bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of Sm2Co17 Micromagnets in a Ferromagnetic Multipolar Microrotor to Enhance MEMS and Micromotor Performance
Authors: Diez-Jimenez Efren , Bollero Alberto , Valiente-Blanco Ignacio , Palmero Ester M. , Fernandez-Munoz Miguel , Lopez-Pascual Diego , Villalba-Alumbreros Gabriel
Published: July 2024

MEMS and micromotors may benefit from the increasing complexity of rotors by integrating a larger number of magnetic dipoles. In this article, a new microassembly and bonding process to integrate multiple Sm2Co17 micromagnets in a ferromagnetic core is presented. We experimentally demonstrate the feasibility of a multipolar micrometric magnetic rotor with 11 magnetic dipoles made of N35 Sm2Co17 micromagnets (length below 250 μm and thickness of 65 μm), integrated on a ferromagnetic core. We explain the micromanufacturing methods and the multistep microassembly process. The core is manufactured on ferromagnetic alloy Fe49Co49V2 and has an external diameter of 800 μm and a thickness of 200 μm. Magnetic and geometric measurements show good geometric fitting and planarity. The manufactured microrotor also shows good agreement among the magnetic measurements and the magnetic simulations which means that there is no magnetic degradation of the permanent magnet during the manufacturing and assembly process. This technique enables new design possibilities to significantly increase the performance of micromotors or MEMS.
Exploring the Capability of Cu-MoS2 Catalysts for Use in Electrocatalytic Overall Water Splitting
Authors: Teli Aviraj M. , Mishra Rajneesh Kumar , Shin Jae Cheol , Jeon Wookhee
Published: July 2024

Herein, we prepare MoS2 and Cu-MoS2 catalysts using the solvothermal method, a widely accepted technique for electrocatalytic overall water-splitting applications. TEM and SEM images, standard tools in materials science, provide a clear view of the morphology of Cu-MoS2. HRTEM analysis, a high-resolution imaging technique, confirms the lattice spacing, lattice plane, and crystal structure of Cu-MoS2. HAADF and corresponding color mapping and advanced imaging techniques reveal the existence of the Cu-doping, Mo, and S elements in Cu-MoS2. Notably, Cu plays a crucial role in improving the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) of the Cu-MoS2 catalyst as compared with the MoS2 catalyst. In addition, the Cu-MoS2 catalyst demonstrates significantly lower overpotential (167.7 mV and 290 mV) and Tafel slopes (121.5 mV dec−1 and 101.5 mV dec−1), standing at −10 mA cm−2 and 10 mA cm−2 for HER and OER, respectively, compared to the MoS2 catalyst. Additionally, the Cu-MoS2 catalyst displays outstanding stability for 12 h at −10 mA cm−2 of HER and 12 h at 10 mA cm−2 of OER using chronopotentiaometry. Interestingly, the Cu-MoS2‖Cu-MoS2 cell displays a lower cell potential of 1.69 V compared with the MoS2‖MoS2 cell of 1.81 V during overall water splitting. Moreover, the Cu-MoS2‖Cu-MoS2 cell shows excellent stability when using chronopotentiaometry for 18 h at 10 mA cm−2.
Piezoelectric Micromachined Microphone with High Acoustic Overload Point and with Electrically Controlled Sensitivity
Authors: Rufer Libor , Esteves Josué , Ekeom Didace , Basrour Skandar
Published: July 2024

Currently, the most advanced micromachined microphones on the market are based on a capacitive coupling principle. Capacitive micro-electromechanical-system-based (MEMS) microphones resemble their millimetric counterparts, both in function and in performance. The most advanced MEMS microphones reached a competitive level compared to commonly used measuring microphones in most of the key performance parameters except the acoustic overload point (AOP). In an effort to find a solution for the measurement of high-level acoustic fields, microphones with the piezoelectric coupling principle have been proposed. These novel microphones exploit the piezoelectric effect of a thin layer of aluminum nitride, which is incorporated in their diaphragm structure. In these microphones fabricated with micromachining technology, no fixed electrode is necessary, in contrast to capacitive microphones. This specificity significantly simplifies both the design and the fabrication and opens the door for the improvement of the acoustic overload point, as well as harsh environmental applications. Several variations of piezoelectric structures together with an idea leading to electrically controlled sensitivity of MEMS piezoelectric microphones are discussed in this paper.
Theoretical Considerations from the Modelling of the Interaction between Road Design and Fuel Consumption on Urban and Suburban Roadways
Authors: Gkyrtis Konstantinos
Published: July 2024

A roadway path is most commonly perceived as a 3-D element structure placed within its surrounding environment either within or outside urban areas. Design guidelines are usually strictly followed to ensure safe and comfort transportation of people and goods, but in full alignment with the terrain configuration and the available space, especially in urban and suburban areas. In the meantime, vehicles travelling along a roadway consume fuel and emit pollutants in a way that depends on both the driving attitude as well as the peculiar characteristics of road design and/or pavement surface condition. This study focuses on the environmental behavior of roadways in terms of fuel consumption, especially of heavy vehicles that mainly serve the purpose of freight transportation within urban areas. The impact of horizontal and vertical profiles of a roadway structure is theoretically considered through the parameters of speed and longitudinal slope, respectively. Based on theoretical calculations with an already developed model, it was found that the slope plays the most critical role, controlling the rate of fuel consumption increase, as an increase ratio of 2.5 was observed for a slope increase from 2% to 7%. The variation was less intense for a speed ranging from 25 to 45 km/h. The investigation additionally revealed useful discussion points for the need to consider the environmental impact of roadways during the operation phase for a more sustainable management of freight transportation procedures, thereby stimulating an ad hoc development of fuel consumption models based on actual measurements so that local conditions can be properly accounted for and used by road engineers and/or urban planners.
Resting Systemic Irisin Concentrations Are Lower in Older versus Younger Males after 12 Weeks of Resistance-Exercise Training While Apelin and IL-15 Concentrations Were Increased in the Whole Cohort
Authors: Cordingley Dean M. , Anderson Judy E. , Cornish Stephen M.
Published: July 2024

Myokines released by exercise are identified as factors that can influence a person’s health and wellbeing. While myokine secretion in response to an acute bout of endurance and resistance-type exercise has been examined, the influence of resistance-exercise training on myokines at rest is less well established. Therefore, this study was designed to evaluate a panel of myokines at rest following a 12-week resistance-exercise training program in younger and older males. Participants (n = 15) completed a 12-week progressive resistance-exercise training program supervised by a certified fitness professional. The training protocol targeted all major muscle groups of the upper and lower body. Resting blood samples were collected before and after completion of the training program to determine concentrations of apelin, fibroblast growth factor-21 (FGF-21), interleukin (IL)-4, IL-6, IL-7, IL-15, leukemia inhibitory factor (LIF), and irisin. Two-way repeated ANOVAs were used to compare variables between time-points and age groups. There was a main effect of time found for apelin (p = 0.003) and IL-15 (p < 0.001), while no main effects for group or time were found for the other myokines (all p > 0.05). Age group × training status interactions were found for IL-6 (p = 0.04) and irisin (p = 0.014) without pairwise differences for IL-6 (p > 0.05), and younger males had higher concentrations of irisin compared to older males post-training (p = 0.036). Overall, the 12-week resistance-exercise training program significantly increased apelin and IL-15 over time but did not change the other resting myokine concentrations for the younger or older males. However, the higher concentration of irisin in younger versus older males post-training suggests a potential explanation for the anabolic resistance observed with aging.
Vibration Analysis of Porous Cu-Si Microcantilever Beams in Fluids Based on Modified Couple Stress Theory
Authors: Jiang Jize , Tang Feixiang , He Siyu , Dong Fang , Liu Sheng
Published: July 2024

The vibrations in functionally graded porous Cu-Si microcantilever beams are investigated based on physical neutral plane theory, modified coupled stress theory, and scale distribution theory (MCST&SDT). Porous microcantilever beams define four pore distributions. Considering the physical neutral plane theory, the material properties of the beams are computed through four different power-law distributions. The material properties of microcantilever beams are corrected by scale effects based on modified coupled stress theory. Considering the fluid driving force, the amplitude-frequency response spectra and resonant frequencies of the porous microcantilever beam in three different fluids are obtained based on the Euler–Bernoulli beam theory. The quality factors of porous microcantilever beams in three different fluids are derived by estimating the equation. The computational analysis shows that the presence of pores in microcantilever beams leads to a decrease in Young’s modulus. Different pore distributions affect the material properties to different degrees. The gain effect of the scale effect is weakened, but the one-dimensional temperature field and amplitude-frequency response spectra show an increasing trend. The quality factor is decreased by porosity, and the degree of influence of porosity increases as the beam thickness increases. The gradient factor n has a greater effect on the resonant frequency. The effect of porosity on the resonant frequency is negatively correlated when the gradient factor is small (n<1) but positively correlated when the gradient factor is large (n>1).
Delay and Disruption Tolerant Networking for Terrestrial and TCP/IP Applications: A Systematic Literature Review
Authors: Castillo Aris , Juiz Carlos , Bermejo Belen
Published: July 2024

Delay and Disruption Tolerant Networking (DTN) is a network architecture created basically to overcome non-continuing connectivity. There has been a great deal of research on this topic, from space communication to terrestrial applications. Since there are still many places on earth where there is no means of communication, the focus of this work is on the latest. A systematic literature review (SLR) was performed to know the main issues and advances related to the implementation of DTN for terrestrial and TCP/IP applications, especially in places where telecommunication infrastructure is lacking. The result is a classification of papers based on key aspects, such as architecture, performance, routing, and applications. A matrix of all the papers about these aspects is included to help researchers find the missing piece and concrete terrestrial solutions. The matrix uses three colors, green, yellow, and red according to the focus, either high, medium, or low, so that it is easy to identify specific papers.
Long-Term Impact of Nutritional Intervention with Increased Polyphenol Intake and Physical Activity Promotion on Oxidative and Inflammatory Profiles in Patients with Metabolic Syndrome
Authors: Quetglas-Llabrés Maria Magdalena , Monserrat-Mesquida Margalida , Bouzas Cristina , García Silvia , Mateos David , Ugarriza Lucía , Gómez Cristina , Sureda Antoni , Tur Josep A.
Published: July 2024

Obesity and overweight pose significant risks to health, contributing to the prevalence of chronic conditions like type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). The current study aimed to assess the impact of a 6-year nutritional and lifestyle intervention on oxidative and inflammatory markers in individuals aged 55 to 75, specifically those at high risk of CVD. A study was carried out in a group of 80 participants with metabolic syndrome (MetS) residing in Mallorca, Spain, who underwent nutritional intervention based on a low-calorie Mediterranean diet (MedDiet) and promotion of physical activity. Before and after the intervention, several parameters including anthropometric data, haematological factors, blood pressure, and physical activity level were measured. Oxidative and inflammatory biomarkers in plasma were analysed. After the 6-year intervention, participants who managed to reduce their body mass index (BMI) had greater reductions in abdominal obesity, waist to heigh ratio (WHtR), diastolic blood pressure, and glucose levels, and increased high density protein cholesterol (HDL-c) compared to those who did not reduce BMI. This higher reduction in BMI was related to reduced energy intake and increased adherence to MedDiet, with greater polyphenol intake, and total physical activity (PA). Furthermore, improvements in oxidative stress and proinflammatory status were observed in participants who reduced their BMI. Significant reductions in the activity of the prooxidant enzyme, myeloperoxidase (MPO), levels of the lipid oxidation marker, malondialdehyde (MDA), and the proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1,) were found in those who reduced their BMI. In contrast, participants who did not improve their BMI exhibited higher levels of proinflammatory markers such as MCP-1 and tumour necrosis factor α (TNFα), as well as increased activity of the antioxidant enzyme catalase (CAT). Current findings suggest that an effective way to reduce BMI is a hypocaloric MedDiet combined with tailored physical activity to improve oxidative stress and proinflammatory status, and potentially reducing the risk of CVD.
Burden of Caregivers of Patients with Chronic Diseases in Primary Health Care: A Cross-Sectional Study in Greece
Authors: Albani Eleni N. , Toska Aikaterini , Togas Constantinos , Rigatos Spyridon , Vus Viktor , Fradelos Evangelos C. , Tzenalis Anastasios , Saridi Maria
Published: July 2024

Background: In the world of elderly people and people with chronic diseases, caregivers give a solution to caring at home. This study aimed to evaluate the burden of caregivers of patients with chronic diseases in primary health care and identify possible demographic and other determinants of it. Methods: This was a cross-sectional study with a convenience sample, which was conducted in two health centers. The sample comprised 291 caregivers who visited the aforementioned health centers in Patra, Greece. A composite questionnaire was utilized: the first part included demographic data and care-related information and the second included the Zarit Burden Interview and the Depression, Anxiety, and Stress Scale-21 (DASS-21). Results: The highest mean score in the DASS was recorded in the depression subscale and the lowest in the stress subscale. Concerning the Zarit Burden Interview, the highest mean score was recorded in the personal strain subscale and the lowest in the management of care subscale. The highest correlation was recorded between role strain and anxiety and the lowest was between management of care and stress. Similarly, the total score in the Zarit Burden Interview correlated significantly (in a positive direction) with depression, anxiety, and stress. Conclusions: Most of the caregivers of patients with chronic diseases in primary health care experienced a moderate to severe burden (especially in the dimension of personal strain) and moderate depression. The experienced burden was positively associated with depression, anxiety, and stress. There were significant differences in the caregivers’ burden according to several demographic and care-related characteristics.
Exposure to Treponema pallidum among Female Sex Workers: A Retrospective Study Conducted in the State of Pará, Brazilian Amazon
Authors: Carvalho Thaís Mayara da Silva , Laurindo Paula do Socorro de Oliveira da Costa , Araújo Diogo Oliveira de , Fonseca Ricardo Roberto de Souza , Laurentino Rogério Valois , Monteiro Jacqueline Cortinhas , Feitosa Rosimar Neris Mantins , Costa Fernando Augusto Miranda da , Santos Leonardo Miranda dos , Oliveira-Filho Aldemir Branco , Machado Luiz Fernando Almeida
Published: July 2024

Background: Syphilis remains a significant global public health issue, and female sex workers (FSWs) are highly vulnerable to the etiological agent of this disease. This study aimed to describe the prevalence of exposure to Treponema pallidum, as well as the vulnerability factors among FSWs in the state of Pará, Brazilian Amazon. Methods: A cross-sectional, retrospective study involving 360 FSWs from five cities in Pará was conducted from 2005 to 2007. Blood samples were collected for treponemal and non-treponemal testing, and epidemiological information was obtained through interviews. Results: The exposure rate to T. pallidum was 37.7% (136/360), and the majority of FSWs had serological results indicating past exposure (21.1%). Among the FSWs exposed to T. pallidum, most of them were single, aged 23 to 42 years old, had less than 8 years of schooling, and had a family income of between 1 and 3 minimum wages. They reported using condoms during sexual intercourse and had no history of sexually transmitted infection (STI). Furthermore, many of the FSWs exposed to T. pallidum reported having more than 20 sexual partners per month, and had partners from other Brazilian states, but not from other countries. An age over 42 years and a reduced level of education were factors associated with exposure to T. pallidum. Finally, a high rate of exposure to T. pallidum among FSWs in the Brazilian state of Pará (from 2005 to 2007) was detected. In later years, epidemiological studies conducted with FSWs recorded that this rate remained high. Measures to control, treat, and prevent syphilis among FSWs were necessary between 2005 and 2007, and they are still imperative today. Actions related to educational programs and STI control, treatment, and prevention measures contained in Brazilian policies aimed at women’s health have not changed the vulnerability scenario of FSWs regarding their exposure to T. pallidum, even after 16 years, and must be reviewed and adapted to the conditions of the Brazilian Amazon.
Salvia verticillata (L.)—Biological Activity, Chemical Profile, and Future Perspectives
Authors: Ivanova Stanislava , Dzhakova Zoya , Staynova Radiana , Ivanov Kalin
Published: July 2024

Species belonging to the genus Salvia, Lamiaceae, have been deeply involved in the folk medicine of different nations since ancient times. Lilac sage, or Salvia verticillata L. (S. verticillata) is a less studied species from the genus. However, it seems to have a prominent potential for the future drug discovery strategies of novel phytopharmaceuticals. This review aims to summarise the data on the biological activity and the phytochemical profile of extracts and essential oils derived from S. verticillata. This review is based on data from 57 in vitro and in vivo studies. The chemical profile of S. verticillata includes different synergic compounds like phenolic acids, flavonoids, terpenes, and salvianolic acids. Although some small amounts of salvianolic acid B were found in S. verticillata extracts, the major compound among the salvianolic acids is salvianolic acid C, a compound associated with the potential for improving liver fibrosis, cardio- and hepatoprotection, and the inhibition of SARS-CoV-2 infection. The cannabinoid type 2 receptor agonist β-caryophyllene is one of the major compounds in S. verticillata essential oils. It is a compound with a prominent potential in regenerative medicine, neurology, immunology, and other medical fields. The in vivo and the in vitro studies, regarding S. verticillata highlighted good antioxidant potential, anti-inflammatory, antibacterial, and antifungal activity. S.verticillata was also reported as a potential source of drug candidates for the treatment of neurodegenerative diseases such as Alzheimer’s disease, because of the inhibitory activity on the acetylcholinesterase. However, the number of studies in this direction is limited.
Fish Oil Supplementation Mitigates High-Fat Diet-Induced Obesity: Exploring Epigenetic Modulation and Genes Associated with Adipose Tissue Dysfunction in Mice
Authors: de Jesus Simão Jussara , de Sousa Bispo Andressa França , Plata Victor Tadeu Gonçalves , Armelin-Correa Lucia Maria , Alonso-Vale Maria Isabel Cardoso
Published: July 2024

This study investigated the effects of fish oil (FO) treatment, particularly enriched with eicosapentaenoic acid (EPA), on obesity induced by a high-fat diet (HFD) in mice. The investigation focused on elucidating the impact of FO on epigenetic modifications in white adipose tissue (WAT) and the involvement of adipose-derived stem cells (ASCs). C57BL/6j mice were divided into two groups: control diet and HFD for 16 weeks. In the last 8 weeks, the HFD group was subdivided into HFD and HFD + FO (treated with FO). WAT was removed for RNA and protein extraction, while ASCs were isolated, cultured, and treated with leptin. All samples were analyzed using functional genomics tools, including PCR-array, RT-PCR, and Western Blot assays. Mice receiving an HFD displayed increased body mass, fat accumulation, and altered gene expression associated with WAT inflammation and dysfunction. FO supplementation attenuated these effects, a potential protective role against HFD-induced obesity. Analysis of H3K27 revealed HFD-induced changes in histone, which were partially reversed by FO treatment. This study further explored leptin signaling in ASCs, suggesting a potential mechanism for ASC dysfunction in the obesity-rich leptin environment of WAT. Overall, FO supplementation demonstrated efficacy in mitigating HFD-induced obesity, influencing epigenetic and molecular pathways, and shedding light on the role of ASCs and leptin signaling in WAT dysfunction associated with obesity.
Synthesis of Silver Nanoparticles Using Extracts from Different Parts of the Paullinia cupana Kunth Plant: Characterization and In Vitro Antimicrobial Activity
Authors: Lima Alan Kelbis Oliveira , Souza Lucas Marcelino dos Santos , Reis Guilherme Fonseca , Junior Alberto Gomes Tavares , Araújo Victor Hugo Sousa , Santos Lucas Carvalho dos , Silva Vitória Regina Pereira da , Chorilli Marlus , Braga Hugo de Campos , Tada Dayane Batista , Ribeiro José Antônio de Aquino , Rodrigues Clenilson Martins , Nakazato Gerson , Muehlmann Luís Alexandre , Garcia Mônica Pereira
Published: July 2024

The green synthesis of silver nanoparticles (AgNPs) can be developed using safe and environmentally friendly routes, can replace potentially toxic chemical methods, and can increase the scale of production. This study aimed to synthesize AgNPs from aqueous extracts of guarana (Paullinia cupana) leaves and flowers, collected in different seasons of the year, as a source of active biomolecules capable of reducing silver ions (Ag+) and promoting the stabilization of colloidal silver (Ag0). The plant aqueous extracts were characterized regarding their metabolic composition by liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS/MS), phenolic compound content, and antioxidant potential against free radicals. The synthesized AgNPs were characterized by UV/Vis spectrophotometry, dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and scanning electron microscopy coupled to energy-dispersive X-ray spectrometry (EDX). The results demonstrated that the chemical characterization indicated the presence of secondary metabolites of many classes of compounds in the studied aqueous extracts studied, but alkaloids and flavonoids were predominant, which are widely recognized for their antioxidant capabilities. It was possible to notice subtle changes in the properties of the nanostructures depending on parameters such as seasonality and the part of the plant used, with the AgNPs showing surface plasmon resonance bands between 410 and 420 nm using the leaf extract and between 440 and 460 nm when prepared using the flower extract. Overall, the average hydrodynamic diameters of the AgNPs were similar among the samples (61.98 to 101.6 nm). Polydispersity index remained in the range of 0.2 to 0.4, indicating that colloidal stability did not change with storage time. Zeta potential was above −30 mV after one month of analysis, which is adequate for biological applications. TEM images showed AgNPs with diameters between 40.72 to 48.85 nm and particles of different morphologies. EDX indicated silver content by weight between 24.06 and 28.81%. The synthesized AgNPs exhibited antimicrobial efficacy against various pathogenic microorganisms of clinical and environmental interest, with MIC values between 2.12 and 21.25 µg/mL, which is close to those described for MBC values. Therefore, our results revealed the potential use of a native species of plant from Brazilian biodiversity combined with nanotechnology to produce antimicrobial agents.
Ginsenoside RK1 Induces Ferroptosis in Hepatocellular Carcinoma Cells through an FSP1-Dependent Pathway
Authors: Jiang Yulang , Yu Yongxin , Pan Ziyang , Wang Ziyuan , Sun Mingyu
Published: July 2024

Background: Hepatocellular carcinoma (HCC), currently ranking as the third most lethal malignancy, poses a grave threat to human health. Ferroptosis, a form of programmed cell demise, has emerged as a promising therapeutic target in HCC treatment. In this study, we investigated the impact of ginsenoside RK1 on ferroptosis induction in HCC cells and elucidated the underlying mechanisms. Methods: The HCC cell line HepG2 was utilized to evaluate the effects of ginsenoside RK1. Distinct dosages of ginsenoside RK1 (25 μM, 50 μM, and 100 μM) were selected based on half-maximal inhibitory concentration (IC50) values. Cellular viability was assessed using a CCK8 assay, cytotoxicity was measured via lactate dehydrogenase (LDH) release assay, and colony-forming ability was evaluated using the clone formation assay. Various inhibitors targeting apoptosis (Z-VAD-FMK 20 μM), necrosis (Nec-1, 10 μM), and ferroptosis (Fer-1, 10 μM; Lip-1, 1 μM) were employed to assess ginsenoside RK1’s impact on cell demise. Intracellular levels of key ions, including glutathione (GSH), malondialdehyde (MDA), and iron ions, were quantified, and the protein expression levels of ferroptosis-related genes were evaluated. The sensitivity of HCC cells to ferroptosis induction by ginsenoside RK1 was examined following the overexpression and silencing of the aforementioned target genes. Results: Ginsenoside RK1 exhibited an inhibitory effect on HCC cells with an IC50 value of approximately 20 μM. It attenuated cellular viability and colony-forming capacity in a dose-dependent manner, concurrently reducing intracellular GSH levels and increasing intracellular Malondialdehyde (MDA) and iron ion contents. Importantly, cell demise induced by ginsenoside RK1 was specifically counteracted by ferroptosis inhibitors. Furthermore, the modulation of Ferroptosis suppressor protein 1 (FSP1) expression influenced the ability of ginsenoside RK1 to induce ferroptosis. FSP1 overexpression or silencing enhanced or inhibited ferroptosis induction by ginsenoside RK1, respectively. Conclusions: Ginsenoside RK1 enhances ferroptosis in hepatocellular carcinoma through an FSP1-dependent pathway.
Antimycobacterial and Anticancer Properties of Myrtus communis Leaf Extract
Authors: Mir Mushtaq Ahmad , Memish Lamis Ahmad , Elbehairi Serag Eldin , Bashir Nasreena , Masoud Faris Saif , Shati Ali A. , Alfaifi Mohammad Y. , Alamri Ahmad M. , Alkahtani Sultan Ahmad , Ahmad Irfan
Published: July 2024

Background: Plant-derived products or extracts are widely used in folk/traditional medicine to treat several infections, ailments, or disorders. A well-known medicinal herb, Myrtus communis is an evergreen fragrant plant native to the Mediterranean region that has been used for ages in traditional medicine around the world. Materials and methods: The microplate alamarBlue assay and the well diffusion method were used to evaluate the zone of inhibition and MIC, respectively. The double-disc diffusion method was used to investigate the synergy between antibiotics and the extract. The crystal violet method was used to investigate biofilm development. The SulphoRhodamine-B assay and DNA flow cytometry were used to investigate the proliferation and subsequent distribution of cells among different phases of the cell cycle. The apoptotic and necrotic phases of the cancer cells were examined using flow cytometry in conjunction with Annexin V-FITC/PI labeling. Using the IBM SPSS statistical program, a one-way ANOVA with Tukey’s post hoc test was employed for statistical analysis. Results: The ethanolic leaf extract of M. communis showed a strong growth inhibition effect (zone of inhibition: 20.3 ± 1.1–26.3 ± 2.5 mm, MIC: 4.88–312.5 µg/mL, and MBC: 39.07–1250 μg/mL) against several rapidly growing and slow-growing mycobacterial strains in a dose-dependent manner. Damage to the cell wall of bacterial cells was determined to be the cause of the antimycobacterial action. The extract inhibited biofilm formation (MBIC of 9.7 µg/mL) and eradicated already-formed mature and ultra-mature biofilms of M. smegmatis, with MBEC values of 78 µg/mL and 156 µg/mL, respectively. Additionally, the extract exhibited potent anticancer effects against diverse cancer cell lines of the breast (MCF-7), liver (HepG2), cervix (HeLa), and colon (HCT116) (IC50 for HCT116: 83 ± 2.5, HepG2: 53.3 ± 0.6, MCF-7: 41.5 ± 0.6, and HeLa: 33.3 ± 3.6) by apoptosis after arresting the cells in the G1 phase of the cell cycle. Conclusions: These results suggest that M. communis leaf extract is a potential source of secondary metabolites that could be further developed as potential anticancer and antimycobacterial agents to treat diverse types of cancers and mycobacterial infections.
Fatty Acid Amides Suppress Proliferation via Cannabinoid Receptors and Promote the Apoptosis of C6 Glioma Cells in Association with Akt Signaling Pathway Inhibition
Authors: Silva Nágila Monteiro da , Lopes Izabella Carla Silva , Galué-Parra Adan Jesus , Ferreira Irlon Maciel , Sena Chubert Bernardo Castro de , Silva Edilene Oliveira da , Macchi Barbarella de Matos , Oliveira Fábio Rodrigues de , do Nascimento José Luiz Martins
Published: July 2024

A glioma is a type of tumor that acts on the Central Nervous System (CNS) in a highly aggressive manner. Gliomas can occasionally be inaccurately diagnosed and treatments have low efficacy, meaning that patients exhibit a survival of less than one year after diagnosis. Due to factors such as intratumoral cell variability, inefficient chemotherapy drugs, adaptive resistance development to drugs and tumor recurrence after resection, the search continues for new drugs that can inhibit glioma cell growth. As such, analogues of endocannabinoids, such as fatty acid amides (FAAs), represent interesting alternatives for inhibiting tumor growth, since FAAs can modulate several metabolic pathways linked to cancer and, thus, may hold potential for managing glioblastoma. The aim of this study was to investigate the in vitro effects of two fatty ethanolamides (FAA1 and FAA2), synthetized via direct amidation from andiroba oil (Carapa guianensis Aublet), on C6 glioma cells. FAA1 and FAA2 reduced C6 cell viability, proliferation and migratory potential in a dose-dependent manner and were not toxic to normal retina glial cells. Both FAAs caused apoptotic cell death through the loss of mitochondrial integrity (ΔΨm), probably by activating cannabinoid receptors, and inhibiting the PI3K/Akt pathway. In conclusion, FAAs derived from natural products may have the potential to treat glioma-type brain cancer.
Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook
Authors: Kollipara Sivacharan , Martins Frederico Severino , Jereb Rebeka , Krajcar Dejan , Ahmed Tausif
Published: July 2024

Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models. Such models are now being extensively used for bioequivalence risk assessment, internal decision-making, and the evaluation of drug and formulation factors related to bioequivalence. Depiction of the above-mentioned factors through the incorporation of variability and development of a virtual population for bioequivalence assessment is of paramount importance in utilizing such models. In this manuscript, we have portrayed our current understanding of VBE. A detailed explanation was provided with respect to study designs, in vivo variability, and the impact of physiological, drug, and formulation factors on the development of the population for VBE. Furthermore, strategies are suggested to incorporate variability in GastroPlus with an emphasis on intra-subject and inter-occasion variability. Two industrial case studies pertaining to immediate and modified release formulation were portrayed wherein VBE was utilized for decision-making and regulatory justification. Finally, regulatory understanding in the area of VBE, along with future perspectives, was detailed.
Optimization of the Search for Neuroprotectors among Bioflavonoids
Authors: Belenichev Igor , Ryzhenko Victor , Popazova Olena , Bukhtiyarova Nina , Gorchakova Nadia , Oksenych Valentyn , Kamyshnyi Oleksandr
Published: July 2024

For the first time, to optimize the creation of new neuroprotective agents based on bioflavonoids, we applied information technologies; these include docking analysis to calculate the binding of candidate molecules to the pharmacological target protein transthyretin as well as a program of virtual screening of NO scavengers. As a result of this approach, the substance catechin was isolated from candidate molecules—quercetin, catechin, Epicatechin gallate, Epicatechin, Procyanidin B1, Procyanidin B2, Procyanidin B3, and Catechin-3-gallate—according to docking analysis. As a result of virtual screening, catechin was identified as a potential NO scavenger (55.15% prediction). The results of the prediction were confirmed by in vitro experiments. Course administration of catechin to animals with experimental multiple sclerosis (MS) against the background of methylprednisolone administration completely eliminated lethal cases, reduced the number of diseased animals by 20% as well as prevented the development of severe neurological symptoms by 20% (compared to the methylprednisolone group) and by 60% compared to the control group. Course administration of catechin with methylprednisolone leads to a decrease in the neurodegradation markers in the cytosol of rats, with EAE: NSE by 37% and S-100 by 54.8%. The combined administration of methylprednisolone significantly exceeds the combination of methylprednisolone with the reference drug mexidol by the degree of NSE reduction. The obtained results indicate a significant neuroprotective effect of ocular combinations of methylprednisolone and catechin. The above-mentioned confirms the correctness of the bioflavonoid selection with the help of a virtual screening program.
Evaluating the Physicochemical Properties–Activity Relationship and Discovering New 1,2-Dihydropyridine Derivatives as Promising Inhibitors for PIM1-Kinase: Evidence from Principal Component Analysis, Molecular Docking, and Molecular Dynamics Studies
Authors: Dib Hanna , Abu-Samha Mahmoud , Younes Khaled , Abdelfattah Mohamed A. O.
Published: July 2024

In this study, we evaluated the physicochemical properties related to the previously reported anticancer activity of a dataset comprising thirty 1,2-dihydropyridine derivatives. We utilized Principal Component Analysis (PCA) to identify the most significant influencing factors. The PCA analysis showed that the first two principal components accounted for 59.91% of the total variance, indicating a strong correlation between the molecules and specific descriptors. Among the 239 descriptors analyzed, 18 were positively correlated with anticancer activity, clustering with the 12 most active compounds based on their IC50 values. Six of these variables—LogP, Csp3, b_1rotN, LogS, TPSA, and lip_don—are related to drug-likeness potential. Thus, we then ranked the 12 compounds according to these six variables and excluded those violating the drug-likeness criteria, resulting in a shortlist of nine compounds. Next, we investigated the binding affinity of these nine shortlisted compounds with the use of molecular docking towards the PIM-1 Kinase enzyme (PDB: 2OBJ), which is overexpressed in various cancer cells. Compound 6 exhibited the best docking score among the docked compounds, with a docking score of −11.77 kcal/mol, compared to −12.08 kcal/mol for the reference PIM-1 kinase inhibitor, 6-(5-bromo-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile. To discover new PIM-1 kinase inhibitors, we designed nine novel compounds featuring hybrid structures of compound 6 and the reference inhibitor. Among these, compound 31 displayed the best binding affinity, with a docking score of −13.11 kcal/mol. Additionally, we performed PubChem database mining using the structure of compound 6 and the similarity search tool, identifying 16 structurally related compounds with various reported biological properties. Among these, compound 52 exhibited the best binding affinity, with a docking score of −13.03 kcal/mol. Finally, molecular dynamics (MD) studies were conducted to confirm the stability of the protein–ligand complexes obtained from docking the studied compounds to PIM-1 kinase, validating the potential of these compounds as PIM-1 kinase inhibitors.
Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages
Authors: Kim Seong-Kyu , Choe Jung-Yoon , Kim Ji-Won , Park Ki-Yeun , Kim Boyoung
Published: July 2024

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.
Computational Exploration of Potential Pharmacological Inhibitors Targeting the Envelope Protein of the Kyasanur Forest Disease Virus
Authors: Achappa Sharanappa , Aldabaan Nayef Abdulaziz , Desai Shivalingsarj V. , Muddapur Uday M. , Shaikh Ibrahim Ahmed , Mahnashi Mater H. , Alshehri Abdullateef A. , Mannasaheb Basheerahmed Abdulaziz , Khan Aejaz Abdullatif
Published: July 2024

The limitations of the current vaccination strategy for the Kyasanur Forest Disease virus (KFDV) underscore the critical need for effective antiviral treatments, highlighting the crucial importance of exploring novel therapeutic approaches through in silico drug design. Kyasanur Forest Disease, caused by KFDV, is a tick-borne disease with a mortality of 3–5% and an annual incidence of 400 to 500 cases. In the early stage of infection, the envelope protein plays a crucial role by facilitating host–virus interactions. The objective of this research is to develop effective antivirals targeting the envelope protein to disrupt the virus–host interaction. In line with this, the 3D structure of the envelope protein was modeled and refined through molecular modeling techniques, and subsequently, ligands were designed via de novo design and pharmacophore screening, yielding 12 potential hits followed by ADMET analysis. The top five candidates underwent geometry optimization and molecular docking. Notably, compounds L4 (SA28) and L3 (CNP0247967) are predicted to have significant binding affinities of −8.91 and −7.58 kcal/mol, respectively, toward the envelope protein, based on computational models. Both compounds demonstrated stability during 200 ns molecular dynamics simulations, and the MM-GBSA binding free-energy values were −85.26 ± 4.63 kcal/mol and −66.60 ± 2.92 kcal/mol for the envelope protein L3 and L4 complexes, respectively. Based on the computational prediction, it is suggested that both compounds have potential as drug candidates for controlling host–virus interactions by targeting the envelope protein. Further validation through in-vitro assays would complement the findings of the present in silico investigations.
A Second Wind for Inorganic APIs: Leishmanicidal and Antileukemic Activity of Hydrated Bismuth Oxide Nanoparticles
Authors: Grafov Andriy , da Silva Chagas Ana Flávia , de Freitas Gomes Alice , Ouedrhiri Wessal , Cerruti Pierfrancesco , Del Barone Maria Cristina , de Souza Mota Breno , de Castro Alves Carlos Eduardo , Brasil Anny Maíza Vargas , Pereira Antonia Maria Ramos Franco , Soares Pontes Gemilson
Published: July 2024

American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology is gaining importance in the field, since it can provide better efficacy and lower toxicity of the drugs. The present study aimed to synthesize, characterize, and evaluate the in vitro leishmanicidal and antileukemic activity of bismuth nanoparticles (BiNPs). Promastigotes and amastigotes of L. (V.) guyanensis and L. (L.) amazonensis were exposed to BiNPs. The efficacy of the nanoparticles was determined by measurement of the parasite viability and the percentage of infected cells, while the cytotoxicity was characterized by the colorimetry. BiNPs did not induce cytotoxicity in murine peritoneal macrophages and showed better efficacy in inhibiting promastigotes (IC50 < 0.46 nM) and amastigotes of L. (L.) amazonensis. This is the first report on the leishmanicidal activity of Bi-based materials against L. (V.) guayanensis. BiNPs demonstrated significant cytotoxic activity against K562 and HL60 cells at all evaluated concentrations. While the nanoparticles also showed some cytotoxicity towards non-cancerous Vero cells, the effect was much lower compared to that on cancer cells. Treatment with BiNPs also had a significant effect on inhibiting and reducing colony formation in HL60 cells. These results indicate that bismuth nanoparticles have the potential for an inhibitory effect on the clonal expansion of cancer cells.
The Advances in Phospholipids-Based Phase Separation Gels for the Sustained Release of Peptides, Proteins, and Chemotherapeutics
Authors: Dong Jianxia , Zhou Xueru , Li Qing , Zheng Ruohui , Chen Jing , Liu Yuzhe , Tong Xin , Wan Zhuoya , Gong Tao
Published: July 2024

Implantable drug delivery systems formed upon injection offer a host of advantages, including localized drug administration, sustained release, minimized side effects, and enhanced patient compliance. Among the various techniques utilized for the development of in situ forming drug implants, solvent-induced phase inversion emerges as a particularly promising approach. However, synthetic polymer-based implants have been associated with undesirable effects arising from polymer degradation. In response to this challenge, a novel category of drug delivery systems, known as phospholipids-based phase separation gels (PPSGs), has emerged. These gels, characterized by their low initial viscosity, exhibit injectability and undergo rapid transformation into in situ implants when exposed to an aqueous environment. A typical PPSG formulation comprises biodegradable components, such as phospholipids, pharmaceutical oil, and a minimal amount of ethanol. The minimized organic solvents in the composition show good biocompatibility. And the relatively simple composition holds promise for industrial-scale manufacturing. This comprehensive review provides an overview of the principles and advancements in PPSG systems, with specific emphasis on their suitability as drug delivery systems for a wide range of active pharmaceutical ingredients (APIs), spanning from small molecules to peptides and proteins. Additionally, we explore the critical parameters and underlying principles governing the formulation of PPSG-based drug delivery strategies, offering valuable insights on optimization strategies.
Investigation of Factors Influencing the Effectiveness of Deformable Nanovesicles for Insulin Nebulization Inhalation
Authors: Yu Jinghan , Meng Yingying , Wen Zhiyang , Jiang Yu , Guo Yiyue , Du Simeng , Liu Yuling , Xia Xuejun
Published: July 2024

Nebulized inhalation offers a noninvasive method for delivering drugs to treat both local respiratory and systemic diseases. In this study, insulin was used as a model drug to design a series of deformable nanovesicles (DNVs) with key quality attributes, including particle size, deformability, and drug load capacity. We investigated the effects of these properties on aerosol generation, macrophage phagocytosis, and bloodstream penetration. The results showed that deformability improved nebulization performance and reduced macrophage phagocytosis, benefiting local and systemic delivery. However, the advantage of DNVs for transmembrane penetration was not evident in the alveolar epithelium. Within the size range of 80–490 nm, the smaller the particle size of IPC-DNVs, the easier it is to evade clearance by macrophages and the more effective the in vivo hypoglycemic efficacy will be. In the drug load range of 3–5 mg/mL, a lower drug load resulted in better hypoglycemic efficacy. The area above the blood glucose decline curve with time (AAC) of nebulized DNVs was 2.32 times higher than that of the insulin solution, demonstrating the feasibility and advantages of DNVs in the pulmonary delivery of biomacromolecule drugs. This study provides insights into the construction and formulation optimization of pulmonary delivery carriers.