bluuebunny/crossref_metadata_2025 huggingface dataset:
High Fat, High Sugar Diet and DJOS Bariatric Surgery Influence Plasma Levels of Fetuin-B, Growth Differentiation Factor-15, and Pentraxin 3 in Diet-Induced Obese Sprague–Dawley Rats
Authors: Poloczek Jakub , Tarnawska Monika , Chełmecka Elżbieta , Łaszczyca Piotr , Gumprecht Janusz , Stygar Dominika
Published: October 2021

The liver plays a central role in glucose and fatty acid metabolism and acts as an endocrine organ that secretes hepatokines with diverse systemic effects. The study aimed to examine the influence of duodenojejunal omega switch (DJOS) bariatric surgery in combination with different diets on glucose administration parameters and hepatokines levels. After 8 weeks on high fat, high sugar diet (HFS) or control diets (CD), Sprague–Dawley rats underwent DJOS or SHAM (control) surgery. For the next 8 weeks after the surgery, half of DJOS and SHAM-operated animals were kept on the same diet as before, and half had a diet change. The oral glucose tolerance test (OGTT) was performed three times: 8 weeks before and 4 and 8 weeks after surgery. Fetuin-B, growth differentiation factor-15 (GDF-15), pentraxin 3 (PTX3) plasma levels were analyzed. DJOS surgery had a beneficial effect on oral glucose tolerance test (OGTT) results and the area under the curve (AUCOGTT). The OGTT results depended on the time elapsed after the surgery, the type of diet used, the surgery performed, and the interaction between these factors. DJOS bariatric surgery reduced fetuin-B and GDF15 plasma levels. Interaction between the type of surgery performed and diet used influenced the fetuin-B and PTX-3 plasma levels. A dietary regime is essential to achieve therapeutic and clinical goals after bariatric surgery.
Educational Intervention of Healthy Life Promotion for Children with a Migrant Background or at Socioeconomic Disadvantage in the North of Italy: Efficacy of Telematic Tools in Improving Nutritional and Physical Activity Knowledge
Authors: Franceschi Roberto , Fornari Elena , Ghezzi Monica , Buzzi Eleonora , Toschi Margherita , Longhi Silvia , Maimone Rosa , Forti Stefano , Carneri Sara , Pirous Fateh Moghadam , Agostini Beatrice , Iori Tommaso , Gibin Marta , Porchia Stefania , Soffiati Massimo , Maffeis Claudio
Published: October 2021

The aim of the “Smuovi La Salute” (“Shake Your Health”) project was to implement an integrated and comprehensive model to prevent and treat overweight and obesity in low socioeconomic status (SES) and minority groups living in three different districts in the north of Italy. An app and a cookbook promoting transcultural nutrition and a healthy lifestyle were developed, and no-cost physical activities were organized. Healthy lifestyle teaching was implemented in 30 primary school classrooms. Learning was assessed through pre- and post-intervention questionnaires. At the Obesity Pediatric Clinic, overweight and obese children of migrant background or low SES were trained on transcultural nutrition and invited to participate in the project. Primary school students increased their knowledge about healthy nutrition and the importance of physical activity (p-value < 0.001). At the Obesity Pediatric Clinic, after 6 months, pre–post-intervention variation in their consumption of vegetables and fruit was +14% (p < 0.0001) and no variation in physical activity habits occurred (p = 0.34). In this group, the BMI z-score was not significantly decreased (−0.17 ± 0.63, p= 0.15). This study demonstrates the feasibility and efficacy of telematic tools and targeted community approaches in improving students’ knowledge with regard to healthy lifestyle, particularly in schools in suburbs with a high density of migrants and SES families. Comprehensive and integrated approaches provided to the obese patients remain mostly ineffective.
Appetite and Satiety Control—Contribution of Gut Mechanisms
Authors: Feinle-Bisset Christine , Horowitz Michael
Published: October 2021

The prevalence of obesity, and its comorbidities, particularly type 2 diabetes, cardiovascular and hepatic disease and certain cancers, continues to rise at an alarming rate worldwide [...]
A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects
Authors: Mertowska Paulina , Mertowski Sebastian , Wojnicka Julia , Korona-Głowniak Izabela , Grywalska Ewelina , Błażewicz Anna , Załuska Wojciech
Published: October 2021

Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient’s microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.
Insulin/IGF-1 Signaling Is Downregulated in Barrett’s Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial
Authors: Arcidiacono Diletta , Zaramella Alice , Fabris Federico , Sánchez-Rodríguez Ricardo , Nucci Daniele , Fassan Matteo , Nardi Mariateresa , Benna Clara , Cristofori Chiara , Morbin Tiziana , Pucciarelli Salvatore , Fantin Alberto , Realdon Stefano
Published: October 2021

Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett’s esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.
Structural and Functional Aspects of Ebola Virus Proteins
Authors: Jain Sahil , Martynova Ekaterina , Rizvanov Albert , Khaiboullina Svetlana , Baranwal Manoj
Published: October 2021

Ebola virus (EBOV), member of genus Ebolavirus, family Filoviridae, have a non-segmented, single-stranded RNA that contains seven genes: (a) nucleoprotein (NP), (b) viral protein 35 (VP35), (c) VP40, (d) glycoprotein (GP), (e) VP30, (f) VP24, and (g) RNA polymerase (L). All genes encode for one protein each except GP, producing three pre-proteins due to the transcriptional editing. These pre-proteins are translated into four products, namely: (a) soluble secreted glycoprotein (sGP), (b) Δ-peptide, (c) full-length transmembrane spike glycoprotein (GP), and (d) soluble small secreted glycoprotein (ssGP). Further, shed GP is released from infected cells due to cleavage of GP by tumor necrosis factor α-converting enzyme (TACE). This review presents a detailed discussion on various functional aspects of all EBOV proteins and their residues. An introduction to ebolaviruses and their life cycle is also provided for clarity of the available analysis. We believe that this review will help understand the roles played by different EBOV proteins in the pathogenesis of the disease. It will help in targeting significant protein residues for therapeutic and multi-protein/peptide vaccine development.
Seroreactivity to Coxiella burnetii in an Agricultural Population and Prevalence of Coxiella burnetii Infection in Ticks of a Non-Endemic Region for Q Fever in South Korea
Authors: Yoo Jeong-Rae , Kim Mi-Sun , Heo Sang-Taek , Oh Hyun-Joo , Oh Jung-Hwan , Ko Seo-Young , Kang Jeong-Ho , Lee Sung-Kgun , Jeong Woo-Seong , Seong Gil-Myeong , Lee Hyun-Jung , Kang Chul-Hoo , Moon Ji-Hyun , Lee Keun-Hwa , Song Sung-Wook
Published: October 2021

Coxiella burnetii infects humans and wild and domesticated animals. Although reported cases on Jeju Island, off the coast of South Korea, are rare, the region is considered to have a high potential for Q fever. We investigated the seroprevalence of antibodies to C. burnetii in 230 farmers living in ten rural areas on Jeju Island between January 2015 and December 2019. Blood samples were collected and examined for C. burnetii Phase I/II IgM and IgG antibodies. Trained researchers collected ticks from rural areas. Clone XCP-1 16S ribosomal RNA gene sequencing was performed to identify Coxiella species from the collected ticks. The overall seroprevalence of antibodies to C. burnetii in farmers was 35.7%. The seroprevalence was significantly higher in fruit farmers. Of the collected ticks, 5.4% (19/351) of the Haemaphysalis longicornis ticks harbored C. burnetti. A high seroprevalence of antibodies to C. burnetii was observed in this region of Jeju Island, confirming that C. burnetti is endemic. Physicians should thus consider Q fever in the differential diagnosis of patients that present with acute fever after participating in outdoor activities.
Low Prevalence of HEV Infection and No Associated Risk of HEV Transmission from Mother to Child among Pregnant Women in Vietnam
Authors: Huy Pham Xuan , Chung Dang Thanh , Linh Dang Thuy , Hang Ngo Thu , Rachakonda Sivaramakrishna , Pallerla Srinivas Reddy , Linh Le Thi Kieu , Tong Hoang Van , Dung Le Minh , Mao Can Van , Wedemeyer Heiner , Bock C-Thomas , Kremsner Peter G. , Song Le Huu , Sy Bui Tien , Toan Nguyen Linh , Velavan Thirumalaisamy P.
Published: October 2021

Infections with HEV in low- and middle-income countries (LMICs) are associated with increased rates of preterm birth, miscarriage, and stillbirth. The aim of the present study was to investigate HEV infections in pregnant women and the possibility of mother-to-child transmission, and associated outcomes. A total of 183 pregnant women in their third trimester were recruited and followed until delivery. Anti-HEV IgG and IgM were determined via enzyme-linked immunosorbent assay (ELISA), and HEV nucleic acids were detected in stool and cord blood samples. HEV genotypes were identified by Sanger sequencing, and phylogenetic analyses were performed. Mother-to-child transmission and associated adverse outcomes were not observed. Only 2% of patients (n = 4/183) tested positive for anti-HEV IgM, and 8% (n = 14/183) tested positive for anti-HEV IgG antibodies. Cord blood (n = 150) analysis showed that there was no IgM detected, while 4% (n = 6/150) tested positive for anti-HEV IgG, which was consistent with mothers testing positive for anti-HEV IgG. Nucleic acid tests for HEV RNA yielded 2% (n = 4/183) from the serum and stool of pregnant women, and none from cord blood. The HEV isolates belonged to the genotype HEV-3a, with 99% homology with humans and 96% with pigs. No association was found between the risk of HEV infection and pregnancy outcomes or HEV transmission from mother to child. HEV-3 infections of zoonotic origin in pregnancy might have eventually resolved without complications.
Pediatric Chronic Migraine Severity and Maternal Stress
Authors: Smirni Daniela , Carotenuto Marco
Published: October 2021

Primary headache is an increasing phenomenon in pediatric age, and very often, it causes disabling limitations in children’s daily activities, negatively affecting family well-being. There are conflicting data in the literature on the impact of children’s migraines on parental experienced stress. This study aimed to evaluate maternal stress in a sample of school-aged children with a migraine without aura (MwoA) and its correlation with migraine intensity and frequency. A total of 474 mothers aged between 31 and 55 participated in the study: 237 were mothers of children with MwoA, and 237 were mothers of typical developing children. All participants were administered the Parent Stress Index-Short Form (PSI-SF) for the assessment of parental stress; the Pediatric Migraine Disability Assessment (PedMIDAS) was administered to children with MwoA to assess the presence of a related disability migraine. The results showed a significantly higher rate of stress in mothers of MwoA children (p < 0.001) in all the domains explored by the PSI-SF and a statistically significant correlation between the maternal stress total score and the intensity and frequency of migraine attacks (p < 0.0001). This study highlights the need for the holistic contribution of the family to be considered in the clinical management of pediatric migraines.
SARS-CoV-2 Fears Green: The Chlorophyll Catabolite Pheophorbide A Is a Potent Antiviral
Authors: Jimenez-Aleman Guillermo H. , Castro Victoria , Londaitsbehere Addis , Gutierrez-Rodríguez Marta , Garaigorta Urtzi , Solano Roberto , Gastaminza Pablo
Published: October 2021

SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against COVID-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here, we exploited the enormous potential of plant metabolism using the bryophyte Marchantia polymorpha L. and identified a potent SARS-CoV-2 antiviral, following a bioactivity-guided fractionation and mass-spectrometry approach. We found that the chlorophyll derivative Pheophorbide a (PheoA), a porphyrin compound similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2, preventing infection of cultured monkey and human cells, without noticeable cytotoxicity. We also show that PheoA targets the viral particle, interfering with its infectivity in a dose- and time-dependent manner. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against enveloped RNA viral pathogens such as HCV, West Nile, and other coronaviruses. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, which together with its previous use in photoactivable cancer therapy in humans, suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.
Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy
Authors: Lee Dong-Hee , Choi Seunghyun , Park Yoon , Jin Hyung-seung
Published: October 2021

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.
The Impact of SARS-CoV-2 Infection, and Application of Immunosuppressive Agents in Kidney Transplant Recipients Suffering from COVID-19
Authors: Tseng Horng-Ta , Wu Xiang-Chi , Huang Chun-Yao , Shih Chun-Ming , Lin Yi-Wen , Lin Feng-Yen
Published: October 2021

In December 2019, the COVID-19 pandemic began to ravage the world quickly, causing unprecedented losses in human life and the economy. A statistical study revealed that the proportion of solid organ transplant (SOT) recipients with severe symptoms and deaths after being infected by SARS-CoV-2 is considerably higher than that of non-SOT recipients, and the prognosis is relatively poor. In addition, the clinical manifestation of SOT recipients suffering from COVID-19 is different from that of general COVID-19 patients. Acute kidney injury (AKI) is a common complication in COVID-19 patients, and it is likely more common among SOT recipients infected with SARS-CoV-2. Clinical experts consider that SOT recipients have long-term treatment with immunosuppressants, and the comorbidities are driven by a high rate of severe symptoms and mortality. Orthotopic kidney allograft transplantation is an effective treatment for patients suffering from end-stage kidney disease/kidney failure through which they can easily extend their life. Indeed, kidney transplant recipients have suffered significant damage during this pandemic. To effectively reduce the severity of symptoms and mortality of kidney transplant recipients suffering from COVID-19, precise application of various drugs, particularly immunosuppressants, is necessary. Therefore, herein, we will collate the current clinical experience of treating COVID-19 infection in kidney transplant recipients and discuss the adjustment of patients using immunosuppressive agents in the face of COVID-19.
Anticandidal Potential of Two Cyanobacteria-Synthesized Silver Nanoparticles: Effects on Growth, Cell Morphology, and Key Virulence Attributes of Candida albicans
Authors: Hamida Reham Samir , Ali Mohamed Abdelaal , Goda Doaa A. , Redhwan Alya
Published: October 2021

Candida albicans is an opportunistic human fungal pathogen responsible for 90–100% of mucosal and nosocomial infections worldwide. The emergence of drug-resistant strains has resulted in adverse consequences for human health, including numerous deaths. Consequently, there is an urgent need to identify and develop new antimicrobial drugs to counter these effects. Antimicrobial nanoagents have shown potent inhibitory activity against a number of pathogens through targeting their defense systems, such as biofilm formation. Here, we investigated the anticandidal activity of silver nanoparticles biosynthesized by the cyanobacterial strains Desertifilum sp. IPPAS B-1220 and Nostoc Bahar_M (D-SNPs and N-SNPs, respectively), along with that of silver nitrate (AgNO3), and examined the mechanisms underlying their lethal effects. For this, we performed agar well diffusion and enzyme activity assays (lactate dehydrogenase, adenosine triphosphatase, glutathione peroxidase, and catalase) and undertook morphological examinations using transmission electron microscopy. The effects of the three treatments on Hwp1 and CDR1 gene expression and protein patterns were assessed using qRT-PCR and SDS–PAGE assays, respectively. All of the three treatments inhibited C. albicans growth; disrupted membrane integrity, metabolic function, and antioxidant activity; induced ultrastructural changes in the cell envelope; and disrupted cytoplasmic and nuclear contents. Of the three agents, D-SNPs showed the greatest biocidal activity against C. albicans. Additionally, the D-SNP treatment significantly reduced the gene expression of Hwp1 and CDR1, suggestive of negative effects on biofilm formation ability and resistance potential of C. albicans, and promoted protein degradation. The mechanism involved in the biocidal effects of both D-SNPs and N-SNPs against C. albicans could be attributed to their ability to interfere with fungal cell structures and/or stimulate oxidative stress, enabling them to be used as a robust antimycotic agent.
Sonazoid-Conjugated Natural Killer Cells for Tumor Therapy and Real-Time Visualization by Ultrasound Imaging
Authors: Song Hyeong-Woo , Lee Han-Sol , Kim Seok-Jae , Kim Ho Yong , Choi You Hee , Kang Byungjeon , Kim Chang-Sei , Park Jong-Oh , Choi Eunpyo
Published: October 2021

Various cell therapy strategies, including chimeric antigen receptor-expressing T or natural killer (NK) cells and cell-mediated drug delivery, have been developed for tumor eradication. However, the efficiency of these strategies against solid tumors remains unclear. We hypothesized that real-time control and visualization of therapeutic cells, such as NK cells, would improve their therapeutic efficacy against solid tumors. In this study, we engineered Sonazoid microbubble-conjugated NK (NK_Sona) cells and demonstrated that they were detectable by ultrasound imaging in real-time and maintained their functions. The Sonazoid microbubbles on the cell membrane did not affect the cytotoxicity and viability of the NK cells in vitro. Additionally, the NK_Sona cells could be visualized by ultrasound imaging and inhibited tumor growth in vivo. Taken together, our findings demonstrate the feasibility of this new approach in the use of therapeutic cells, such as NK cells, against solid tumors.
3D-Printed Mucoadhesive Collagen Scaffolds as a Local Tetrahydrocurcumin Delivery System
Authors: Andonegi Mireia , Carranza Teresa , Etxabide Alaitz , de la Caba Koro , Guerrero Pedro
Published: October 2021

Native collagen doughs were processed using a syringe-based extrusion 3D printer to obtain collagen scaffolds. Before processing, the rheological properties of the doughs were analyzed to determine the optimal 3D printing conditions. Samples showed a high shear-thinning behavior, reported beneficial in the 3D printing process. In addition, tetrahydrocurcumin (THC) was incorporated into the dough formulation and its effect on collagen structure, as well as the resulting scaffold’s suitability for wound healing applications, were assessed. The denaturation peak observed by differential scanning calorimetry (DSC), along with the images of the scaffolds’ surfaces assessed using scanning electron microscopy (SEM), showed that the fibrillar structure of collagen was maintained. These outcomes were correlated with X-ray diffraction (XRD) results, which showed an increase of the lateral packaging of collagen chains was observed in the samples with a THC content up to 4%, while a higher content of THC considerably decreased the structural order of collagen. Furthermore, physical interactions between collagen and THC molecules were observed using Fourier transform infrared (FTIR) spectroscopy. Additionally, all samples showed swelling and a controlled release of THC. These results along with the mucoadhesive properties of collagen suggested the potential of these THC–collagen scaffolds as sustained THC delivery systems.
Development of Lactoferrin-Loaded Liposomes for the Management of Dry Eye Disease and Ocular Inflammation
Authors: López-Machado Ana , Díaz-Garrido Natalia , Cano Amanda , Espina Marta , Badia Josefa , Baldomà Laura , Calpena Ana Cristina , Souto Eliana B. , García María Luisa , Sánchez-López Elena
Published: October 2021

Dry eye disease (DED) is a high prevalent multifactorial disease characterized by a lack of homeostasis of the tear film which causes ocular surface inflammation, soreness, and visual disturbance. Conventional ophthalmic treatments present limitations such as low bioavailability and side effects. Lactoferrin (LF) constitutes a promising therapeutic tool, but its poor aqueous stability and high nasolacrimal duct drainage hinder its potential efficacy. In this study, we incorporate lactoferrin into hyaluronic acid coated liposomes by the lipid film method, followed by high pressure homogenization. Pharmacokinetic and pharmacodynamic profiles were evaluated in vitro and ex vivo. Cytotoxicity and ocular tolerance were assayed both in vitro and in vivo using New Zealand rabbits, as well as dry eye and anti-inflammatory treatments. LF loaded liposomes showed an average size of 90 nm, monomodal population, positive surface charge and a high molecular weight protein encapsulation of 53%. Biopharmaceutical behaviour was enhanced by the nanocarrier, and any cytotoxic effect was studied in human corneal epithelial cells. Developed liposomes revealed the ability to reverse dry eye symptoms and possess anti-inflammatory efficacy, without inducing ocular irritation. Hence, lactoferrin loaded liposomes could offer an innovative nanotechnological tool as suitable approach in the treatment of DED.
Molecular Epidemiology, Antimicrobial Surveillance, and PK/PD Analysis to Guide the Treatment of Neisseria gonorrhoeae Infections
Authors: Alonso Rodrigo , Rodríguez-Achaerandio Ainara , Aguirre-Quiñonero Amaia , Artetxe Aitor , Martínez-Ballesteros Ilargi , Rodríguez-Gascón Alicia , Garaizar Javier , Canut Andrés
Published: October 2021

The aim of this study was to apply molecular epidemiology, antimicrobial surveillance, and PK/PD analysis to guide the antimicrobial treatment of gonococci infections in a region of the north of Spain. Antibiotic susceptibility testing was performed on all isolates (2017 to 2019, n = 202). A subset of 35 isolates intermediate or resistant to at least two antimicrobials were selected to search for resistance genes and genotyping through WGS. By Monte Carlo simulation, we estimated the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the antimicrobials used to treat gonorrhea, both indicative of the probability of treatment success. In total, 2.0%, 6.4%, 5.4%, and 48.2% of the isolates were resistant to ceftriaxone, cefixime, azithromycin, and ciprofloxacin, respectively. Twenty sequence types were identified. Detected mutations were related to antibiotic resistance. PK/PD analysis showed high probability of treatment success of the cephalosporins. In conclusion, multiple populations of N. gonorrhoeae were identified. We can confirm that ceftriaxone (even at the lowest dose: 250 mg) and oral cefixime are good candidates to treat gonorrhea. For patients allergic to cephalosporins, ciprofloxacin should be only used if the MIC is known and ≤0.125 mg/L; this antimicrobial is not recommended for empirical treatment.
Essential Oils of Melaleuca, Citrus, Cupressus, and Litsea for the Management of Infections Caused by Candida Species: A Systematic Review
Authors: Silva Rafael Alves da , Antonieti Flávia Maria Pinto Monteiro , Röder Denise Von Dolinger de Brito , Pedroso Reginaldo dos Santos
Published: October 2021

Candida is a common agent of infection in humans, which has a wide distribution and is a colonizer fungus of the body, occasionally assuming the role of a pathogen. The type of treatment depends on the site of infection and the clinical condition of the patient. Superficial infections, such as mucosal infections, can be treated with topical medications. So-called alternative therapies have rarely been studied, although the literature records the effectiveness of some treatments, especially as complementary therapy. The aims of this review were to analyze evidence of the anti-Candida inhibitory activity of essential oils of the Citrus, Cupressus, Litsea, and Melaleuca species; in addition to addressing the chemical composition, probable mechanisms of antifungal action and studies of toxicity, cytotoxicity, and genotoxicity were included. The literature from Medline/PubMed, Science Direct, Scopus, Web of Science, and the Brazilian database Periodic Capes was reviewed. Thirty-eight articles were selected, which included two articles on Litsea spp., seven on Cupressus spp., thirteen articles on Citrus spp., and twenty-one articles on Melaleuca spp. In conclusion, this study showed in vitro evidence for the use of essential oils of the plant species evaluated for the treatment of infections caused by different Candida species.
A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms
Authors: Gueche Yanis A. , Sanchez-Ballester Noelia M. , Bataille Bernard , Aubert Adrien , Rossi Jean-Christophe , Soulairol Ian
Published: October 2021

The aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature was evaluated individually, and it was revealed that this parameter was critical for printability, as a sufficiently high temperature (100 °C) is necessary to avoid curling. Secondly, the effects of laser power, scan speed, and layer thickness were determined using a Box–Behnken design. The measured responses, printing yield, height, weight, hardness, disintegration time, and percentage of drug release at 10 min showed the following ranges of values: 55.6–100%, 2.92–3.96 mm, 98.2–187.2 mg, 9.2–83.4 N, 9.7–997.7 s, and 25.8–99.9%, respectively. Analysis of variance (ANOVA) proved that the generated quadratic models and the effect of the three–process parameters were significant (p < 0.05). Yield improved at high laser power, low scan speed, and increased layer thickness. Height was proportional to laser power, and inversely proportional to scan speed and layer thickness. Variations in the other responses were related to the porosity of the SOFs, which were dependent on the value of energy density. Low laser power, fast scan speed, and high layer thickness values favored a lower energy density, resulting in low weight and hardness, rapid disintegration, and a high percentage of drug release at 10 min. Finally, an optimization was performed, and an additional experiment validated the model. In conclusion, by applying a Quality by Design approach, this study demonstrates that process parameters are critical for printability, but also offer a way to personalize the properties of the SOFs.
A Critical Overview of FDA and EMA Statistical Methods to Compare In Vitro Drug Dissolution Profiles of Pharmaceutical Products
Authors: Muselík Jan , Komersová Alena , Kubová Kateřina , Matzick Kevin , Skalická Barbora
Published: October 2021

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.
Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy
Authors: Yoshimoto Mitsuyoshi , Yoshii Yukie , Matsumoto Hiroki , Shinada Mitsuhiro , Takahashi Masashi , Igarashi Chika , Hihara Fukiko , Tachibana Tomoko , Doi Ayano , Higashi Tatsuya , Fujii Hirofumi , Washiyama Kohshin
Published: October 2021

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.
Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
Authors: Coombes Zoe , Plant Katie , Freire Cristina , Basit Abdul W. , Butler Philip , Conlan R. Steven , Gonzalez Deyarina
Published: October 2021

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.
Critical Drug Loss Induced by Silicone and Polyurethane Implantable Catheters in a Simulated Infusion Setup with Three Model Drugs
Authors: Tokhadzé Nicolas , Chennell Philip , Pereira Bruno , Mailhot-Jensen Bénédicte , Sautou Valérie
Published: October 2021

Silicone and polyurethane are biocompatible materials used for the manufacture of implantable catheters, but are known to induce drug loss by sorption, causing potentially important clinical consequences. Despite this, their impact on the drugs infused through them is rarely studied, or they are studied individually and not part of a complete infusion setup. The aim of this work was to experimentally investigate the drug loss that these devices can cause, on their own and within a complete infusion setup. Paracetamol, diazepam, and insulin were chosen as models to assess drug sorption. Four commonly used silicone and polyurethane catheters were studied independently and as part of two different setups composed of a syringe, an extension set, and silicone or polyurethane implantable catheter. Simulated infusion through the catheter alone or through the complete setup were tested, at flowrates of 1 mL/h and 10 mL/h. Drug concentrations were monitored by liquid chromatography, and the silicone and polyurethane materials were characterized by ATR-IR spectroscopy and Zeta surface potential measurements. The losses observed with the complete setups followed the same trend as the losses induced individually by the most sorptive device of the setup. With the complete setups, no loss of paracetamol was observed, but diazepam and insulin maximum losses were respectively of 96.4 ± 0.9% and 54.0 ± 5.6%, when using a polyurethane catheter. Overall, catheters were shown to be the cause of some extremely high drug losses that could not be countered by optimizing the extension set in the setup.
Preformulation Studies and Bioavailability Enhancement of Curcumin with a ‘Two in One’ PEG-β-Cyclodextrin Polymer
Authors: Haimhoffer Ádám , Dossi Eleftheria , Béresová Monika , Bácskay Ildikó , Váradi Judit , Afsar Ashfaq , Rusznyák Ágnes , Vasvári Gábor , Fenyvesi Ferenc
Published: October 2021

Drug delivery systems are used to improve the biopharmaceutical properties of curcumin. Our aim was to investigate the effect of a water-soluble ‘two in one’ polymer containing covalently bonded PEG and βCD moieties (βCPCD) on the solubility and bioavailability of curcumin and compare it to a polymeric β-cyclodextrin (βCDP) cross-linked with epichlorohydrin. Phase-solubility and dynamic light scattering (DLS) experiments showed that the solubility of curcumin increased significantly in 10 m/m % βCPCD and βCDP solutions, but βCPCD–curcumin particles had higher hydrodynamic volume. The formation of the βCPCD–curcumin complex in solution and sedimented phase was confirmed by NMR spectroscopy. Biocompatibility and permeability experiments were performed on Caco-2 cells. Polymers did not show cytotoxicity up to 10 m/m % and βCPCD significantly increased the permeability of curcumin. DLS measurements revealed that among the interaction of polymers with mucin, βCPCD formed bigger aggregates compared to βCDP. Curcumin complexes were lyophilized into capsules and structurally characterized by micro-CT spectroscopy. Drug release was tested in a pH 1.2 medium. Lyophilized complexes had a solid porous matrix and both βCPCD and βCDP showed rapid drug release. βCPCD provides an opportunity to create a swellable, mucoadhesive matrix system for oral drug delivery.
Curated Database and Preliminary AutoML QSAR Model for 5-HT1A Receptor
Authors: Czub Natalia , Pacławski Adam , Szlęk Jakub , Mendyk Aleksander
Published: October 2021

Introduction of a new drug to the market is a challenging and resource-consuming process. Predictive models developed with the use of artificial intelligence could be the solution to the growing need for an efficient tool which brings practical and knowledge benefits, but requires a large amount of high-quality data. The aim of our project was to develop quantitative structure–activity relationship (QSAR) model predicting serotonergic activity toward the 5-HT1A receptor on the basis of a created database. The dataset was obtained using ZINC and ChEMBL databases. It contained 9440 unique compounds, yielding the largest available database of 5-HT1A ligands with specified pKi value to date. Furthermore, the predictive model was developed using automated machine learning (AutoML) methods. According to the 10-fold cross-validation (10-CV) testing procedure, the root-mean-squared error (RMSE) was 0.5437, and the coefficient of determination (R2) was 0.74. Moreover, the Shapley Additive Explanations method (SHAP) was applied to assess a more in-depth understanding of the influence of variables on the model’s predictions. According to to the problem definition, the developed model can efficiently predict the affinity value for new molecules toward the 5-HT1A receptor on the basis of their structure encoded in the form of molecular descriptors. Usage of this model in screening processes can significantly improve the process of discovery of new drugs in the field of mental diseases and anticancer therapy.
The Impact of Bilayer Rigidity on the Release from Magnetoliposomes Vesicles Controlled by PEMFs
Authors: Trilli Jordan , Caramazza Laura , Paolicelli Patrizia , Casadei Maria Antonietta , Liberti Micaela , Apollonio Francesca , Petralito Stefania
Published: October 2021

Stimuli-sensitive nanocarriers have recently been developed as a powerful tool in biomedical applications such as drug delivery, detection, and gene transfer techniques. Among the external triggers investigated, low intensity magnetic fields represent a non-invasive way to remotely control the release of compounds from a magneto-sensitive carrier. Magnetoliposomes (MLs), i.e., liposomes entrapping magnetic nanoparticles (MNPs), are studied due to their capacity to transport hydrophobic and hydrophilic agents, their easy production, and due to the ability of MNPs to respond to a magnetic actuation determining the triggered release of the encapsulated compounds. Here we investigated the design and optimization of the MLs to obtain an efficient on-demand release of the transported compounds, due to the magneto-mechanical actuation induced by applying low-intensity pulsed electromagnetic fields (PEMFs). In particular we studied the effect of the bilayer packing on the ability of MLs, with oleic acid-coated MNPs encapsulated in the bilayer, to respond to PEMFs application. Three kinds of MLs are produced with an increasing rigidity of the bilayer, defined as Liquid Disorder, Liquid Order, and Gel MLs and the delivery of a hydrophilic dye (as a model drug) is investigated. Results demonstrate the efficacy of the magnetic trigger on high-ordered bilayers, which are unable to dampen the perturbation produced by MNPs motion.
Polyelectrolytes Formulated with Primary Unconjugated Bile Acid Optimised Pharmacology of Bio-Engineered Implant
Authors: Mooranian Armin , Ionescu Corina , Wagle Susbin , Kovacevic Bozica , Walker Daniel , Jones Melissa , Chester Jacqueline , Foster Thomas , Johnston Edan , Kojic Sanja , Stojanovic Goran , Mikov Momir , Al-Salami Hani
Published: October 2021

Introduction. Several studies have shown that different biomaterials and hydrogels comprising various bile acids such as chenodeoxycholic acid (CDCA), as well as excipients such as poly-(styrene)-sulphonate (PSS) and poly-(allyl)-amine (PAA), exhibited positive biological effects on encapsulated viable pancreatic β-cells. Hence, this study aimed to investigate whether incorporating CDCA with PSS and PAA will optimise the functions of encapsulated pancreatic islets post-transplantation in Type 1 diabetes (T1D). Methods. Mice were made T1D, divided into two equal groups, and transplanted with encapsulated islets in PSS-PAA (control) or with CDCA-PSS-PAA (treatment) microcapsules. The effects of transplanted microcapsules on blood glucose, inflammation and the bile acid profile were measured post-transplantation. Results and Conclusion. Compared with control, the treatment group showed better survival rate, improved glycaemic control, and lower inflammatory profile, illustrated by ↓ interleukin 1-β, interleukin-6, interleukin-12, and tumour-necrosis factor-α, and ↓ levels of the bile acid, as well as lithocholic acid in the plasma, liver, large intestine and faeces. The results suggest that CDCA incorporation with PSS-PAA microcapsules exerted beneficial effects on encapsulated islets and resulted in enhanced diabetes treatment, post-transplantation, at the local and systemic levels.
Improving Curcumin Bioavailability: Current Strategies and Future Perspectives
Authors: Tabanelli Rita , Brogi Simone , Calderone Vincenzo
Published: October 2021

Curcumin possesses a plethora of interesting pharmacological effects. Unfortunately, it is also characterized by problematic drug delivery and scarce bioavailability, representing the main problem related to the use of this compound. Poor absorption, fast metabolism, and rapid systemic clearance are the most important factors contributing to low curcumin levels in plasma and tissues. Accordingly, to overcome these issues, numerous strategies have been proposed and are investigated in this article. Due to advances in the drug delivery field, we describe here the most promising strategies for increasing curcumin bioavailability, including the use of adjuvant, complexed/encapsulated curcumin, specific curcumin formulations, and curcumin nanoparticles. We analyze current strategies, already available in the market, and the most advanced technologies that can offer a future perspective for effective curcumin formulations. We focus the attention on the effectiveness of curcumin-based formulations in clinical trials, providing a comprehensive summary. Clinical trial results, employing various delivery methods for curcumin, showed that improved bioavailability corresponds to increased therapeutic efficacy. Furthermore, advances in the field of nanoparticles hold great promise for developing curcumin-based complexes as effective therapeutic agents. Summarizing, suitable delivery methods for this polyphenol will ensure the possibility of using curcumin-derived formulations in clinical practice as preventive and disease-modifying therapeutics.