in the expression of the collagen (COL1A1), elastin (ELN) and involucrin (IVL) genes, while a reduction of peroxisome proliferator-activated receptor-gamma (PPARγ) gene expression and a reduction of SA-βgal-positive cells were found. Moreover, the treatment did not interfere with normal steroid 5-alpha reductase (5RDA3) gene expression levels. (4) Conclusions: Data collected demonstrated the biosafety of the lotion, the non-comedogenic property and a multi targets anti-aging effect. In particular, data collected on the booster lotion make it a valid way to counteract the pore dilatation aging related.
Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds
Authors: Keller Josephine Geertsen , Petersen Kamilla Vandsø , Mizielinski Karol , Thiesen Celine , Bjergbæk Lotte , Reguera Rosa M. , Pérez-Pertejo Yolanda , Balaña-Fouce Rafael , Trejo Angela , Masdeu Carme , Alonso Concepcion , Knudsen Birgitta R. , Tesauro Cinzia
Published: April 2023

With the increasing need for effective compounds against cancer or pathogen-borne diseases, the development of new tools to investigate the enzymatic activity of biomarkers is necessary. Among these biomarkers are DNA topoisomerases, which are key enzymes that modify DNA and regulate DNA topology during cellular processes. Over the years, libraries of natural and synthetic small-molecule compounds have been extensively investigated as potential anti-cancer, anti-bacterial, or anti-parasitic drugs targeting topoisomerases. However, the current tools for measuring the potential inhibition of topoisomerase activity are time consuming and not easily adaptable outside specialized laboratories. Here, we present rolling circle amplification-based methods that provide fast and easy readouts for screening of compounds against type 1 topoisomerases. Specific assays for the investigation of the potential inhibition of eukaryotic, viral, or bacterial type 1 topoisomerase activity were developed, using human topoisomerase 1, Leishmania donovani topoisomerase 1, monkeypox virus topoisomerase 1, and Mycobacterium smegmatis topoisomerase 1 as model enzymes. The presented tools proved to be sensitive and directly quantitative, paving the way for new diagnostic and drug screening protocols in research and clinical settings.
In Vitro and In Vivo Effects of Ulvan Polysaccharides from Ulva rigida
Authors: García-Márquez Jorge , Moreira Bruna Rodrigues , Valverde-Guillén Piedad , Latorre-Redoli Sofía , Caneda-Santiago Candela T. , Acién Gabriel , Martínez-Manzanares Eduardo , Marí-Beffa Manuel , Abdala-Díaz Roberto T.
Published: April 2023

One of the main bioactive compounds of interest from the Ulva species is the sulfated polysaccharide ulvan, which has recently attracted attention for its anticancer properties. This study investigated the cytotoxic activity of ulvan polysaccharides obtained from Ulva rigida in the following scenarios: (i) in vitro against healthy and carcinogenic cell lines (1064sk (human fibroblasts), HACAT (immortalized human keratinocytes), U-937 (a human leukemia cell line), G-361 (a human malignant melanoma), and HCT-116 (a colon cancer cell line)) and (ii) in vivo against zebrafish embryos. Ulvan exhibited cytotoxic effects on the three human cancer cell lines tested. However, only HCT-116 demonstrated sufficient sensitivity to this ulvan to make it relevant as a potential anticancer treatment, presenting an LC50 of 0.1 mg mL−1. The in vivo assay on the zebrafish embryos showed a linear relationship between the polysaccharide concentration and growth retardation at 7.8 hpf mL mg−1, with an LC50 of about 5.2 mg mL−1 at 48 hpf. At concentrations near the LC50, toxic effects, such as pericardial edema or chorion lysis, could be found in the experimental larvae. Our in vitro study supports the potential use of polysaccharides extracted from U. rigida as candidates for treating human colon cancer. However, the in vivo assay on zebrafish indicated that the potential use of ulvan as a promising, safe compound should be limited to specific concentrations below 0.001 mg mL−1 since it revealed side effects on the embryonic growth rate and osmolar balance.
In Silico-Motivated Discovery of Novel Potent Glycogen Synthase-3 Inhibitors: 1-(Alkyl/arylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione Identified as a Scaffold for Kinase Inhibitor Development
Authors: Emmerich Thomas D. , Hayes Joseph M.
Published: April 2023

Glycogen synthase kinase-3 (GSK-3) isoforms α and β have diverse roles within cell biology, and have been linked with multiple diseases that include prominent CNS conditions such as Alzheimer’s disease and several psychiatric disorders. In this study, motivated by computation, we aimed to identify novel ATP-binding site inhibitors of GSK-3 with CNS-active potential. A ligand screening (docking) protocol against GSK-3β was first optimized, employing an active/decoy benchmarking set, with the final protocol selected based on statistical performance analysis. The optimized protocol involved pre-filtering of ligands using a three-point 3D-pharmacophore, followed by Glide-SP docking applying hinge region hydrogen bonding constraints. Using this approach, the Biogenic subset of the ZINC15 compound database was screened, focused on compounds with potential for CNS-activity. Twelve compounds (generation I) were selected for experimental validation using in vitro GSK-3β binding assays. Two hit compounds, 1 and 2, with 6-amino-7H-benzo[e]perimidin-7-one and 1-(phenylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione type scaffolds were identified with IC50 values of 1.63 µM and 20.55 µM, respectively. Ten analogues of 2 (generation II) were selected for structure activity relationship (SAR) analysis and revealed four low micromolar inhibitors (<10 µM), with 19 (IC50 = 4.1 µM)~five times more potent than initial hit compound 2. Selectivity screening of low micromolar inhibitors 14 and 19 (comparing aryl- and alkyl-substituents) against 10 homologous kinases revealed unique selectivity profiles, with both compounds more potent against the GSK-3α isoform (IC50s~2 µM) and, additionally, inhibitors of PKBβ (IC50s < 25 µM). Compound 14 also inhibited ERK2 and 19, PKCγ, but generally good selectivity for GSK-3 isoforms over the other kinases was observed. The compounds had excellent predicted oral bioavailability and CNS-activity profiles, presenting promising candidates for future testing in cellular models of disease.
Natural Products for the Prevention and Treatment of Common Cold and Viral Respiratory Infections
Authors: Mammari Nour , Albert Quentin , Devocelle Marc , Kenda Maša , Kočevar Glavač Nina , Sollner Dolenc Marija , Mercolini Laura , Tóth Jaroslav , Milan Nagy , Czigle Szilvia , Varbanov Mihayl ,   on behalf of the OEMONOM
Published: April 2023

The common cold is generally considered a usually harmless infectious disease of the upper respiratory pathway, with mostly mild symptoms. However, it should not be overlooked, as a severe cold can lead to serious complications, resulting in hospitalization or death in vulnerable patients. The treatment of the common cold remains purely symptomatic. Analgesics as well as oral antihistamines or decongestants may be advised to relieve fever, and local treatments can clear the airways and relieve nasal congestion, rhinorrhea, or sneezing. Certain medicinal plant specialties can be used as therapy or as complementary self-treatment. Recent scientific advances discussed in more detail in this review have demonstrated the plant’s efficiency in the treatment of the common cold. This review presents an overview of plants used worldwide in the treatment of cold diseases.
GRK2 Mediates Macrophage Polarization by Regulating EP4-cAMP-pCREB Signaling in Ulcerative Colitis and the Therapeutic Effect of Paroxetine on Mice with DSS-Induced Colitis
Authors: Zhang Jiawei , Zhang Xianzheng , Lu Mingdian , Chang Yan , Wang Qingtong , Tu Jiajie , Wu Huaxun , Wang Chun , Hong Zhongyang , Xiong Maoming , Song Lihua , Wei Wei
Published: April 2023

G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and reduces the level of cyclic adenosine monophosphate (cAMP) to regulate macrophage polarization. However, the role of GRK2 in the pathophysiology of ulcerative colitis (UC) remains unclear. In this study, we investigated the role of GRK2 in macrophage polarization in UC, using biopsies from patients, a GRK2 heterozygous mouse model with dextran sulfate sodium (DSS)-induced colitis, and THP-1 cells. The results showed that a high level of prostaglandin E2 (PGE2) stimulated the receptor EP4 and enhanced the transmembrane activity of GRK2 in colonic lamina propria mononuclear cells (LPMCs), resulting in a down-regulation of membrane EP4 expression. Then, the suppression of cAMP–cyclic AMP responsive element-binding (CREB) signal inhibited M2 polarization in UC. Paroxetine is acknowledged as one of the selective serotonin reuptake inhibitors (SSRI), which is also considered as a potent GRK2 inhibitor with a high selectivity for GRK2. We found that paroxetine could alleviate symptoms of DSS-induced colitis in mice by regulating GPCR signaling to affect macrophage polarization. Taken together, the current results show that GRK2 may act as a novel therapeutic target in UC by regulating macrophage polarization, and paroxetine as a GRK2 inhibitor may have therapeutic effect on mice with DSS-induced colitis.
Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1
Authors: Morsy Mohamed A. , Abdel-Gaber Seham A. , Mokhemer Sahar A. , Kandeel Mahmoud , Sedik Wael F. , Nair Anroop B. , Venugopala Katharigatta N. , Khalil Hany Ezzat , Al-Dhubiab Bandar E. , Mohamed Mervat Z.
Published: April 2023

The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.
Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen
Authors: Nedeljković Nikola , Dobričić Vladimir , Bošković Jelena , Vesović Marina , Bradić Jovana , Anđić Marijana , Kočović Aleksandar , Jeremić Nevena , Novaković Jovana , Jakovljević Vladimir , Vujić Zorica , Nikolić Miloš
Published: April 2023

The aim of the study was a synthesis and investigation of the dose-dependent anti-inflammatory effect of new thiourea derivatives of naproxen with selected aromatic amines and esters of aromatic amino acids. The results of the in vivo study indicate that derivatives of m-anisidine (4) and N-methyl tryptophan methyl ester (7) showed the most potent anti-inflammatory activity four hours after injection of carrageenan, with the percentage of inhibition of 54.01% and 54.12%, respectively. In vitro assays of COX-2 inhibition demonstrated that none of the tested compounds achieved 50% inhibition at concentrations lower than 100 µM. On the other hand, the aromatic amine derivatives (1–5) accomplished significant inhibition of 5-LOX, and the lowest IC50 value was observed for compound 4 (0.30 μM). High anti-edematous activity of compound 4 in the rat paw edema model, together with potent inhibition of 5-LOX, highlight this compound as a promising anti-inflammatory agent.
Chemical Analysis and Molecular Modelling of Cyclodextrin-Formulated Propofol and Its Sodium Salt to Improve Drug Solubility, Stability and Pharmacokinetics (Cytogenotoxicity)
Authors: Wilhelms Benedikt , Broscheit Jens , Shityakov Sergey
Published: April 2023

Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.
Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase
Authors: Battisti Umberto Maria , Monjas Leticia , Akladios Fady , Matic Josipa , Andresen Eric , Nagel Carolin H. , Hagkvist Malin , Håversen Liliana , Kim Woonghee , Uhlen Mathias , Borén Jan , Mardinoğlu Adil , Grøtli Morten
Published: April 2023

The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure–activity analysis of urolithin C was carried out. More than 50 analogues were synthesized and tested regarding the chemical features responsible for the desired activity. These data could pave the way to the development of more potent and selective PKL allosteric inhibitors.
Comprehensive Insights into Medicinal Research on Imidazole-Based Supramolecular Complexes
Authors: Li Shu-Rui , Tan Yi-Min , Zhang Ling , Zhou Cheng-He
Published: April 2023

The electron-rich five-membered aromatic aza-heterocyclic imidazole, which contains two nitrogen atoms, is an important functional fragment widely present in a large number of biomolecules and medicinal drugs; its unique structure is beneficial to easily bind with various inorganic or organic ions and molecules through noncovalent interactions to form a variety of supramolecular complexes with broad medicinal potential, which is being paid an increasing amount of attention regarding more and more contributions to imidazole-based supramolecular complexes for possible medicinal application. This work gives systematical and comprehensive insights into medicinal research on imidazole-based supramolecular complexes, including anticancer, antibacterial, antifungal, antiparasitic, antidiabetic, antihypertensive, and anti-inflammatory aspects as well as ion receptors, imaging agents, and pathologic probes. The new trend of the foreseeable research in the near future toward imidazole-based supramolecular medicinal chemistry is also prospected. It is hoped that this work provides beneficial help for the rational design of imidazole-based drug molecules and supramolecular medicinal agents and more effective diagnostic agents and pathological probes.
Microneedles: An Emerging Vaccine Delivery Tool and a Prospective Solution to the Challenges of SARS-CoV-2 Mass Vaccination
Authors: Feng Ya-Xiu , Hu Huan , Wong Yu-Yuen , Yao Xi , He Ming-Liang
Published: April 2023

Vaccination is an effective measure to prevent infectious diseases. Protective immunity is induced when the immune system is exposed to a vaccine formulation with appropriate immunogenicity. However, traditional injection vaccination is always accompanied by fear and severe pain. As an emerging vaccine delivery tool, microneedles overcome the problems associated with routine needle vaccination, which can effectively deliver vaccines rich in antigen-presenting cells (APCs) to the epidermis and dermis painlessly, inducing a strong immune response. In addition, microneedles have the advantages of avoiding cold chain storage and have the flexibility of self-operation, which can solve the logistics and delivery obstacles of vaccines, covering the vaccination of the special population more easily and conveniently. Examples include people in rural areas with restricted vaccine storage facilities and medical professionals, elderly and disabled people with limited mobility, infants and young children afraid of pain. Currently, in the late stage of fighting against COVID-19, the main task is to increase the coverage of vaccines, especially for special populations. To address this challenge, microneedle-based vaccines have great potential to increase global vaccination rates and save many lives. This review describes the current progress of microneedles as a vaccine delivery system and its prospects in achieving mass vaccination against SARS-CoV-2.
Saponin Fraction CIL1 from Lysimachia ciliata L. Enhances the Effect of a Targeted Toxin on Cancer Cells
Authors: Koczurkiewicz-Adamczyk Paulina , Grabowska Karolina , Karnas Elżbieta , Piska Kamil , Wnuk Dawid , Klaś Katarzyna , Galanty Agnieszka , Wójcik-Pszczoła Katarzyna , Michalik Marta , Pękala Elżbieta , Fuchs Hendrik , Podolak Irma
Published: April 2023

Saponins are plant metabolites that possess multidirectional biological activities, among these is antitumor potential. The mechanisms of anticancer activity of saponins are very complex and depend on various factors, including the chemical structure of saponins and the type of cell they target. The ability of saponins to enhance the efficacy of various chemotherapeutics has opened new perspectives for using them in combined anticancer chemotherapy. Co-administration of saponins with targeted toxins makes it possible to reduce the dose of the toxin and thus limit the side effects of overall therapy by mediating endosomal escape. Our study indicates that the saponin fraction CIL1 of Lysimachia ciliata L. can improve the efficacy of the EGFR-targeted toxin dianthin (DE). We investigated the effect of cotreatment with CIL1 + DE on cell viability in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, on proliferation in a crystal violet assay (CV) and on pro-apoptotic activity using Annexin V/7 Actinomycin D (7-AAD) staining and luminescence detection of caspase levels. Cotreatment with CIL1 + DE enhanced the target cell-specific cytotoxicity, as well as the antiproliferative and proapoptotic properties. We found a 2200-fold increase in both the cytotoxic and antiproliferative efficacy of CIL1 + DE against HER14-targeted cells, while the effect on control NIH3T3 off-target cells was less profound (6.9- or 5.4-fold, respectively). Furthermore, we demonstrated that the CIL1 saponin fraction has a satisfactory in vitro safety profile with a lack of cytotoxic and mutagenic potential.
Capsules with Ileocolonic-Targeted Release of Vitamin B2, B3, and C (ColoVit) Intended for Optimization of Gut Health: Development and Validation of the Production Process
Authors: Ahmed Aisha A. , Otten Antonius T. , Gareb Bahez , Huijmans Judith E. , Eissens Anko C. , Rehman Ateequr , Dijkstra Gerard , Kosterink Jos G. W. , Frijlink Henderik W. , Schellekens Reinout C. A.
Published: April 2023

The ileocolonic-targeted delivery of vitamins can establish beneficial alterations in gut microbial composition. Here, we describe the development of capsules containing riboflavin, nicotinic acid, and ascorbic acid covered with a pH-sensitive coating (ColoVit) to establish site-specific release in the ileocolon. Ingredient properties (particle size distribution, morphology) relevant for formulation and product quality were determined. Capsule content and the in vitro release behaviour were determined using a HPLC-method. Uncoated and coated validation batches were produced. Release characteristics were evaluated using a gastro-intestinal simulation system. All capsules met the required specifications. The contents of the ingredients were in the 90.0–120.0% range, and uniformity requirements were met. In the dissolution test a lag-time in drug release of 277–283 min was found, which meets requirements for ileocolonic release. The release itself is immediate as shown by dissolution of the vitamins of more than 75% in 1 h. The production process of the ColoVit formulation was validated and reproducible, it was shown that the vitamin blend was stable during the production process and in the finished coated product. The ColoVit is intended as an innovative treatment approach for beneficial microbiome modulation and optimization of gut health.
A Novel Approach for the Treatment of Aerobic Vaginitis: Azithromycin Liposomes-in-Chitosan Hydrogel
Authors: Čačić Ana , Amidžić Klarić Daniela , Keser Sabina , Radiković Maja , Rukavina Zora , Jøraholmen May Wenche , Uzelac Lidija , Kralj Marijeta , Škalko-Basnet Nataša , Šegvić Klarić Maja , Vanić Željka
Published: April 2023

Biocompatible mucoadhesive formulations that enable a sustained drug delivery at the site of action, while exhibiting inherent antimicrobial activity, are of great importance for improved local therapy of vaginal infections. The aim of this research was to prepare and evaluate the potential of the several types of azithromycin (AZM)-liposomes (180–250 nm) incorporated into chitosan hydrogel (AZM-liposomal hydrogels) for the treatment of aerobic vaginitis. AZM-liposomal hydrogels were characterized for in vitro release, and rheological, texture, and mucoadhesive properties under conditions simulating the vaginal site of application. The role of chitosan as a hydrogel-forming polymer with intrinsic antimicrobial properties was explored against several bacterial strains typical for aerobic vaginitis as well as its potential effect on the anti-staphylococcal activity of AZM-liposomes. Chitosan hydrogel prolonged the release of the liposomal drug and exhibited inherent antimicrobial activity. Additionally, it boosted the antibacterial effect of all tested AZM-liposomes. All AZM-liposomal hydrogels were biocompatible with the HeLa cells and demonstrated mechanical properties suitable for vaginal application, thus confirming their potential for enhanced local therapy of aerobic vaginitis.
Using ChEMBL to Complement Schistosome Drug Discovery
Authors: Padalino Gilda , Coghlan Avril , Pagliuca Giampaolo , Forde-Thomas Josephine E. , Berriman Matthew , Hoffmann Karl F.
Published: April 2023

Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development.
Comparative Efficacy of East Asian Herbal Formulae Containing Astragali Radix–Cinnamomi Ramulus Herb-Pair against Diabetic Peripheral Neuropathy and Mechanism Prediction: A Bayesian Network Meta-Analysis Integrated with Network Pharmacology
Authors: Jo Hee-Geun , Baek Eunhye , Lee Donghun
Published: April 2023

The Astragali Radix–Cinnamomi Ramulus herb-pair (ACP) has been widely used in the treatment of diabetic peripheral neuropathy (DPN) as part of East Asian herbal medicine (EAHM). Eligible randomized controlled trials (RCTs) were identified by searching 10 databases. The outcomes investigated were response rate, sensory nerve conduction velocity (SNCV), and motor nerve conduction velocity (MNCV) in four regions of the body. The compounds in the ACP and their targets of action, disease targets, common targets, and other relevant information were filtered using network pharmacology. Forty-eight RCTs, with 4308 participants, and 16 different interventions were identified. Significant differences were observed in the response rate, MNCV, and SNCV, as all EAHM interventions were superior to conventional medicine or lifestyle modification. The EAHM formula containing the ACP ranked highest in more than half of the assessed outcomes. Furthermore, major compounds, such as quercetin, kaempferol, isorhamnetin, formononetin, and beta-sitosterol, were found to suppress the symptoms of DPN. The results of this study suggest that EAHM may increase therapeutic efficacy in DPN management, and EAHM formulations containing the ACP may be more suitable for improving treatment response rates to NCV and DPN therapy.