bluuebunny/crossref_metadata_2025 huggingface dataset:
Curcumin Reduces Depression in Obese Patients with Type 2 Diabetes: A Randomized Controlled Trial
Authors: Yaikwawong Metha , Jansarikit Laddawan , Jirawatnotai Siwanon , Chuengsamarn Somlak
Published: July 2024

Type 2 diabetes and depression co-occur in a bidirectional manner. Curcumin supplements exhibit antidepressant effects that may mitigate depression by modulating neurotransmitters and reducing inflammatory and oxidative stress pathways. This study aimed to evaluate the efficacy of curcumin in improving depression severity in obese type 2 diabetes patients. The study employed a randomized, double-blind, placebo-controlled trial design with 227 participants. The primary end-point was depression severity assessed using the Patient Health Questionnaire-9. Biomarkers were measured at baseline and at 3-, 6-, 9-, and 12-month intervals. The biomarkers assessed were serotonin levels, pro-inflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha), antioxidant activities (total antioxidant status, glutathione peroxidase, and superoxide dismutase), and malondialdehyde. After 12 months, the curcumin group exhibited significantly improved depression severity (p = 0.000001). The curcumin group had higher levels of serotonin (p < 0.0001) but lower levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p < 0.001 for all) than the placebo group. Total antioxidant status, glutathione peroxidase activity, and superoxide dismutase activity were elevated in the curcumin group, whereas malondialdehyde levels were greater in the placebo group (p < 0.001 for all). These findings suggest curcumin may have antidepressant effects on obese type 2 diabetes patients.
Associations of Obstructive Sleep Apnea Risk with Obesity, Body Composition and Metabolic Abnormalities in School-Aged Children and Adolescents
Authors: Liao Zijun , Chen Yiren , Wu Lijun , Huang Yiying , Li Shaoli , Liu Junting , Zong Xinnan , Tai Jun , Chen Fangfang
Published: July 2024

The objective of this study is to explore the associations between obesity, body composition, and the self-reported risk of obstructive sleep apnea (OSA) and to examine whether the risk of OSA is related to metabolic abnormalities in children and adolescents aged 6–17 years. Utilizing data from the 2022 to 2023 Beijing Children and Adolescents Health Cohort baseline survey, 5000 school-aged participants were analyzed. OSA risk was assessed via the Pediatric Sleep Questionnaire, with anthropometric and body composition measurements taken. Metabolic markers included blood pressure, lipid levels, blood glucose, and uric acid. Associations were analyzed using logistic regression and generalized linear models. Results showed that 88.6% were low-risk and 11.4% were high-risk for OSA. Overweight (aOR 1.53, 95% CI 1.22–1.92), obesity (aOR 1.94, 95% CI 1.57–2.40), and abdominal obesity (aOR 1.59, 95% CI 1.31–1.93) significantly increased OSA risk. High fat mass was a critical factor, while muscle mass was not, especially in those who were overweight and obese. Associations of OSA risk with metabolic abnormalities were non-significant after adjusting for BMI. Our research highlights the significant associations of obesity and body composition with OSA risk, with child BMI influencing the relationship between OSA and metabolic abnormalities. Future research should explore causative relationships and the enduring impacts of OSA on metabolic health in children.
The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review
Authors: Aaseth Jan O. , Finnes Trine Elisabeth , Askim Merete , Alexander Jan
Published: July 2024

The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.
Exploring Factors Influencing Pregnant Women’s Perceptions and Attitudes Towards Midwifery Care in Romania: Implications for Maternal Health Education Strategies
Authors: Radu Mihaela Corina , Armean Mihai Sebastian , Pop-Tudose Melania , Medar Cosmin , Manolescu Loredana Sabina Cornelia
Published: July 2024

Background: Midwives are strong advocates for vaginal births. However, their visibility and accessibility are poorly perceived by women in Romania. Consequently, the women’s options are limited to a single direction when pregnancy occurs, involving the family doctor, the obstetrician, and often an interventional technical approach at the time of birth. The aim of this research is to identify specific variables that affect the perceptions and attitudes of pregnant women towards the care provided by midwives. This knowledge could contribute to the development of more effective education and information strategies within maternal health services. Methods: A cross-sectional observational analytical survey was conducted in Romania among pregnant women from the general population. Data were collected through a self-administered questionnaire, with informed consent obtained from each participating pregnant woman. The questionnaire was administered online using the cloud-based Google Forms platform and was available on the internet for seven months, from January to July 2023. The questionnaire was distributed through various media channels, both individually and in communication groups, in the form of a link. All questions were mandatory, and the questionnaire could only be submitted after answering all questions. Results: A total of 1301 individual responses were collected. The analysis of the socio-demographic and obstetrical profile of the pregnant women revealed that approximately half, 689 (52.95%), of the participants were aged between 18–29 years, and 1060 (81.47%) of the participants were married. Among our group of 1301 pregnant women, 973 (74.78%) had higher education, and 987 (75.86%) had a regular job. A majority of the survey participants, 936 (71.94%), lived in an urban geographic area, while 476 (36.58%) had attended childbirth education courses, and 791 (60.79%) were in the third trimester of pregnancy. A total of 298 (22.9%) respondents did not want to give birth in a hospital, and one-third, 347 (26.67%), did not place significant importance on control over the childbirth process. Conclusions: The main factors influencing women’s decisions regarding perinatal care and the importance of midwives as a component of the maternal-infant care team are modifiable, and thorough educational and psychological preparation would reduce the increasing predominance of preference for cesarean section, thereby promoting healthier and more woman- and child-centered perinatal care.
Association between Regular Use of Analgesics before Cancer Diagnosis and Occurrence of Mood Disorders
Authors: Oh Hyun Sook , Noh Subin , Seo Hwa Jeong
Published: July 2024

We aimed to determine the relationship between the use of analgesics prescribed for pain management and the onset and progression of mood disorders using a large-scale cohort database. We calculated hazard ratios (HR) with 95% confidence intervals (CI) for patient risk of developing mood disorders based on age, income, health-related variables, disease history, Charlson comorbidity index, and analgesics prescription behavior (Models 1–3). Additionally, we determined the risk of mood disorder occurrence by age group (Model 4) using a proportional hazards regression model. The age- and income-adjusted HR (Model 1) was 1.8275. The age-, income-, BMI-, and physical-activity-adjusted HR (Model 2) was 1.882. The fully adjusted HR (Model 3) was 1.698. Compared with no analgesic use, nonregular use (HR = 1.386) and regular use (HR = 1.698) was associated with a higher risk of mood disorders. Among patients older than 50 years, those who participated in physical activity (less than five days) had a lower risk of mood disorders than those who did not. This suggests that it may be useful for preventing mood disorders in older cancer survivors. A high risk of comorbidities and regular use of analgesics are risk factors for developing mood disorders. Therefore, our results suggest that cancer survivors with a high risk of comorbidities and a history of regular analgesic use should undergo careful psychiatric consultation.
The Public’s Perception of Florence Nightingale’s Legacy in the Digital Media: A Critical Discourse Analysis
Authors: Conte Gianluca , Magon Arianna , Palmeri Maria Angela , Paglione Giulia , Baroni Irene , Belloni Silvia , Angolani Miriam , Arcidiacono Marco Alfredo , Arrigoni Cristina , Stievano Alessandro , Caruso Rosario
Published: July 2024

This study critically examines the public’s perception of Florence Nightingale’s legacy through a critical discourse analysis (CDA) of digital media, specifically podcasts and YouTube. Nightingale, who is often remembered as “The Lady with the Lamp”, holds a complex identity within modern narratives that is celebrated for her pioneering contributions to nursing and public health, even if there are some disagreements about her, given the colonialist setting that may have shaped some of her opinions and decisions. This research employed CDA to analyze 25 podcasts and 18 YouTube videos, which were systematically included according to a priori inclusion criteria. The study synthesized how these media products portray Nightingale and, by extension, shape public discourse about the nursing profession. The findings reveal five thematic representations of Nightingale: as a legendary figure, a modern feminist, a dedicated statistician, a pioneer in public health, and a pivotal STEM contributor. These portrayals challenge traditional nursing stereotypes by emphasizing Nightingale’s role as a rigorous scientist and reformer, suggesting broader perceptions of nurses that encompass leadership, analytical skills, and strategic thinking. The study supports the hypothesis that digital narratives significantly influence the public’s understanding and appreciation of nursing, advocating for a more nuanced professional identity that integrates traditional caregiving roles with critical and analytical capabilities.
Lewis Acid-Initiated Ring-Opening Reactions of Five- and Six-Membered Cyclic Ethers Based on the Oxonium Ylide Intermediates
Authors: Jiang Dandan , Xiao Jun , Zhang Yingzhen , Liu Kunming , Li Juanhua , Liu Jinbiao
Published: July 2024

In light of the small ring strain of five/six-membered cyclic ethers, constructing complex molecules via ring-opening reactions has consistently been a highly challenging topic in organic synthesis. Induced by Lewis acids, the charge redistribution in cyclic ethers forms oxonium ylide intermediates, thereby activating the C–O bond and subsequently facilitating nucleophilic attack for ring opening. In recent years, a variety of novel Lewis acids, encompassing those with new metal centers and frustrated Lewis pairs (FLPs), have been effectively utilized to induce the formation of oxonium ylides, offering a diverse array of methods for the ring opening of five/six-membered cyclic ethers. This review conveys the extensive application advancements of diverse Lewis acid types for cyclic ether ring-opening reactions over the past two decades, originating from the perspective of the classification of Lewis acids. Furthermore, the substrate applicability and chemical transformation efficiency of these Lewis acids in the ring-opening reactions of cyclic ethers have also been discussed herein.
Evaluation of Immune Status of Pigs against Classical Swine Fever for Three Years after the Initiation of Vaccination in Gifu Prefecture, Japan
Authors: Kuwata Keisuke , Kuninaga Naotoshi , Kimura Yoko , Makita Kohei , Isoda Norikazu , Shimizu Yukio , Sakoda Yoshihiro
Published: July 2024

In 2018, classical swine fever (CSF) reemerged in Gifu Prefecture, Japan, after 26 years of absence, and vaccination of domestic pigs using a live attenuated vaccine was initiated in 2019. Because the vaccine efficacy in piglets is influenced by the maternal antibody levels, vaccination should be administered at the optimal age by assuming the antibody level in sows. In this study, the shift in the antibody titer distribution in sows due to the initiation of vaccination to naïve herds and its influence on the vaccine-induced immunity rate in fattening pigs were investigated for 3 years. The results indicated that higher antibody titers were induced in first-generation sows after vaccine initiation because they were immunologically naïve, but the distribution of antibody titers shifted to lower levels along with their replacement with second-generation sows. The average vaccination age of fattening pigs became earlier year by year, and the vaccine-induced antibody rate was almost ≥80%. Based on the estimation of the optimal age for vaccination, it was found that vaccination at a younger age may reduce the risk of CSF infection. Taken together, the risk of CSF outbreaks can be reduced by administering vaccines at the optimal age based on the sequential monitoring of the sow’s immune status.
Predictive Role of Fluorescein Angiography in Retinopathy of Prematurity
Authors: Dini Gianluca , Beccasio Alfredo , Della Lena Francesco , Verrotti Alberto , Cagini Carlo
Published: July 2024

Background: Fluorescein angiography (FA) has been a pivotal tool for studying the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA to assess the predictive value of angiographic features. Methods: This is an observational retrospective cohort study of eyes screened for ROP with a binocular indirect ophthalmoscope and FA. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care unit of Santa Maria Hospital of Perugia. The masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Results: A total of 80 eyes of 40 patients were included for this study. Among the angiographic features evaluated, leakage, shunts, and tangles were predictive of the development of treatment-requiring ROP (p < 0.05). Conclusions: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.
Close Cardiovascular Monitoring during the Early Stages of Treatment for Patients Receiving Immune Checkpoint Inhibitors
Authors: Delombaerde Danielle , Vulsteke Christof , Van de Veire Nico , Vervloet Delphine , Moerman Veronique , Van Calster Lynn , Willems Anne-Marie , Croes Lieselot , Gremonprez Félix , De Meulenaere Astrid , Elzo Kraemer Ximena , Wouters Kristien , Peeters Marc , Prenen Hans , De Sutter Johan
Published: July 2024

Background: There is an unmet medical need for the early detection of immune checkpoint inhibitor (ICI)-induced cardiovascular (CV) adverse events due to a lack of adequate biomarkers. This study aimed to provide insights on the incidence of troponin elevations and echocardiographic dynamics during ICI treatment in cancer patients and their role as potential biomarkers for submyocardial damage. In addition, it is the first study to compare hs-TnT and hs-TnI in ICI-treated patients and to evaluate their interchangeability in the context of screening. Results: Among 59 patients, the mean patient age was 68 years, and 76% were men. Overall, 25% of patients received combination therapy. Although 10.6% [95% CI: 5.0–22.5] of the patients developed troponin elevations, none experienced a CV event. No significant changes were found in 3D left ventricular (LV) ejection fraction nor in global longitudinal strain f (56 ± 6% vs. 56 ± 6%, p = 0.903 and −17.8% [−18.5; −14.2] vs. −17.0% [−18.8; −15.1], p = 0.663) at 3 months. There were also no significant changes in diastolic function and right ventricular function. In addition, there was poor agreement between hs-TnT and hs-TnI. Methods: Here, we present a preliminary analysis of the first 59 patients included in our ongoing prospective clinical trial (NCT05699915) during the first three months of treatment. All patients underwent electrocardiography and echocardiography along with blood sampling at standardized time intervals. This study aimed to investigate the incidence of elevated hs-TnT levels within the first three months of ICI treatment. Elevations were defined as hs-TnT above the upper limit of normal (ULN) if the baseline value was normal, or 1.5 ≥ times baseline if the baseline value was above the ULN. Conclusions: Hs-TnT elevations occurred in 10.6% of the patients. However, no significant changes were found on 3D echocardiography, nor did any of the patients develop a CV event. There were also no changes found in NT-proBNP. The study is still ongoing, but these preliminary findings do not show a promising role for cardiac troponins nor for echocardiographic dynamics in the prediction of CV events during the early stages of ICI treatment.
Medicinal Plant Extracts against Cardiometabolic Risk Factors Associated with Obesity: Molecular Mechanisms and Therapeutic Targets
Authors: Gutiérrez-Cuevas Jorge , López-Cifuentes Daniel , Sandoval-Rodriguez Ana , García-Bañuelos Jesús , Armendariz-Borunda Juan
Published: July 2024

Obesity has increasingly become a worldwide epidemic, as demonstrated by epidemiological and clinical studies. Obesity may lead to the development of a broad spectrum of cardiovascular diseases (CVDs), such as coronary heart disease, hypertension, heart failure, cerebrovascular disease, atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. In addition to hypertension, there are other cardiometabolic risk factors (CRFs) such as visceral adiposity, dyslipidemia, insulin resistance, diabetes, elevated levels of fibrinogen and C-reactive protein, and others, all of which increase the risk of CVD events. The mechanisms involved between obesity and CVD mainly include insulin resistance, oxidative stress, inflammation, and adipokine dysregulation, which cause maladaptive structural and functional alterations of the heart, particularly left-ventricular remodeling and diastolic dysfunction. Natural products of plants provide a diversity of nutrients and different bioactive compounds, including phenolics, flavonoids, terpenoids, carotenoids, anthocyanins, vitamins, minerals, fibers, and others, which possess a wide range of biological activities including antihypertensive, antilipidemic, antidiabetic, and other activities, thus conferring cardiometabolic benefits. In this review, we discuss the main therapeutic interventions using extracts from herbs and plants in preclinical and clinical trials with protective properties targeting CRFs. Molecular mechanisms and therapeutic targets of herb and plant extracts for the prevention and treatment of CRFs are also reviewed.
A First Metabolite Analysis of Norfolk Island Pine Resin and Its Hepatoprotective Potential to Alleviate Methotrexate (MTX)-Induced Hepatic Injury
Authors: Sweilam Sherouk Hussein , Ali Dalia E. , Atwa Ahmed M. , Elgindy Ali M. , Mustafa Aya M. , Esmail Manar M. , Alkabbani Mahmoud Abdelrahman , Senna Mohamed Magdy , El-Shiekh Riham A.
Published: July 2024

Drug-induced liver injury (DILI) represents a significant clinical challenge characterized by hepatic dysfunction following exposure to diverse medications. Methotrexate (MTX) is a cornerstone in treating various cancers and autoimmune disorders. However, the clinical utility of MTX is overshadowed by its ability to induce hepatotoxicity. The current study aims to elucidate the hepatoprotective effect of the alcoholic extract of Egyptian Araucaria heterophylla resin (AHR) on MTX-induced liver injury in rats. AHR (100 and 200 mg/kg) significantly decreased hepatic markers (AST, ALT, and ALP), accompanied by an elevation in the antioxidant’s markers (SOD, HO-1, and NQO1). AHR extract also significantly inhibited the TGF-β/NF-κB signaling pathway as well as the downstream cascade (IL-6, JAK, STAT-3, and cyclin D). The extract significantly reduced the expression of VEGF and p38 with an elevation in the BCL2 levels, in addition to a significant decrease in the IL-1β and TNF-α levels, with a prominent effect at a high dose (200 mg/kg). Using LC-HRMS/MS analysis, a total of 43 metabolites were tentatively identified, and diterpenes were the major class. This study presents AHR as a promising hepatoprotective agent through inhibition of the TGF-β/NF-κB and JAK/STAT3 pathways, besides its antioxidant and anti-inflammatory effects.
Strong Early Impact of Letrozole on Ovulation Induction Outperforms Clomiphene Citrate in Polycystic Ovary Syndrome
Authors: Vajna Rita Zsuzsanna , Géczi András Mihály , Meznerics Fanni Adél , Ács Nándor , Hegyi Péter , Feig Emma Zoé , Fehérvári Péter , Kiss-Dala Szilvia , Várbíró Szabolcs , Hetthessy Judit Réka , Sára Levente
Published: July 2024

Polycystic ovary syndrome is a common endocrine disorder, characterized by hyperandrogenism and/or chronic oligo/anovulation, which leads to infertility. The aim of this systematic review and meta-analysis was to explore the efficacy of letrozole compared with clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome. The study protocol has been registered with PROSPERO (registration number CRD42022376611). The literature search included randomized clinical trials. We conducted our systematic literature search across three medical databases: MEDLINE (via PubMed), Cochrane Library (CENTRAL), and Embase. The data synthesis employed a random effects model. Out of the 1994 articles screened, 25 studies fulfilled the inclusion criteria. The letrozole group exhibited a significant increase in endometrial thickness (mean difference = 1.70, confidence interval: 0.55–2.86; I2 = 97%, p-value = 0.008). The odds of ovulation (odds ratio = 1.8, confidence interval: 1.21–2.69; I2 = 51%, p-value = 0.010) and pregnancy (odds ratio = 1.96, confidence interval: 1.37–2.81; I2 = 32%, p-value = 0.002) were significantly higher. The resistance index of the subendometrial arteries showed a significant decrease (mean difference = −0.15, confidence interval: −0.27 to −0.04; I2 = 92%, p-value = 0.030). Women diagnosed with polycystic ovarian syndrome and treated with letrozole for ovulation induction had increased ovulation and pregnancy rates and increased endometrial thickness. The lower resistance index of subendometrial arteries can enhance intrauterine circulation, creating more favorable conditions for embryo implantation and development.
A Review of Therapeutic Agents Given by Convection-Enhanced Delivery for Adult Glioblastoma
Authors: Rolfe Nathaniel , Dadario Nicholas , Canoll Peter , Bruce Jeffrey
Published: July 2024

Glioblastoma remains a devastating disease with a bleak prognosis despite continued research and numerous clinical trials. Convection-enhanced delivery offers researchers and clinicians a platform to bypass the blood–brain barrier and administer drugs directly to the brain parenchyma. While not without significant technological challenges, convection-enhanced delivery theoretically allows for a wide range of therapeutic agents to be delivered to the tumoral space while preventing systemic toxicities. This article provides a comprehensive review of the antitumor agents studied in clinical trials of convection-enhanced delivery to treat adult high-grade gliomas. Agents are grouped by classes, and preclinical evidence for these agents is summarized, as is a brief description of their mechanism of action. The strengths and weaknesses of each clinical trial are also outlined. By doing so, the difficulty of untangling the efficacy of a drug from the technological challenges of convection-enhanced delivery is highlighted. Finally, this article provides a focused review of some therapeutics that might stand to benefit from future clinical trials for glioblastoma using convection-enhanced delivery.
A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Effectiveness and Safety of Melatonin and Three Formulations of Floraworks Proprietary TruCBN™ for Improving Sleep
Authors: Kolobaric Antonija , Saleska Jessica , Hewlings Susan J. , Bryant Corey , Colwell Christopher S. , D’Adamo Christopher R. , Chen Jeff , Pauli Emily K.
Published: July 2024

The phytocannabinoid cannabinol (CBN) has a potential mechanism of action as an alternative sleep aid but there is minimal evidence to support its effectiveness. The aim of this randomized, double-blind, placebo-controlled study was to assess the safety and effects of three formulations of a hemp-derived CBN sleep aid, TruCBN™ [25 mg (n = 206), 50 mg (n = 205), 100 mg (n = 203)], on sleep quality (PROMIS Sleep Disturbance 8A), relative to placebo (n = 204). The effectiveness and safety of these formulations relative to 4 mg of melatonin (n = 202) was assessed. Exploratory measures were stress (PROMIS Stress 4A), anxiety (Anxiety 4A), pain (PROMIS™ PEG), and well-being (WHO 5). All groups and the 4 mg melatonin group experienced significant improvement in sleep quality relative to the placebo group with no significant differences between any group and the melatonin group. Participants taking 100 mg showed a larger decrease in stress compared to the placebo group. There were no significant differences in anxiety, pain, well-being, or the frequency of side effects between any group and the placebo group. There was no significant difference in improvements in sleep quality between any of the treatment groups and the 4 mg melatonin group. Orally ingested CBN, at 25 mg, 50 mg, and 100 mg, is a safe and effective alternative for the improvement of sleep.
pH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy
Authors: Eissa Essam M. , El Sisi Amani M. , Bekhet Marina A. , El-Ela Fatma I. Abo , Kharshoum Rasha M. , Ali Adel A. , Alrobaian Majed , Ali Ahmed M. Abdelhaleem
Published: July 2024

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box–Behnken layout. Optimization of composition parameters used to fabricate desired NVMs’ physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of −28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.
Differential Interactions of Flavonoids with the Aryl Hydrocarbon Receptor In Silico and Their Impact on Receptor Activity In Vitro
Authors: Santana Monique Reis de , Santos Ylanna Bonfim dos , Santos Késsia Souza , Santos Junior Manoelito Coelho , Victor Mauricio Moraes , Ramos Gabriel dos Santos , Nascimento Ravena Pereira do , Costa Silvia Lima
Published: July 2024

The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR’s activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin’s newly described antagonistic potential. It underscores the importance of understanding flavonoid’s molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules.
Development of a Novel, Easy-to-Prepare, and Potentially Valuable Peptide Coupling Technology Utilizing Amide Acid as a Linker
Authors: Wang Yaling , Yang Fan , Li Hongyan
Published: July 2024

The process of synthesizing radionuclide-coupled drugs, especially shutdown technology that links bipotent chelators with biomolecules, utilizes traditional coupling reactions, including emerging click chemistry; these reactions involve different drawbacks, such as complex and cumbersome reaction steps, long reaction times, and the use of catalysts at various pH values, which can negatively impact the effects of the chelating agent. To address the above problems in this study, This research designed a novel bipotent chelator coupled with peptides. In the present study, dichloromethane was used as a solvent, and the reaction was conducted at room temperature for 12 h. A one-step ring-opening method was employed to introduce the coupling functional group of tridentate amide acid. The coupling materials consisted of the amino active site of the peptide and diethylene glycol anhydride. In this paper, this study explored the reactions between different equivalents of acid anhydride coupled to the peptide (peptide sequence: HLRKLRKR) and determined that the maximum conversion of the peptide feedstock was 87%. To determine the selectivity of the reaction sites in this polypeptide, This study identified the peptide sequence at the reaction site using nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry (LC-MS). For the selected peptide, the first reactive site was on the terminal amino group, followed by the amino group on the tetra- and hepta-lysine side chains. The tridentate amic acid framework functions as a chelating agent, capable of binding a range of lanthanide ions. This significantly reduces and optimizes the time and cost associated with synthesizing radionuclide-coupled drugs.
Therapeutic Efficacy of Helianthemum lippii Extract and Silver Nanoparticles Synthesized from the Extract against Cadmium-Induced Renal Nephrotoxicity in Wistar Rats
Authors: Laib Ibtissam , Ali Boutlilis Djahra , Alsalme Ali , Cornu David , Bechelany Mikhael , Barhoum Ahmed
Published: July 2024

This study explored the therapeutic efficacy of Helianthemum lippii and silver nanoparticles (Ag NPs) synthesized using a H. lippii extract to alleviate cadmium-induced nephrotoxicity in Wistar rats. Sub-acute toxicity assessments of H. lippii (100 mg/kg, 1000 mg/kg, and 4000 mg/kg) and Ag NPs (2 mg/kg and 10 mg/kg) did not find any significant difference, compared with untreated control rats (n = 3 animals/group). Then, the adult Wistar rats were divided into one control (untreated/unexposed) and six experimental groups (n = 5/group): Ag NPs alone, H. lippii alone, exposure to 50 mg/kg CdCl2 in drinking water for 35 days, exposure to CdCl2 for 35 days followed by treatment with 0.1 mg/kg/day Ag NPs (intraperitoneal injection) and/or 100 mg/kg/day H. lippii by gavage for 15 days. In the CdCl2-exposed group, body weight decreased; urea, creatinine, and uric acid concentrations increased (p < 0.05 vs. control), indicative of nephrotoxicity, antioxidant defenses (SOD, GSH, and CAT) were reduced, and malondialdehyde concentration increased. Moreover, the kidney’s architecture in CdCl2-exposed rats was altered: fibrosis, inflammatory cell infiltration, glomerular destruction, and tubular dilatation. Treatment with H. lippii and/or Ag NPs after CdCl2 exposure improved some of the renal function and architecture alterations induced by CdCl2, and also increased body weight. This study underscores the potential therapeutic applications of H. lippii and Ag NPs to decrease oxidative stress and promote xenobiotic detoxification, in line with the growing emphasis on environmentally conscious practices in scientific research and healthcare.
Kynurenines and Inflammation: A Remarkable Axis for Multiple Sclerosis Treatment
Authors: Carrillo-Mora Paul , Landa-Solís Carlos , Valle-Garcia David , Luna-Angulo Alexandra , Avilés-Arnaut Hamlet , Robles-Bañuelos Benjamín , Sánchez-Chapul Laura , Rangel-López Edgar
Published: July 2024

Multiple sclerosis (MS) is a chronic inflammatory autoimmune neurological disease characterized by the recurrent appearance of demyelinating lesions and progressive disability. Currently, there are multiple disease-modifying treatments, however, there is a significant need to develop new therapeutic targets, especially for the progressive forms of the disease. This review article provides an overview of the most recent studies aimed at understanding the inflammatory processes that are activated in response to the accumulation of kynurenine pathway (KP) metabolites, which exacerbate an imbalance between immune system cells (e.g., Th1, Th2, and T reg) and promote the release of pro-inflammatory interleukins that modulate different mechanisms: membrane-receptors function; nuclear factors expression; and cellular signals. Together, these alterations trigger cell death mechanisms in brain cells and promote neuron loss and axon demyelination. This hypothesis could represent a remarkable approach for disease-modifying therapies for MS. Here, we also provide a perspective on the repositioning of some already approved drugs involved in other signaling pathways, which could represent new therapeutic strategies for MS treatment.
Lycopene and Garcinia cambogia Induce White-to-Brown Adipose Differentiation: An Innovative Strategy to Curb Obesity
Authors: Mannino Federica , Arcoraci Vincenzo , Vermiglio Giovanna , Labellarte Davide , Pirrotta Igor , Giorgi Domenico Antonio , Scarfone Alessandro , Bitto Alessandra , Minutoli Letteria , Vaccaro Mario , Galeano Mariarosaria , Pallio Giovanni , Irrera Natasha
Published: July 2024

Obesity is considered one of the main risk factors for cardiovascular diseases. The browning process has been recently recognized as a promising anti-obesity therapy. Lycopene (LYC) and Garcinia cambogia fruit extract (GE) might be important resources for anti-obesity drugs; therefore, the aim of this study was to investigate the anti-obesity effects of LYC and GE on 3T3-L1 adipocytes and Zucker rats. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes and then treated with LYC (0.5 μM), GE (30 mg/mL) or LYC + GE for 24 h. Moreover, male Zucker Crl:ZUC-Leprfa rats were randomly assigned to 5 groups of 10 animals to orally receive Vehicle (Ctrl), Orlistat (20 mg/kg), LYC (5 mg/kg), GE (1000 mg/kg) or LYC + GE for 28 days. LYC, GC extracts and even more LYC + GE stimulated the mRNA and protein expression of thermogenic genes UCP1, CIDEA and DIO2, significantly reduced lipid droplet size and increased lipid droplet number in adipocytes. UCP1 mRNA and protein expression was also increased in the visceral adipose tissue of the rats that received the dietary intake of LYC, GE and even more LYC + GE. Moreover, LYC + GE induced the reorganization of visceral fat depots that showed a great number of small adipocytes and a significant reduction in weight gain and food intake compared to the control group. The obtained results demonstrated that LYC + GE might be used as new approaches for obesity management in order to induce the browning process and achieve a metabolically active tissue instead of a tissue characterized by lipid depot accumulation.
Development of a Clonal and High-Yield Mammalian Cell Line for the Manufacturing of a Hyperactive Human DNase I with Extended Plasma Half-Life Using PASylation® Technology
Authors: Stamm Serge M. , Wagner Roland , Lang Dietmar A. , Skerra Arne , Gebauer Michaela
Published: July 2024

Cumulative evidence from several pre-clinical studies suggests that restoration of plasma DNase activity in a thrombo-inflammatory state may improve clinical outcomes. Following injury, hyperactivated immune cells release large amounts of granular proteins together with DNA, which often accumulate in the surrounding environment in so-called neutrophil extracellular traps (NETs). Degradation of excess NETs by systemic DNase administration offers a promising therapeutic approach to ameliorate inflammation and dissolve intravascular clots. In order to expand the therapeutic utility of human DNase I, a variant of the enzyme was developed that has both a prolonged systemic half-life and a higher catalytic activity compared to Dornase alfa (Pulmozyme®), the recombinant form of DNase I approved for inhaled therapy of cystic fibrosis. The hyperactive enzyme was “PASylated” by genetic fusion with a strongly hydrophilic and biodegradable PAS-polypeptide to increase its hydrodynamic volume and retard kidney filtration. A stable TurboCell™ CHO-K1-based cell line was generated which is suitable for the future production of PASylated DNase I according to good manufacturing practice (GMP). Furthermore, a robust bioprocess strategy was devised and an effective downstream process was developed. The final protein product is characterized by excellent purity, favorable physicochemical properties, a 14-fold higher DNA-degrading activity than Dornase alfa and a sustained pharmacokinetic profile, with a 22-fold slower clearance in rats.
Green Synthesis of Chitosan/Silver Nanoparticles Using Citrus paradisi Extract and Its Potential Anti-Cryptosporidiosis Effect
Authors: Alsulami Muslimah N. , El-Wakil Eman S.
Published: July 2024

Cryptosporidium parvum (C. parvum) is one of the most prevalent species infecting humans and animals. Currently, the only FDA-licensed drug to treat cryptosporidiosis is nitazoxanide (NTZ), with no efficacy in immunocompromised hosts. Citrus paradisi (C. paradisi) has demonstrated anti-protozoal activities. This study aimed to investigate the anti-cryptosporidiosis effect of C. paradisi peel extract, either alone or in mediating the green synthesis of chitosan silver nanoparticles (Cs/Ag NPs), compared to NTZ. Mice were sorted into nine different groups. The effectiveness of the treatments was evaluated using parasitology, histopathology, immunohistochemistry, and immunology. C. paradisi outperformed nitazoxanide regarding oocyst shedding (79% vs. 61%). The effectiveness of NTZ Cs/Ag NPs and Citrus Cs/Ag NPs was enhanced to 78% and 91%, respectively. The highest oocyst inhibition was obtained by combining NTZ and Citrus Cs/Ag NPs (96%). NF-κB, TNF-α, and Il-10 levels increased in response to infection and decreased in response to various treatments, with the highest reduction in the group treated with combined NTZ citrus Cs/Ag NPs. Combining C. paradisi with NTZ could have a synergistic effect, making it a potentially effective anti-cryptosporidiosis agent. Utilizing C. paradisi in the green synthesis of Cs/Ag NPs improves the therapeutic response and can be used to produce novel therapeutic antiparasitic drugs.
Inulin Amphiphilic Copolymer-Based Drug Delivery: Unraveling the Structural Features of Graft Constructs
Authors: Sardo Carla , Auriemma Giulia , Mazzacano Carmela , Conte Claudia , Piccolo Virgilio , Ciaglia Tania , Denel-Bobrowska Marta , Olejniczak Agnieszka B. , Fiore Donatella , Proto Maria Chiara , Gazzerro Patrizia , Aquino Rita Patrizia
Published: July 2024

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic “inulinated” analog of the “pegylated” PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation concentration (CAC), NMR, DLS, LDE, and SEM analyses, was conducted to elucidate the core/shell architecture of the carriers and in vitro cyto- and hemo-compatibility were assayed. The entrapment and in vitro delivery of sorafenib tosylate (ST) were also studied. INU-PLA copolymers exhibit distinctive features: (1) Crew-cut aggregates are formed with coronas of 2–4 nm; (2) a threshold surface density of 1 INU/nm2 triggers a configuration change; (3) INU surface density influences PLA core dynamics, with hydrophilic segment stretching affecting PLA distribution towards the interface. INU-PLA2NPs demonstrated an outstanding loading of ST and excellent biological profile, with effective internalization and ST delivery to HepG2 cells, yielding a comparable IC50.
Recent Progress in Multifunctional Stimuli-Responsive Combinational Drug Delivery Systems for the Treatment of Biofilm-Forming Bacterial Infections
Authors: MubarakAli Davoodbasha , Saravanakumar Kandasamy , Ganeshalingam Archchana , Santosh Sugavaneswaran Siva , De Silva Shanali , Park Jung Up , Lee Chang-Min , Cho Su-Hyeon , Kim Song-Rae , Cho Namki , Thiripuranathar Gobika , Park SeonJu
Published: July 2024

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0–5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.
Physicochemical Stability of Doravirine (Pifeltro®): Characterization of Main Degradation Products and Assessment of Stability of Tablets Repackaged in Single-Dose Unit Containers
Authors: Houssen Moïse , Secretan Philippe-Henri , Nobilet Loup , Jossot Kilian , Guichard Laura , Mwamba Cédric , Ngy David , Hassani Lamia , Solgadi Audrey , Antignac Marie , Do Bernard , Junot Helga , Sadou Yayé Hassane
Published: July 2024

Doravarine (DOR) is an antiviral drug with a marketed authorization for the management of occupational blood and body fluid exposure. The currently existing packaging, consisting of multiple unit bottles comprising 30 tablets, is not fully appropriate for daily nominative dispensing at the hospital. This study aims at assessing the impact of the change in packaging on the key attributes of the drug: assay, impurity profile, and dissolution. As the first step, which is not fully depicted in the literature, the main potential impurities that could appear during storage (i.e., degradation products (DPs) of DOR) were characterized using a forced degradation protocol followed by an LC-MS/MS analysis. These results paved the way for in silico toxicological assessment and targeted degradation product profiling. Based on this study, the assessment of the implication of repackaging on the formation of DOR’s degradation products should be a primary focus.
Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically-Based Pharmacokinetics, and First-Principles Models
Authors: Arav Yehuda
Published: July 2024

Oral drug absorption is the primary route for drug administration. However, this process hinges on multiple factors, including the drug’s physicochemical properties, formulation characteristics, and gastrointestinal physiology. Given its intricacy and the exorbitant costs associated with experimentation, the trial-and-error method proves prohibitively expensive. Theoretical models have emerged as a cost-effective alternative by assimilating data from diverse experiments and theoretical considerations. These models fall into three categories: (i) data-driven models, encompassing classical pharmacokinetics, quantitative-structure models (QSAR), and machine/deep learning; (ii) mechanism-based models, which include quasi-equilibrium, steady-state, and physiologically-based pharmacokinetics models; and (iii) first principles models, including molecular dynamics and continuum models. This review provides an overview of recent modeling endeavors across these categories while evaluating their respective advantages and limitations. Additionally, a primer on partial differential equations and their numerical solutions is included in the appendix, recognizing their utility in modeling physiological systems despite their mathematical complexity limiting widespread application in this field.