bluuebunny/crossref_metadata_2025 huggingface dataset:
E-Cigarette Vapour Alters High-Fat Diet-Induced Systemic Inflammatory Responses but Has No Effect on High-Fat Diet-Induced Changes in Gut Microbiota
Authors: Chen Hui , Burke Catherine , Donovan Chantal , Faiz Alen , Saad Sonia , Oliver Brian G.
Published: April 2023

Background: The gut microbiome, which can be altered by different diets or smoking, has been implicated in the pathogenesis of lung conditions. E-cigarette vaping is now recognised to have detrimental health effects, with several of these being similar to cigarette smoking. However, whether e-cigarettes can alter high-fat diet (HFD)-induced systemic effects and gut microbiota is unknown. In this study, we investigated the effects of HFD in the absence/presence of e-cigarette exposure on systemic inflammation, lipid metabolic markers, and the gut microbiome. Methods: Mice were fed a HFD (or chow) in the absence/presence of e-vapour exposure (±nicotine) and serum inflammation, lipid levels, and microbial diversity were assessed. Results: HFD increased the circulating levels of both triglycerides and non-esterified fatty acids, which were significantly reduced by e-vapour exposure in HFD-fed mice. Serum TNF-α was increased by HFD consumption or e-vapour. HFD had a significant effect on microbial diversity, but there were no additional effects of e-vapour exposure. Conclusions: This study highlights both similarities and differences in how the body responds to e-cigarette vapours, and it is therefore likely that the long-term sequelae of e-cigarette vapour exposure/vaping might not involve the significant alteration of the gut microbiome.
Nutritional State and COPD: Effects on Dyspnoea and Exercise Tolerance
Authors: Tramontano Angela , Palange Paolo
Published: April 2023

Chronic Obstructive Pulmonary Disease (COPD) is a disease that is spreading worldwide and is responsible for a huge number of deaths annually. It is characterized by progressive and often irreversible airflow obstruction, with a heterogeneous clinical manifestation based on disease severity. Along with pulmonary impairment, COPD patients display different grades of malnutrition that can be linked to a worsening of respiratory function and to a negative prognosis. Nutritional impairment seems to be related to a reduced exercise tolerance and to dyspnoea becoming a major determinant in patient-perceived quality of life. Many strategies have been proposed to limit the effects of malnutrition on disease progression, but there are still limited data available to determine which of them is the best option to manage COPD patients. The purpose of this review is to highlight the main aspects of COPD-related malnutrition and to underline the importance of poor nutritional state on muscle energetics, exercise tolerance and dyspnoea.
Lifestyle Intervention Guided by Group and Internet-Based Counseling in the T2D-GENE Trial Supports Its Applicability and Feasibility
Authors: Schwab Ursula , Lankinen Maria , Uusitupa Matti , Laakso Markku
Published: April 2023

Type 2 diabetes (T2D) can be prevented or postponed by lifestyle modifications as shown by previous intervention studies. In most of these studies, participants have received resource-demanding individual counseling. In the 3-year T2D-GENE trial with lifestyle intervention, we investigated whether a less resource-demanding form of group and internet-based counseling is feasible and effective in preventing T2D in people with an increased risk for T2D. Altogether, 628 middle-aged to elderly men either with a high number or low number of T2D risk alleles were recruited. Five to seven group sessions were organized during the intervention, in addition to information and activities delivered via the web portal, and weekly monitoring of body weight and physical activity. Four-day food records with personal feedback were documented five times during the study. Of the 549 participants completing the study, over 90% participated in the group sessions and kept the food records. The four self-feedback tasks delivered during the second and the third years of the study were completed by 80–89% of the participants. In conclusion, a group and web portal-based lifestyle intervention is applicable for middle-aged to elderly men as a lifestyle modification aiming to prevent T2D.
Estimated Phytate Intake Is Associated with Bone Mineral Density in Mediterranean Postmenopausal Women
Authors: Sanchis Pilar , Prieto Rafael María , Konieczna Jadwiga , Grases Félix , Abete Itziar , Salas-Salvadó Jordi , Martín Vicente , Ruiz-Canela Miguel , Babio Nancy , García-Gavilán Jesús Francisco , Goday Albert , Costa-Bauza Antonia , Martínez José Alfredo , Romaguera Dora
Published: April 2023

The main objective of this work was to explore the association of dietary phytate intake with bone mineral density (BMD) in a Mediterranean population of postmenopausal women. For this purpose, a cross-sectional analysis of 561 women aged 55–75 years with overweight/obesity and metabolic syndrome from a Mediterranean area and with data on dual-energy X-ray absorptiometry (DXA) scans in femur and lumbar spine was performed. Estimated phytate intake was calculated using a validated food frequency questionnaire. Our results indicated that phytate intake was associated with BMD [β(95%CI) per each 25 mg/100 kcal] in femoral neck [0.023(0.060–0.040) g/cm2], femoral Ward’s triangle [0.033(0.013–0.054) g/cm2], total femur [0.018(0.001–0.035) g/cm2], and all the analyzed lumbar spine sites [L1–L4: 0.033(0.007–0.059) g/cm2] after adjusting for potential confounders. The sensitivity analysis showed that phytate intake was directly associated with lumbar spine BMD in women younger than 66 years, with a body mass index higher than 32.6 kg/cm2 and without type 2 diabetes (all p-for interactions < 0.05). The overall results indicated that phytate, a substance present in food as cereals, legumes and nuts, was positively associated with BMD in Mediterranean postmenopausal women. Phytate may have a protective effect on bone resorption by adsorbing on the surfaces of HAP. Nevertheless, large, long-term, and randomized prospective clinical studies must be performed to assess the possible benefits of phytate consumption on BMD in postmenopausal women.
Effects on Serum Hormone Concentrations after a Dietary Phytoestrogen Intervention in Patients with Prostate Cancer: A Randomized Controlled Trial
Authors: Ahlin Rebecca , Nørskov Natalja P. , Nybacka Sanna , Landberg Rikard , Skokic Viktor , Stranne Johan , Josefsson Andreas , Steineck Gunnar , Hedelin Maria
Published: April 2023

Phytoestrogens have been suggested to have an anti-proliferative role in prostate cancer, potentially by acting through estrogen receptor beta (ERβ) and modulating several hormones. We primarily aimed to investigate the effect of a phytoestrogen intervention on hormone concentrations in blood depending on the ERβ genotype. Patients with low and intermediate-risk prostate cancer, scheduled for radical prostatectomy, were randomized to an intervention group provided with soybeans and flaxseeds (∼200 mg phytoestrogens/d) added to their diet until their surgery, or a control group that was not provided with any food items. Both groups received official dietary recommendations. Blood samples were collected at baseline and endpoint and blood concentrations of different hormones and phytoestrogens were analyzed. The phytoestrogen-rich diet did not affect serum concentrations of testosterone, insulin-like growth factor 1, or sex hormone-binding globulin (SHBG). However, we found a trend of decreased risk of increased serum concentration of estradiol in the intervention group compared to the control group but only in a specific genotype of ERβ (p = 0.058). In conclusion, a high daily intake of phytoestrogen-rich foods has no major effect on hormone concentrations but may lower the concentration of estradiol in patients with prostate cancer with a specific genetic upset of ERβ.
The Hidden Dangers of Plant-Based Diets Affecting Bone Health: A Cross-Sectional Study with U.S. National Health and Nutrition Examination Survey (NHANES) Data from 2005–2018
Authors: Zheng Yi , Wang Jiacheng , Wang Yawen , Xu Kelin , Chen Xingdong
Published: April 2023

The plant-based dietary pattern has been recommended for its potential health and environmental benefits, but its association with bone loss needs to be further explored. This study aimed to investigate the association between three plant-based diet indexes and bone loss in 16,085 adults, using data from the National Health and Nutrition Examination Survey. Three plant-based diet indexes (PDI, hPDI, and uPDI) were calculated from two NHANES 24-h dietary recall interviews, to characterize a plant-based diet. A multinomial logistic regression model was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). Higher hPDI and PDI were associated with increased risk of bone loss (ORQ5 vs. Q1 = 1.50; 95% CI: 1.24–1.81 for hPDI; ORQ5 vs. Q1 = 1.22; 95% CI: 1.03–1.45 for PDI), while higher uPDI was associated with increased risk of osteoporosis (ORQ5 vs. Q1 = 1.48; 95% CI: 1.04–2.11). A harmful association between plant-based diet indexes (hPDI and PDI) and osteopenia was observed at the lumbar spine rather than the femoral neck. We conducted several sensitivity analyses to ensure the robustness of results, including subgroup analysis, exclusion of people taking anti-osteoporotic and estrogenic drugs, further adjustment for menopausal status, corticosteroid usage, and dietary supplements, and calculation of E-value. Our study demonstrates the deleterious effects of a plant-based diet on bone health and emphasizes the importance of a balanced diet.
Longitudinal Examination of Body Mass Index and Cognitive Function in Older Adults: The HELIAD Study
Authors: Grapsa Ismini , Mamalaki Eirini , Ntanasi Eva , Kosmidis Mary H. , Dardiotis Efthimios , Hadjigeorgiou Georgios M. , Sakka Paraskevi , Scarmeas Nikolaos , Yannakoulia Mary
Published: April 2023

Given the increase in the aging population and thus in the prevalence of dementia, the identification of protective factors against cognitive decline is necessary. In a cohort of 1076 non-demented adults ≥ 65 years old (59.7% women) from the HELIAD study, we assessed whether changes in body mass index (BMI) were associated with changes in cognition over a 3-year follow-up period separately for those ≤ 75 and >75 years old. We identified six BMI trajectory groups based on participants’ BMI status at baseline and at the first follow-up visit; normal to normal BMI was the reference group. Major cognitive domains were evaluated, and a composite index reflecting global cognition was calculated. In participants aged ≤75 years, weight loss—moving from obesity to overweight or normal BMI—was associated with less decline in the memory composite score over time (β = 0.141; p = 0.035), while 3-year maintenance of a BMI ≥ 25 kg/m2 was related to greater reduction in the visuospatial composite score over time (β = −0.093; p = 0.020). Regarding participants aged >75 years, 3-year maintenance of a BMI ≥ 30 kg/m2 contributed to a slower rate of decline in the memory composite score over time (β = 0.102; p = 0.042), whereas weight loss—from overweight to normal BMI—was associated with a decreased attention/processing speed composite score longitudinally (β = −0.275; p = 0.043). Our findings indicated that the association between changes in BMI and cognitive functioning was modified by age. Weight management may have the potential to delay cognitive decline in older adults.
Training Behaviors and Periodization Outline of Omnivorous, Vegetarian, and Vegan Recreational Runners (Part A)—Results from the NURMI Study (Step 2)
Authors: Wirnitzer Katharina , Tanous Derrick , Motevalli Mohamad , Raschner Christian , Wagner Karl-Heinz , Wirnitzer Gerold , Leitzmann Claus , Rosemann Thomas , Knechtle Beat
Published: April 2023

Runners train for long-distance competitions based on underlying motivations, which may be similar to individual dietary motivations (e.g., well-being and performance). Fundamental training differences may arise in recreational runners following different diet types (omnivore, vegetarian, vegan) considering possible motive variations. Following a cross-sectional design, distance runners completed a survey (online), including a thorough assessment of training behaviors with generic training details and periodization specifics in three phases: 1. an intermediary and rebound stage, 2. a main preparatory stage, and 3. a main event stage (tapering or interim event level/s). Kruskal–Wallis and chi-squared tests were used in the statistical analysis. A total of 245 fit recreational runners following omnivore (n = 109), vegetarian (n = 45), and vegan diets (n = 91) were included. Significant differences in the initial running motivation were found across dietary subgroups (p = 0.033) as well as for current motivations (p = 0.038), with vegetarians being the least health motivated (27% and 9%, respectively). No differences in each of the specific periods were found between diet types across the outline (p > 0.05). The present evidence shows that there is a lack of fundamental training differences based on recreational runners following different generic types of diets. The results of the present investigation may be especially relevant for future studies on safety, sustainability, and performance-enhancing dietary practices among athletes.
Ameliorative Effects of Flavonoids from Platycodon grandiflorus Aerial Parts on Alloxan-Induced Pancreatic Islet Damage in Zebrafish
Authors: Nam Youn Hee , Kim Eun Bin , Kang Ji Eun , Kim Ju Su , Jeon Yukyoung , Shin Sung Woo , Kang Tong Ho , Kwak Jong Hwan
Published: April 2023

Platycodon grandiflorus (balloon flower), used as a food reserve as well as in traditional herbal medicine, is known for its multiple beneficial effects. In particular, this plant is widely used as a vegetable in Republic of Korea. We examined the ameliorative effects of P. grandiflorus on alloxan-induced pancreatic islet damage in zebrafish. The aerial part treatment led to a significant recovery in pancreatic islet size and glucose uptake. The efficacy of the aerial part was more potent than that of the root. Eight flavonoids (1–8) were isolated from the aerial part. Structures of two new flavone glycosides, designated dorajiside I (1) and II (2), were elucidated to be luteolin 7-O-α-L-rhamno-pyranosyl (1 → 2)-(6-O-acetyl)-β-D-glucopyranoside and apigenin 7-O-α-L-rhamnopyranosyl (1 → 2)-(6-O-acetyl)-β-D-glucopyranoside, respectively, by spectroscopic analysis. Compounds 1, 3, 4 and 6–8 yielded the recovery of injured pancreatic islets in zebrafish. Among them, compound 7 blocked KATP channels in pancreatic β-cells. Furthermore, compounds 3, 4, 6 and 7 showed significant changes with respect to the mRNA expression of GCK, GCKR, GLIS3 and CDKN2B compared to alloxan-induced zebrafish. In conclusion, the aerial part of P. grandiflorus and its constituents conferred a regenerative effect on injured pancreatic islets.
A U.S. Isolate of Theileria orientalis Ikeda Is Not Transstadially Transmitted to Cattle by Rhipicephalus microplus
Authors: Onzere Cynthia K. , Herndon David R. , Hassan Amany , Oyen Kennan , Poh Karen C. , Scoles Glen A. , Fry Lindsay M.
Published: April 2023

Theileria orientalis Ikeda has caused an epidemic of bovine anemia and abortion across several U.S. states. This apicomplexan hemoparasite is transmitted by Haemaphysalis longicornis ticks; however, it is unknown if other North American ticks are competent vectors. Since the disease movement is largely determined by the host tick range(s), the prediction of the T. orientalis spread among U.S. cattle populations requires determination of additional competent tick vectors. Although Rhipicephalus microplus has mostly been eradicated from the U.S., outbreaks in populations occur frequently, and the U.S. remains at risk for reintroduction. Since R. microplus is a vector of Theileria equi and T. orientalis DNA has been detected in R. microplus, the goal of this study was to determine whether R. microplus is a competent vector of T. orientalis. Larval R. microplus were applied to a splenectomized, T. orientalis Ikeda-infected calf for parasite acquisition, removed as molted adults, and applied to two T. orientalis naïve, splenectomized calves for transmission. After 60 days, the naïve calves remained negative for T. orientalis by PCR and cytology. Additionally, T. orientalis was not detected in the salivary glands or larval progeny of acquisition-fed adults. These data suggest that R. microplus is not a competent vector of the U.S. T. orientalis Ikeda isolate.
Limnotrachelobdella hypophthalmichthysa n. sp. (Hirudinida: Piscicolidae) on Gills of Bighead Carp Hypophthalmichthys nobilis in China
Authors: Lin Lin , Cheng Houda , Li Wenxiang , Li Ming , Zou Hong , Wang Guitang
Published: April 2023

We describe the characterization of a novel fish leech species found on the gills of bighead carp (Hypophthalmichthys nobilis) from lakes and reservoirs in China. This leech is morphologically similar to Limnotrachelobdella sinensis recorded on goldfish and common carp. However, there are 0–2 pairs of symmetrical or asymmetrical eyes and 10 pairs of pulsatile vesicles in the newly discovered leech, in remarkable contrast to L. sinensis. Except for bighead carp, where it demonstrated a higher than 90% prevalence, and silver carp (H. molitrix), where there was low infection, this leech was not detected on any other fish from the Qiandao reservoir in China that were examined during this investigation. Molecular analyses indicated 87.8% ITS sequence identity with L. sinensis and 85.0 and 86.1% COX1 sequence identity with L. sinensis and L. okae, respectively. The uncorrected p-distance based on the COX1 sequence was found to be 15.1 and 14.0% for L. sinensis and L. okae, respectively, suggesting interspecific variation. Phylogenetic analyses based on the combination of 18S and COX1 sequences showed that the newly discovered leech groups with Limnotrachelobdella species. Histopathological observation indicated that attachment of the leech on the gill rakers and gill arches causes a loss of connective tissue, hemorrhage, and ulceration. Based on the morphology, molecular analyses, and host specificity, we conclude that this leech is a new species of Limnotrachelobdella and named it Limnotrachelobdella hypophthalmichthysa n. sp.
Human Papilloma Virus: An Unraveled Enigma of Universal Burden of Malignancies
Authors: Khan Ishrat , Harshithkumar R , More Ashwini , Mukherjee Anupam
Published: April 2023

HPV, or Human Papilloma Virus, has been the primary causative agent of genital warts and cervical cancer worldwide. It is a sexually transmitted infection mainly affecting women of reproductive age group, also infecting men and high-risk group individuals globally, resulting in high mortality. In recent years, HPV has also been found to be the major culprit behind anogenital cancers in both gender and oropharyngeal and colorectal cancers. Few studies have reported the incidence of HPV in breast cancers as well. For a few decades, the burden of HPV-associated malignancies has been increasing at an alarming rate due to a lack of adequate awareness, famine vaccine coverage and hesitancy. The effectiveness of currently available vaccines has been limited to prophylactic efficacy and does not prevent malignancies associated with post-exposure persistent infection. This review focuses on the current burden of HPV-associated malignancies, their causes and strategies to combat the growing prevalence of the cancers. With the advent of new technologies associated with treatment pertaining to therapeutic interventions and employing effective vaccine coverage, the burden of this disease may be reduced in the population.
Interacting Abiotic Factors Affect Growth and Mycotoxin Production Profiles of Alternaria Section Alternaria Strains on Chickpea-Based Media
Authors: Romero Donato Cindy J. , Nichea María J. , Cendoya Eugenia , Zachetti Vanessa G. L. , Ramirez María L.
Published: April 2023

Chickpea is susceptible to fungal infection and mycotoxin contamination. Argentina exports most of its chickpea production; thus, its quality is of concern. The Alternaria fungal genus was found to be prevalent in chickpea samples from Argentina. The species within this genus are able to produce mycotoxins, such as alternariol (AOH), alternariol monomethyl ether (AME), and tenuazonic acid (TA). In this context, we evaluated the effect of water activity (0.99, 0.98, 0.96, 0.95, 0.94, 0.92, and 0.90 aW), temperature (4, 15, 25, and 30 °C), incubation time (7, 14, 21, and 28 days), and their interactions on mycelial growth and AOH, AME, and TA production on chickpea-based medium by two A. alternata strains and one A. arborescens strain isolated from chickpea in Argentina. Maximum growth rates were obtained at the highest aW (0.99) and 25 °C, with growth decreasing as the aW of the medium and the temperature were reduced. A. arborescens grew significantly faster than A. alternata. Mycotoxin production was affected by both variables (aW and temperature), and the pattern obtained was dependent on the strains/species evaluated. In general, both A. alternata strains produced maximum amounts of AOH and AME at 30 °C and 0.99–0.98 aW, while for TA production, both strains behaved completely differently (maximum levels at 25 °C and 0.96 aW for one strain and 30 °C and 0.98 aW for the other). A. arborescens produced maximum amounts of the three toxins at 25 °C and 0.98 aW. Temperature and aW conditions for mycotoxin production were slightly narrower than those for growth. Temperature and aW conditions assayed are those found during chickpea grain development in the field, and also could be present during storage. This study provides useful data on the conditions representing a risk for contamination of chickpea by Alternaria toxins.
Consistent Measurement of Parasite-Specific Antigen Levels in Sera of Patients with Neurocysticercosis Using Two Different Monoclonal Antibody (mAb)-Based Enzyme-Linked Immunosorbent Assays
Authors: Castillo Yesenia , Toribio Luz M. , Guzman Carolina , Arroyo Gianfranco , Espinoza Cindy , Saavedra Herbert , Bustos Javier A. , Dorny Pierre , O’Neal Seth E. , Garcia Hector H.
Published: April 2023

Monoclonal antibody (mAb)-based enzyme-linked immunosorbent assay (ELISA) is a complementary diagnosis technique for neurocysticercosis (NCC), which detects circulating parasite antigen (Ag) indicative of viable infection and Ag levels that correlate well with the parasite burden. In this study, we compared the performance of two Ag-ELISA techniques for the detection of NCC. We assessed the agreement between our in-house TsW8/TsW5 Ag-ELISA and the widely used B158/B60 Ag-ELISA for measuring T. solium antigen levels in the sera from 113 patients with calcified, parenchymal, and subarachnoid NCC. Concordance was demonstrated evaluating the limits of agreement (LoAs) stratified by the type of NCC. Both ELISA’s detected 47/48 (97.8%) subarachnoid NCC cases. In parenchymal and calcified NCC, the B158/B60 Ag-ELISA detected 19/24 (79.2%) and 18/41 (43.9%) cases, while the TsW8/TsW5 Ag-ELISA detected 21/24 (87.5%) and 13/41 (31.7%), respectively. Parenchymal and calcified NCC obtained a perfect agreement (100%), indicating that all sample results were within the predicted LoA, while for subarachnoid NCC, the agreement was 89.6%. The high concordance between the assays was confirmed by Lin’s concordance coefficient (LCC = 0.97). Patients with viable parenchymal NCC (LCC = 0.95) obtained the highest concordance between assays, followed by subarachnoid NCC (LCC = 0.93) and calcified NCC (LCC = 0.92). The TsW8/TsW5 Ag-ELISA and B158/B60 Ag-ELISA showed high Ag measurement correlations across diverse types of NCC.
Caregivers’ Self-Rated General Health, Physical and Mental Health Status, Disease Morbidity and Association with Uncontrolled Asthma in Children
Authors: Oparanma Chisa O. , Ogbu Chukwuemeka E. , Ezeh Ebubechukwu , Ogbu Stella C. , Ujah Otobo I. , Kirby Russell S.
Published: April 2023

This study examined the association between caregivers’ self-rated general health, poor physical/mental health days, disease morbidity and asthma control in children from the United States with current asthma. The data analyzed for this study were obtained from 7522 children aged 0–17 years who participated in the 2012–2014, 2015–2017, 2018, and 2019 cycles of the Behavioral Risk Factor Surveillance System Asthma Call-back Survey (ACBS). We employed univariate analysis to describe the study population and weighted binary logistic regression to examine the association of predictors with asthma control. Approximately 50% of the children had uncontrolled asthma. The results show that caregivers who reported fair general health had a 61% higher likelihood of reporting uncontrolled asthma in their children compared to those who reported good/very good/excellent health (adjusted odds ratio [aOR] = 1.61; 95% confidence interval [CI], 1.14–2.26). Poor caregiver general health did not reach statistical significance in predicting uncontrolled asthma (aOR = 1.05, 95% CI, 0.62–1.75). Furthermore, having 1 to 14 poor physical/mental health days ([aOR] = 1.70; 95% CI, 1.28–2.227) and ≥15 poor physical/mental health days (aOR = 1.82, 95% CI, 1.31–2.53) was predictive of uncontrolled asthma in children. Additionally, endorsing one reported disease (aOR = 1.49, 95% CI, 1.15–1.93) and ≥2 diseases (aOR = 1.38, 95% CI, 1.08–1.78) was associated with uncontrolled child asthma. These findings underscore the association between caregivers’ self-reported general health, poor mental/physical health days, disease morbidity and uncontrolled asthma among children from the U.S. with asthma. Pediatricians and child health practitioners should recall the importance of this relationship. To facilitate the identification of caregivers at risk and provide more comprehensive and effective care for children with asthma, healthcare practitioners should utilize every child asthma care encounter to inquire about the overall health of caregivers.
Identification of Compounds of Crocus sativus by GC-MS and HPLC/UV-ESI-MS and Evaluation of Their Antioxidant, Antimicrobial, Anticoagulant, and Antidiabetic Properties
Authors: Drioiche Aziz , Ailli Atika , Handaq Nadia , Remok Firdaous , Elouardi Mohamed , Elouadni Hajar , Al Kamaly Omkulthom , Saleh Asmaa , Bouhrim Mohamed , Elazzouzi Hanane , El Makhoukhi Fadoua , Zair Touriya
Published: April 2023

In order to valorize the species Crocus sativus from Morocco and to prepare new products with high added value that can be used in the food and pharmaceutical industry, our interest was focused on the phytochemical characterization and the biological and pharmacological properties of the stigmas of this plant. For this purpose, the essential oil of this species, extracted by hydrodistillation and then analyzed by GC-MS, revealed a predominance of phorone (12.90%); (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (11.65%); isopropyl palmitate (9.68%); dihydro-β-ionone (8.62%); safranal (6.39%); trans-β-ionone (4.81%); 4-keto-isophorone (4.72%); and 1-eicosanol (4.55%) as the major compounds. The extraction of phenolic compounds was performed by decoction and Soxhlet extraction. The results of the determination of flavonoids, total polyphenols, condensed tannins, and hydrolyzable tannins determined by spectrophotometric methods on aqueous and organic extracts have proved the richness of Crocus sativus in phenolic compounds. Chromatographic analysis by HPLC/UV-ESI-MS of Crocus sativus extracts revealed the presence of crocin, picrocrocin, crocetin, and safranal molecules specific to this species. The study of antioxidant activity by three methods (DPPH, FRAP, and total antioxidant capacity) has proved that C. sativus is a potential source of natural antioxidants. Antimicrobial activity of the aqueous extract (E0) was investigated by microdilution on a microplate. The results have revealed the efficacy of the aqueous extract against Acinetobacter baumannii and Shigella sp. with MIC ≤ 600 µg/mL and against Aspergillus niger, Candida kyfer, and Candida parapsilosis with MIC = 2500 µg/mL. Measurements of pro-thrombin time (PT) and activated partial thromboplastin time (aPTT) in citrated plasma obtained from routine healthy blood donors were used to determine the anticoagulant activity of aqueous extract (E0). The anticoagulant activity of the extract (E0) studied showed that this extract can significantly prolong the partial thromboplastin time (p < 0.001) with a 359 µg/mL concentration. The antihyperglycemic effect of aqueous extract was studied in albino Wistar rats. The aqueous extract (E0) showed strong in vitro inhibitory activity of α-amylase and α-glucosidase compared with acarbose. Thus, it very significantly inhibited postprandial hyperglycemia in albino Wistar rats. According to the demonstrated results, we can affirm the richness of Crocus sativus stigmas in bioactive molecules and its use in traditional medicine.
Improved Local Anesthesia at Inflamed Tissue Using the Association of Articaine and Copaiba Oil in Avocado Butter Nanostructured Lipid Carriers
Authors: Rodrigues da Silva Gustavo Henrique , Paes Lemes Julia Borges , Geronimo Gabriela , de Carvalho Fabíola Vieira , Mendonça Talita Cesarim , Malange Kauê Franco , de Lima Fernando Freitas , Breitkreitz Márcia Cristina , Parada Carlos Amilcar , Dalla Costa Teresa , de Paula Eneida
Published: April 2023

Unsuccessful anesthesia often occurs under an inflammatory tissue environment, making dentistry treatment extremely painful and challenging. Articaine (ATC) is a local anesthetic used at high (4%) concentrations. Since nanopharmaceutical formulations may improve the pharmacokinetics and pharmacodynamics of drugs, we encapsulated ATC in nanostructured lipid carriers (NLCs) aiming to increase the anesthetic effect on the inflamed tissue. Moreover, the lipid nanoparticles were prepared with natural lipids (copaiba (Copaifera langsdorffii) oil and avocado (Persia gratissima) butter) that added functional activity to the nanosystem. NLC-CO-A particles (~217 nm) showed an amorphous lipid core structure according to DSC and XDR. In an inflammatory pain model induced by λ-carrageenan in rats, NLC-CO-A improved (30%) the anesthetic efficacy and prolonged anesthesia (3 h) in relation to free ATC. In a PGE2-induced pain model, the natural lipid formulation significantly reduced (~20%) the mechanical pain when compared to synthetic lipid NLC. Opioid receptors were involved in the detected analgesia effect since their blockage resulted in pain restoration. The pharmacokinetic evaluation of the inflamed tissue showed that NLC-CO-A decreased tissue ATC elimination rate (ke) by half and doubled ATC’s half-life. These results present NLC-CO-A as an innovative system to break the impasse of anesthesia failure in inflamed tissue by preventing ATC accelerated systemic removal by the inflammatory process and improving anesthesia by its association with copaiba oil.
Synthesis, Evaluation of Enzyme Inhibition and Redox Properties of Potential Dual COX-2 and 5-LOX Inhibitors
Authors: Bošković Jelena , Dobričić Vladimir , Mihajlović Marija , Kotur-Stevuljević Jelena , Čudina Olivera
Published: April 2023

Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (1–13) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as N-hydroxyurea derivatives (1, 2 and 3), 3,5-di-tert-butylphenol derivatives (4, 5, 6, 7 and 13), urea derivatives (8, 9 and 10) and “type B hydroxamic acids” (11 and 12). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (1, 2, 3, 5, 6, 11 and 12) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors 1, 3, 5, 11 and 12 showed good antioxidant properties.
The Potential of Alternative Therapies and Vaccine Candidates against Helicobacter pylori
Authors: Sukri Asif , Hanafiah Alfizah , Patil Sandip , Lopes Bruno S.
Published: April 2023

Alternative therapies and vaccination are essential to combat the emergence of multidrug-resistant Helicobacter pylori and to prevent the development of gastroduodenal diseases. This review aimed to systematically review recent studies on alternative therapies, i.e., probiotics, nanoparticles, and natural products from plants, as well as recent progress in H. pylori vaccines at the preclinical stage. Articles published from January 2018 to August 2022 were systematically searched using PubMed, Scopus, Web of Science, and Medline. After the screening process, 45 articles were eligible for inclusion in this review. Probiotics (n = 9 studies) and natural products from plants (n = 28 studies) were observed to inhibit the growth of H. pylori, improve immune response, reduce inflammation, and reduce the pathogenic effects of H. pylori virulence factors. Natural products from plants also showed anti-biofilm activity against H. pylori. However, clinical trials of natural products from plants and probiotics are still lacking. A paucity of data assessing the nanoparticle activity of N-acylhomoserine lactonase-stabilized silver against H. pylori was observed. Nonetheless, one nanoparticle study showed anti-biofilm activity against H. pylori. Promising results of H. pylori vaccine candidates (n = 7) were observed at preclinical stage, including elicitation of a humoral and mucosal immune response. Furthermore, the application of new vaccine technology including multi-epitope and vector-based vaccines using bacteria was investigated at the preclinical stage. Taken together, probiotics, natural products from plants, and nanoparticles exhibited antibacterial activity against H. pylori. New vaccine technology shows promising results against H. pylori.
TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC
Authors: Tammaccaro Salvina Laura , Prigent Philippe , Le Bail Jean-Christophe , Dos-Santos Odette , Dassencourt Laurent , Eskandar Myriam , Buzy Armelle , Venier Olivier , Guillemot Jean-Claude , Veeranagouda Yaligara , Didier Michel , Spanakis Emmanuel , Kanno Tokuwa , Cesaroni Matteo , Mathieu Stephane , Canard Luc , Casse Alhassan , Windenberger Fanny , Calvet Loreley , Noblet Laurence , Sidhu Sukhvinder , Debussche Laurent , Moll Jurgen , Valtingojer Iris
Published: April 2023

KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.
Fabrication and Characterization of Celecoxib-Loaded Chitosan/Guar Gum-Based Hydrogel Beads
Authors: Batool Rukhsana , Mudassir Jahanzeb , Khan Mahtab Ahmad , Zafar Saman , Rana Sadia Jafar , Abbas Nasir , Hussain Amjad , Arshad Muhammad Sohail , Muhammad Sajjad
Published: April 2023

The aim of this study was to fabricate celecoxib-loaded chitosan/guar gum (CS/GG) single (SC) and dual (DC) crosslinked hydrogel beads using the ionotropic gelation approach. The prepared formulations were evaluated for entrapment efficiency (EE%), loading efficiency (LE%), particle size and swelling studies. The performance efficiency was assessed by in vitro drug release, ex-vivo mucoadhesion, permeability, ex-in vivo swelling and in vivo anti-inflammatory studies. The EE% was found to be ~55% and ~44% for SC5 and DC5 beads, respectively. The LE% was ~11% and ~7% for SC5 and DC5 beads, respectively. The beads showed a matrix-like network with thick fibers. The particle size of beads ranged from ~2.74 to 1.91 mm. About 74% and 24% celecoxib was released from SC and DC hydrogel beads, respectively, within 24 h. The SC formulation showed higher %swelling and permeability than the DC counterpart, while the %mucoadhesion was relatively higher for DC beads. During the in vivo study, a significant decrease in the inflammation of the rat paw and inflammatory markers including C-reactive proteins (CRP) and interleukin-6 (IL-6) was observed following treatment with the prepared hydrogel beads; however, the SC formulation showed better therapeutic efficiency. In conclusion, celecoxib-loaded crosslinked CS/GG hydrogel beads can provide sustained drug release and act as potential candidates for managing inflammatory conditions.
Drug Repurposing of FDA Compounds against α-Glucosidase for the Treatment of Type 2 Diabetes: Insights from Molecular Docking and Molecular Dynamics Simulations
Authors: Rashid Rebwar Saeed M. , Temurlu Selin , Abourajab Arwa , Karsili Pelin , Dinleyici Meltem , Al-Khateeb Basma , Icil Huriye
Published: April 2023

Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one’s carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible for carbohydrate degradation. Currently, drugs for type 2 diabetes have limitations in terms of safety, efficiency, and potency, while cases are rapidly increasing. For this reason, the study planned and moved towards drug repurposing by utilizing food and drug administration (FDA)-approved drugs against α-glucosidase, and investigated the molecular mechanisms. The target protein was refined and optimized by introducing missing residues, and minimized to remove clashes to find the potential inhibitor against α-glucosidase. The most active compounds were selected after the docking study to generate a pharmacophore query for the virtual screening of FDA-approved drug molecules based on shape similarity. The analysis was performed using Autodock Vina (ADV)—based on binding affinities (−8.8 kcal/mol and −8.6 kcal/mol) and root-mean-square-deviation (RMSD) values (0.4 Å and 0.6 Å). Two of the most potent lead compounds were selected for a molecular dynamics (MD) simulation to determine the stability and specific interactions between receptor and ligand. The docking score, RMSD values, pharmacophore studies, and MD simulations revealed that two compounds, namely Trabectedin (ZINC000150338708) and Demeclocycline (ZINC000100036924), are potential inhibitors for α-glucosidase compared to standard inhibitors. These predictions showed that the FDA-approved molecules Trabectedin and Demeclocycline are potential suitable candidates for repurposing against type 2 diabetes. The in vitro studies showed that trabectedin was significantly effective with an IC50 of 1.263 ± 0.7 μM. Further investigation in the laboratory is needed to justify the safety of the drug to be used in vivo.
Overexpression of Krüppel-Like Factor 9 Enhances the Antitumor Properties of Paclitaxel in Malignant Melanoma-Derived Cell Lines
Authors: Altonsy Mohammed O. , Song-Zhao George X. , Mostafa Mahmoud M. , Mydlarski Paule Régine
Published: April 2023

Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response in melanoma.
Influence of Intramuscular Injection Sites on Pharmacokinetics of Amoxicillin in Olive Flounder (Paralichthys olivaceus) and Its Implication for Antibacterial Efficacy
Authors: Lee Ji-Hoon , Kim Ga-Won , Kang Hyun-Woo , Hong Joo-Won , Lee Hyo-Eun , Kwon Mun-Gyeong , Seo Jung-Soo
Published: April 2023

This study aimed to investigate the effects of different injection sites, including dorsal, cheek, and pectoral fin muscles, on the pharmacological properties of amoxicillin (AMOX) in olive flounder (Paralichthys olivaceus) after a single intramuscular (IM) injection of 40 mg/kg. The AMOX concentration was measured using high-performance liquid chromatography-tandem mass spectrometry, followed by a non-compartmental model analysis. The peak serum concentrations (Cmax) achieved 3 h after dorsal, cheek, and pectoral fin IM injections were 202.79, 203.96, and 229.59 μg/mL, respectively. The area under the concentration-time curve (AUC) was 1697.23, 2006.71, and 1846.61 µg/mL·h, respectively. The terminal half-life (t1/2λZ) was prolonged for cheek and pectoral fin IM injections (10.12 and 10.33 h, respectively) compared to dorsal IM injection (8.89 h). In the pharmacokinetic-pharmacodynamic analysis, a higher T > minimum inhibitory concentration (MIC) and AUC/MIC values were observed after AMOX was injected into the cheek and pectoral fin muscles compared to the dorsal muscle. Muscle residue depletion was below the maximum residue level from day 7 after IM injection at all three sites. These findings suggest that the cheek and pectoral fin sites provide advantages regarding systemic drug exposure and prolonged action compared with the dorsal site.
Design and Characterization of Carboplatin and Paclitaxel Loaded PCL Filaments for 3D Printed Controlled Release Intrauterine Implants
Authors: Varan Cem , Aksüt Davut , Şen Murat , Bilensoy Erem
Published: April 2023

Uterine cancer is the fourth most common cancer in women. Despite various chemotherapy approaches, the desired effect has not yet been achieved. The main reason is each patient responds differently to standard treatment protocols. The production of personalized drugs and/or drug-loaded implants is not possible in today’s pharmaceutical industry; 3D printers allow for the rapid and flexible preparation of personalized drug-loaded implants. However, the key point is the preparation of drug-loaded working material such as filament for 3D printers. In this study, two different anticancer (paclitaxel, carboplatin) drug-loaded PCL filaments with a 1.75 mm diameter were prepared with a hot-melt extruder. To optimize the filament for a 3D printer, different PCL Mn, cyclodextrins and different formulation parameters were tried, and a series of characterization studies of filaments were conducted. The encapsulation efficiency, drug release profile and in vitro cell culture studies have shown that 85% of loaded drugs retain their effectiveness, provide a controlled release for 10 days and cause a decrease in cell viability of over 60%. In conclusion, it is possible to prepare optimum dual anticancer drug-loaded filaments for FDM 3D printers. Drug-eluting personalized intra-uterine devices can be designed for the treatment of uterine cancer by using these filaments.
Encapsulation of PI3K Inhibitor LY294002 within Polymer Nanoparticles Using Ion Pairing Flash Nanoprecipitation
Authors: Fergusson Austin D. , Zhang Rui , Riffle Judy S. , Davis Richey M.
Published: April 2023

Flash nanoprecipitation (FNP) is a turbulent mixing process capable of reproducibly producing polymer nanoparticles loaded with active pharmaceutical ingredients (APIs). The nanoparticles produced with this method consist of a hydrophobic core surrounded by a hydrophilic corona. FNP produces nanoparticles with very high loading levels of nonionic hydrophobic APIs. However, hydrophobic compounds with ionizable groups are not as efficiently incorporated. To overcome this, ion pairing agents (IPs) can be incorporated into the FNP formulation to produce highly hydrophobic drug salts that efficiently precipitate during mixing. We demonstrate the encapsulation of the PI3K inhibitor, LY294002, within poly(ethylene glycol)-b-poly(D,L lactic acid) nanoparticles. We investigated how incorporating two hydrophobic IPs (palmitic acid (PA) and hexadecylphosphonic acid (HDPA)) during the FNP process affected the LY294002 loading and size of the resulting nanoparticles. The effect of organic solvent choice on the synthesis process was also examined. While the presence of either hydrophobic IP effectively increased the encapsulation of LY294002 during FNP, HDPA resulted in well-defined colloidally stable particles, while the PA resulted in ill-defined aggregates. The incorporation of hydrophobic IPs with FNP opens the door for the intravenous administration of APIs that were previously deemed unusable due to their hydrophobic nature.
Molecular Interactions between APIs and Enteric Polymeric Excipients in Solid Dispersion: Insights from Molecular Simulations and Experiments
Authors: Gupta Krishna M. , Chin Xavier , Kanaujia Parijat
Published: April 2023

Solid dispersion of poorly soluble APIs is known to be a promising strategy to improve dissolution and oral bioavailability. To facilitate the development and commercialization of a successful solid dispersion formulation, understanding of intermolecular interactions between APIs and polymeric carriers is essential. In this work, first, we assessed the molecular interactions between various delayed-release APIs and polymeric excipients using molecular dynamics (MD) simulations, and then we formulated API solid dispersions using a hot melt extrusion (HME) technique. To assess the potential API–polymer pairs, three quantities were evaluated: (a) interaction energy between API and polymer [electrostatic (Ecoul), Lenard-Jones (ELJ), and total (Etotal)], (b) energy ratio (API–polymer/API–API), and (c) hydrogen bonding between API and polymer. The Etotal quantities corresponding to the best pairs: NPX-Eudragit L100, NaDLO–HPMC(P), DMF–HPMC(AS) and OPZ–HPMC(AS) were −143.38, −348.04, −110.42, and −269.43 kJ/mol, respectively. Using a HME experimental technique, few API–polymer pairs were successfully extruded. These extruded solid forms did not release APIs in a simulated gastric fluid (SGF) pH 1.2 environment but released them in a simulated intestinal fluid (SIF) pH 6.8 environment. The study demonstrates the compatibility between APIs and excipients, and finally suggests a potential polymeric excipient for each delayed-release API, which could facilitate the development of the solid dispersion of poorly soluble APIs for dissolution and bioavailability enhancement.