bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the Mediterranean Diet Pattern Associated with Weight Related Health Complications in Adults? A Cross-Sectional Study of Australian Health Survey
Authors: Seifu Canaan , Fahey Paul , Ahmed Kedir , Atlantis Evan
Published: November 2021

We hypothesized that unhealthy dietary pattern would be associated with weight related complications among overweight. We analysed data from the Australian Health Survey conducted from 2011 to 2013. A total of 5055 adults with at least overweight (body mass index ≥25 kg/m2) were analysed. We used logistic regression to assess the association between unhealthy dietary pattern, defined by low adherence to Mediterranean Diet Score (MDS), and weight related complications, defined by the Edmonton Obesity Staging System (EOSS). We repeated the logistic regression models by age and socio-economic disadvantage strata in sensitivity analyses. We also repeated the main analysis on a propensity score matched dataset (n = 3364). Complications by EOSS ≥2 was present in 3036 (60.1%) participants. There was no statistically significant association between unhealthy dietary pattern and weight related complication (odds ratio 0.98 (95%confidence interval: 0.85, 1.12)). The null association remained the same after repeating the analysis on three age and five socio-economic indexes for areas strata. The finding persisted after the analysis was repeated on a propensity score matched dataset. We found no evidence to support the hypothesis that unhealthy dietary pattern was associated with weight related complications in this cross-sectional study of the Australian population with overweight or obesity.
Vitamins as Possible Cancer Biomarkers: Significance and Limitations
Authors: Venturelli Sascha , Leischner Christian , Helling Thomas , Burkard Markus , Marongiu Luigi
Published: November 2021

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as ‘hidden hunger’), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.
Enabling Better Nutrition for Adolescents from Middle Eastern Backgrounds: Semi-Structured Interviews with Parents
Authors: Hayba Nematullah , Shi Yumeng , Allman-Farinelli Margaret
Published: November 2021

The unyielding obesity epidemic in adolescents from Middle Eastern (ME) backgrounds warrants culturally-responsive and co-designed prevention measures. This study aimed to capture the opinions of ME parents residing in Australia on the crisis and their enablers and barriers to healthy eating interventions given their influence on adolescent eating behaviors. Twenty-six semi-structured interviews were conducted with ME mothers, aged 35–59 years, and most residing in low socioeconomic areas (n = 19). A reflexive thematic analysis using the Capability, Opportunity, Motivation-Behaviour model and Theoretical Domain Framework was conducted. Parents expressed confidence in knowledge of importance of healthy eating, but were reluctant to believe behaviours were engaged in outside of parental influence. Time management skills are needed to support working mothers and to minimize reliance on nearby fast-food outlets, which was heightened during COVID-19 with home-delivery. Time constraints also meant breakfast skipping was common. A culture of feeding in light of diet acculturation and intergenerational trauma in this diaspora was also acknowledged. Parents pleaded for upstream policy changes across government and school bodies to support parental efforts in the form of increased regulation of fast-food and subsidization of healthy products. Opportunities for weight-inclusive programs including parenting workshops underpinned by culturally-responsive pedagogy were recommended.
Protective Effects of Nootkatone on Renal Inflammation, Apoptosis, and Fibrosis in a Unilateral Ureteral Obstructive Mouse Model
Authors: Chen Chang-Mu , Lin Chen-Yu , Chung Yao-Pang , Liu Chia-Hung , Huang Kuo-Tong , Guan Siao-Syun , Wu Cheng-Tien , Liu Shing-Hwa
Published: November 2021

Nootkatone is one of the major active ingredients of Alpiniae oxyphyllae, which has been used as both food and medicinal plants for the treatment of diarrhea, ulceration, and enuresis. In this study, we aimed to investigate whether nootkatone treatment ameliorated the progression of chronic kidney diseases (CKD) and clarified its underlying mechanisms in an obstructive nephropathy (unilateral ureteral obstructive; UUO) mouse model. Our results revealed that nootkatone treatment preventively decreased the pathological changes and significantly mitigated the collagen deposition as well as the protein expression of fibrotic markers. Nootkatone could also alleviate oxidative stress-induced injury, inflammatory cell infiltration, and renal cell apoptotic death in the kidneys of UUO mice. These results demonstrated for the first time that nootkatone protected against the progression of CKD in a UUO mouse model. It may serve as a potential therapeutic candidate for CKD intervention.
Effect of Phenolic Compounds on Human Health
Authors: González-Burgos Elena , Gómez-Serranillos M. Pilar
Published: November 2021

This book, based on a Special Issue of Nutrients, contains a total of 12 papers (8 original research and 4 reviews) on the effect of phenolic compounds on human health [...]
Identity of Microfilariae Circulating in Dogs from Western and South-Western Romania in the Last Decade
Authors: Giubega Simona , Imre Mirela , Ilie Marius Stelian , Imre Kálmán , Luca Iasmina , Florea Tiana , Dărăbuș Gheorghe , Morariu Sorin
Published: November 2021

Dirofilaria infections in dogs are recognized as widespread mosquito-borne diseases with zoonotic potential, that are caused by the filarioid nematode (Onchocercidae) species Dirofilaria immitis and Dirofilaria repens. The long-term survey conducted in western and south-western Romania was undertaken in order to provide valuable data on the occurrence of Dirofilaria infections in dogs. Blood samples from 1088 dogs, originating from 73 localities of 11 western and south-western counties in Romania, were collected and examined using the modified Knott test. Subsequently, all of the microscopically positive samples were subjected to molecular analysis for confirmation. Altogether, the data obtained showed the percentage of dogs with circulating microfilariae to be 21.42% (233/1088) of dogs tested in the investigated region. The identified species, in cases of monoinfections, were D. immitis, D. repens, and Acanthocheilonema reconditum in 106 (9.74%) samples, 102 (9.38%) samples, and 1 (0.09%) sample, respectively. Twenty-four (2.21%) samples were simultaneously positive for D. immitis and D. repens. There was no association (p > 0.05) between infection status and breed; however, sex and lifestyle were positively associated (p < 0.05) with the percentage of dogs with circulating microfilariae and might be regarded as risk factors for infection. The results of the present investigation indicate potential zoonotic risks for humans living in the screened area and support the imperative to increase awareness among both veterinarians and physicians, regarding the continuous spread of these zoonotic filariae.
The Oryx Antelope (Oryx gazella): An Unexpected Host for Porcine Circovirus-2 (PCV-2)
Authors: Molini Umberto , Coetzee Lauren Michelle , Hemberger Maria Yvonne , Khaiseb Siegfried , Cattoli Giovanni , Dundon William G. , Franzo Giovanni
Published: November 2021

For several years after its discovery, Porcine circovirus 2 (PCV-2) represented a major threat to the swine industry through economic losses due to the associated clinical syndromes, decreased production performances in both symptomatic and asymptomatic animals and disease management costs. Widespread vaccination administration has largely reduced the impact of this infection and represents the most effective control measure. The efficacy of vaccination is threatened by the emergence of novel (or uncommon) PCV-2 genotypes. In addition to domestic pigs, PCV-2 has been detected in several other species, a fact which could have an impact on new variant emergence and maintenance. Considering this, the present study assessed the distribution of the minor PCV-2c genotype in non-Suidae ungulates in Namibia. Red hartebeests (Alcelaphus buselaphus caama) (n = 44), kudus (Tragelaphus strepsiceros) (n = 10) and oryxes (Oryx gazella) (n = 54), whose mediastinal lymph nodes were sampled after slaughtering during the period 2019–2021, were included in the study. Two oryxes (3.7%; 95% CI = 0.45–12.75%) were PCV-2-positive by PCR. Complete genome sequence was obtained for the two samples identifying them as PCV-2c genotype. The sequences were identical and shared a high percentage of identity (~99.9%) with those recently obtained from warthogs living in the same area. The present study confirms the presence of the PCV-2c genotype (previously considered extinct) in Namibian wild animal populations and demonstrates greater than expected PCV-2 host plasticity. Because of the role these niches can have in the maintenance and evolution of minor PCV-2 genotypes, more extensive and dedicated studies should be performed to prepare authorities to promptly react to potential emerging threats from these viruses.
First Evidence of Chelonid Herpesvirus 5 (ChHV5) Infection in Green Turtles (Chelonia mydas) from Sabah, Borneo
Authors: Loganathan Aswini Leela , Palaniappan Pushpa , Subbiah Vijay Kumar
Published: November 2021

Fibropapillomatosis (FP) of sea turtles is characterised by cutaneous tumours and is associated with Chelonid herpesvirus 5 (ChHV5), an alphaherpesvirus from the family Herpesviridae. Here, we provide the first evidence of ChHV5-associated FP in endangered Green turtles (Chelonia mydas) from Sabah, which is located at the northern region of Malaysian Borneo. The aims of our study were firstly, to determine the presence of ChHV5 in both tumour exhibiting and tumour-free turtles using molecular techniques and secondly, to determine the phylogeography of ChHV5 in Sabah. We also aim to provide evidence of ChHV5 infection through histopathological examinations. A total of 115 Green turtles were sampled from Mabul Island, Sabah. We observed three Green turtles that exhibited FP tumours and were positive for ChHV5. In addition, six clinically healthy turtles (with no presence of tumours) were also positive for the virus based on Polymerase Chain Reaction of three viral genes (Capsid protein gene UL18, Glycoprotein H gene UL22, and Glycoprotein B gene UL27). The prevalence of the ChHV5 was 5.22% in asymptomatic Green turtles. Epidermal intranuclear inclusions were identified in tumour lesions upon histopathological examination. In addition, phylogenetic analyses of the UL18, UL22, UL27, and UL30 gene sequences showed a worldwide distribution of the ChHV5 strain with no clear distinction based on geographical location suggesting an interoceanic connection and movement of the sea turtles. Thus, the emergence of ChHV5 in Green turtles in the waters of Sabah could indicate a possible threat to sea turtle populations in the future and requires further monitoring of the populations along the Bornean coast.
Tissue Pathogens and Cancers: A Review of Commonly Seen Manifestations in Histo- and Cytopathology
Authors: Chua Tzy Harn , Punjabi Lavisha S , Khor Li Yan
Published: November 2021

Tissue pathogens are commonly encountered in histopathology and cytology practice, where they can present as either benign mimickers of malignancy or true malignancies. The aim of this review is to provide a timely synthesis of our understanding of these tissue pathogens, with an emphasis on pertinent diagnostic conundrums associated with the benign mimickers of malignancy that can be seen with viral infections and those which manifest as granulomas. The oncogenic pathogens, including viruses, bacteria, and parasites, are then discussed with relationship to their associated malignancies. Although not exhaustive, the epidemiology, clinical manifestations, pathogenesis, and histological findings are included, along with a short review of emerging therapies.
Plant Food Allergy Improvement after Grass Pollen Sublingual Immunotherapy: A Case Series
Authors: Furci Fabiana , Ricciardi Luisa
Published: November 2021

Background: Cross-reactivity between pollens and plant food has been widely described. Pollen extract subcutaneous immunotherapy in patients with pollens and plant food allergy has been shown to improve tolerance not only to inhalant allergens but also to reduce symptoms in patients with various food allergies. Methods: We retrospectively report our experience with 15 female patients with a positive history for moderate, persistent allergic rhinitis due to grass pollen and oropharyngeal symptoms after ingestion of different plant food. These patients followed a five-grass pollen sublingual tablet immunotherapy for three years in a discontinuous pre-co-seasonal scheme. Results: All 15 patients treated with the 5-grass pollen sublingual tablet immunotherapy, taken once daily for 3 years on a 7-month course, showed improved ocular/nasal symptoms, with a reduction in the use of symptomatic drugs (e.g., nasal corticosteroids and H1 antihistamines). After the first seven-month course of immunotherapy, all patients declared a good tolerance to the intake of fruits and vegetables, and in particular, good tolerance to the offending foods. Conclusions: In conclusion, we have observed improvement of both respiratory and plant food allergies after sublingual immunotherapy (SLIT) with a five-grass pollen tablet.
Variant CJD: Reflections a Quarter of a Century on
Authors: Ritchie Diane L. , Peden Alexander H. , Barria Marcelo A.
Published: November 2021

Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine spongiform encephalopathy (BSE) agent. This hypothesis has since been confirmed though a large body of experimental evidence, predominantly using animal models of the disease. Today, the clinical, pathological and biochemical phenotype of vCJD is well characterized and demonstrates a unique and remarkably consistent pattern between individual cases when compared to other human prion diseases. While the numbers of vCJD cases remain reassuringly low, with 178 primary vCJD cases reported in the UK and a further 54 reported worldwide, concerns remain over the possible appearance of new vCJD cases in other genetic cohorts and the numbers of asymptomatic individuals in the population harboring vCJD infectivity. This review will provide a historical perspective on vCJD, examining the origins of this acquired prion disease and its association with BSE. We will investigate the epidemiology of the disease along with the unique clinicopathological and biochemical phenotype associated with vCJD cases. Additionally, this review will examine the impact vCJD has had on public health in the UK and the ongoing concerns raised by this rare group of disorders.
Rapid Detection of Equine Piroplasms Using Multiplex PCR and First Genetic Characterization of Theileria haneyi in Egypt
Authors: Elsawy Bassma S. M. , Nassar Ahmed M. , Alzan Heba F. , Bhoora Raksha V. , Ozubek Sezayi , Mahmoud Mona S. , Kandil Omnia M. , Mahdy Olfat A.
Published: November 2021

Equine Piroplasmosis (EP) is an infectious disease caused by the hemoprotozoan parasites Theileria equi, Babesia caballi, and the recently identified species T. haneyi. Hereby, we used a multiplex PCR (mPCR) targeting the 18S rRNA gene of T. equi and B. caballi for the simultaneous detection of EP in Egyptian equids and examined the presence of T. haneyi infections in Egypt. Blood samples from 155 equids (79 horses and 76 donkeys) collected from different governorates of Egypt were examined by mPCR and PCR targeting T. hayeni. The mPCR method revealed a prevalence of T. equi of 20.3% in horses and of 13.1% in donkeys and a prevalence of B. caballi of 1.2% in horses. B. caballi was not detected in donkeys in the current study. The mPCR method also detected coinfections with both species (2.5% and 1.3% in horses and donkeys, respectively). Additionally, we report the presence of T. haneyi in Egypt for the first time in 53.1% of the horse and 38.1% of the donkey tested samples. Coinfection with T. haneyi and T. equi was found in 13.5% of the samples, while infection with the three EP species was found in 1.9% of the samples.
Seroprevalence of Toxoplasma gondii in Pinnipeds under Human Care and in Wild Pinnipeds
Authors: Martins Micaela , Urbani Nuno , Flanagan Carla , Siebert Ursula , Gross Stephanie , Dubey Jitender P. , Cardoso Luís , Lopes Ana Patrícia
Published: November 2021

Toxoplasma gondii infection has been reported in numerous species of marine mammals, some of them with fatal consequences. A serosurvey for T. gondii infection was conducted in pinnipeds from an oceanographic park in Portugal (n = 60); stranded pinnipeds on the Portuguese coast (n = 10); and pinnipeds captured in Lorenzensplate, Germany (n = 99). Sera from 169 pinnipeds were tested for the presence of antibodies to T. gondii by the modified agglutination test with a cut-off titre of 25. An overall seroprevalence of 8.9% (95% confidence interval: 5.1–14.2) was observed. Antibody titres of 25, 50, 100, 1600 and ≥3200 were found in five (33.3%), two (13.3%), five (33.3%), one (6.7%) and two (13.3%) animals, respectively. Pinnipeds under human care had a seroprevalence of 20.0% (12/60), in contrast to 2.8% (3/109) in wild pinnipeds (p < 0.001). General results suggest a low exposure of wild pinnipeds to T. gondii, while the seroprevalence found in pinnipeds under human care highlights the importance of carrying out further studies. This is the first serological survey of T. gondii in pinnipeds in Portugal and the first infection report in South African fur seal (Arctocephalus pusillus pusillus).
Effects of Partially Hydrolyzed Guar Gum Supplementation on the Fecal Microbiotas of Piglets
Authors: Inoue Ryo , Otabi Hikari , Yamashita Taiga , Takizawa Naoya , Kido Toshinobu , Sugiyama Akira , Ozeki Makoto , Abe Aya , Tsukahara Takamitsu
Published: November 2021

Probiotics and prebiotics have become viable alternatives of growth-promoting antimicrobials in animal production. Here, we tested partially hydrolyzed guar gum (PHGG) as a possible prebiotic for piglets in the commercial farm. Five hundred and ninety-four piglets were used for the experiments, with 293 given a normal pig feed (control), while the rest the feed plus 0.06% (w/w) of PHGG (PHGG). One and three months post-PHGG supplementation, fecal samples were collected from randomly selected 20 piglets in each group and analyzed for microbiota and organic acid concentrations. Notably, the abundance of Streptococcus, and unclassified Ruminococcaceae were lower (p < 0.05) in PHGG than in control, one-month post-supplementation. Lactobacillus and Prevotella were higher (p < 0.05), while Streptococcus was lower (p < 0.05), in PHGG than in control, three months post-supplementation. The concentrations of acetate, propionate, and butyrate were greater in PHGG than in control, three months post-supplementation. Finally, PHGG grew faster and had fewer deaths until slaughter time (p < 0.05), than control. We concluded that PHGG not only was an effective prebiotic to alter gut microbiota of weanling piglets but also can possibly promote body weight accretion and health.
Polydeoxyribonucleotide: A Promising Biological Platform to Accelerate Impaired Skin Wound Healing
Authors: Galeano Mariarosaria , Pallio Giovanni , Irrera Natasha , Mannino Federica , Bitto Alessandra , Altavilla Domenica , Vaccaro Mario , Squadrito Giovanni , Arcoraci Vincenzo , Colonna Michele Rosario , Lauro Rita , Squadrito Francesco
Published: November 2021

The normal wound healing process is characterized by a complex, highly integrated cascade of events, requiring the interactions of many cell types, including inflammatory cells, fibroblasts, keratinocytes and endothelial cells, as well as the involvement of growth factors and enzymes. However, several diseases such as diabetes, thermal injury and ischemia could lead to an impaired wound healing process characterized by wound hypoxia, high levels of oxygen radicals, reduced angiogenesis, decreased collagen synthesis and organization. Polydeoxyribonucleotide (PDRN) has been used to improve wound healing through local and systemic administration thanks to its ability to promote cell migration and growth, angiogenesis, and to reduce inflammation on impaired wound healing models in vitro, in vivo and clinical studies. In light of all these observations, the aim of this review is to provide a full overview of PDRN applications on skin regeneration. We reviewed papers published in the last 25 years on PubMed, inserting “polydeoxyribonucleotide and wound healing” as the main search term. All data obtained proved the ability of PDRN in promoting physiological tissue repair through adenosine A2A receptor activation and salvage pathway suggesting that PDRN has proven encouraging results in terms of healing time, wound regeneration and absence of side effects.
Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review
Authors: Mottaghipisheh Javad , Taghrir Hadi , Boveiri Dehsheikh Anahita , Zomorodian Kamiar , Irajie Cambyz , Mahmoodi Sourestani Mohammad , Iraji Aida
Published: November 2021

Many flavonoids, as eminent phenolic compounds, have been commercialized and consumed as dietary supplements due to their incredible human health benefits. In the present study, a bioactive flavone glycoside linarin (LN) was designated to comprehensively overview its phytochemical and biological properties. LN has been characterized abundantly in the Cirsium, Micromeria, and Buddleja species belonging to Asteraceae, Lamiaceae, and Scrophulariaceae families, respectively. Biological assessments exhibited promising activities of LN, particularly, the remedial effects on central nervous system (CNS) disorders, whereas the remarkable sleep enhancing and sedative effects as well as AChE (acetylcholinesterase) inhibitory activity were highlighted. Of note, LN has indicated promising anti osteoblast proliferation and differentiation, thus a bone formation effect. Further biological and pharmacological assessments of LN and its optimized semi-synthetic derivatives, specifically its therapeutic characteristics on osteoarthritis and osteoporosis, might lead to uncovering potential drug candidates.
Hydroquinone 5-O-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc
Authors: Hongwiangchan Nattamon , Sriratanasak Nicharat , Wichadakul Duangdao , Aksorn Nithikoon , Chamni Supakarn , Chanvorachote Pithi
Published: November 2021

Cancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the hydroquinone 5-O-cinnamoyl ester of renieramycin M (CIN-RM) was demonstrated to suppress lung cancer CSCs. CIN-RM was toxic to lung cancer cells with a half-maximal inhibitory concentration of around 15 µM. CIN-RM suppressed CSCs by inhibiting colony and tumor spheroid formation. In addition, the CSC population was isolated and treated and the CSCs were dispatched in response to CIN-RM within 24 h. CIN-RM was shown to abolish cellular c-Myc, a central survival and stem cell regulatory protein, with the depletion of CSC markers and stem cell transcription factors ALDH1A1, Oct4, Nanog, and Sox2. For up-stream regulation, we found that CIN-RM significantly inhibited Akt and consequently decreased the pluripotent transcription factors. CIN-RM also inhibited mTOR, while slightly decreasing p-GSK3β (Ser9) but rarely affected the protein kinase C (PKC) signal. Inhibiting Akt/mTOR induced ubiquitination of c-Myc and promoted degradation. The mechanism of how Akt regulates the stability of c-Myc was validated with the Akt inhibitor wortmannin. The computational analysis further confirmed the strong interaction between CIN-RM and the Akt protein with a binding affinity of −10.9 kcal/mol at its critical active site. Taken together, we utilized molecular experiments, the CSC phenotype, and molecular docking methods to reveal the novel suppressing the activity of this compound on CSCs to benefit CSC-targeted therapy for lung cancer treatment.
New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors
Authors: Fareed Momen R. , Shoman Mai E. , Hamed Mohammed I. A. , Badr Mohamed , Bogari Hanin A. , Elhady Sameh S. , Ibrahim Tarek S. , Abuo-Rahma Gamal El-Din A. , Ali Taha F. S.
Published: November 2021

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.
Generation of a Transgenic Zebrafish Line for In Vivo Assessment of Hepatic Apoptosis
Authors: Higuchi Aina , Wakai Eri , Tada Tomoko , Koiwa Junko , Adachi Yuka , Shiromizu Takashi , Goto Hidemasa , Tanaka Toshio , Nishimura Yuhei
Published: November 2021

Hepatic apoptosis is involved in a variety of pathophysiologic conditions in the liver, including hepatitis, steatosis, and drug-induced liver injury. The development of easy-to-perform and reliable in vivo assays would thus greatly enhance the efforts to understand liver diseases and identify associated genes and potential drugs. In this study, we developed a transgenic zebrafish line that was suitable for the assessment of caspase 3 activity in the liver by using in vivo fluorescence imaging. The larvae of transgenic zebrafish dominantly expressed Casper3GR in the liver under control of the promoter of the phosphoenolpyruvate carboxykinase 1 gene. Casper3GR is composed of two fluorescent proteins, tagGFP and tagRFP, which are connected via a peptide linker that can be cleaved by activated caspase 3. Under tagGFP excitation conditions in zebrafish that were exposed to the well-characterized hepatotoxicant isoniazid, we detected increased and decreased fluorescence associated with tagGFP and tagRFP, respectively. This result suggests that isoniazid activates caspase 3 in the zebrafish liver, which digests the linker between tagGFP and tagRFP, resulting in a reduction in the Förster resonance energy transfer to tagRFP upon tagGFP excitation. We also detected isoniazid-induced inhibition of caspase 3 activity in zebrafish that were treated with the hepatoprotectants ursodeoxycholic acid and obeticholic acid. The transgenic zebrafish that were developed in this study could be a powerful tool for identifying both hepatotoxic and hepatoprotective drugs, as well as for analyzing the effects of the genes of interest to hepatic apoptosis.
Evaluation of Amyloid Polypeptide Aggregation Inhibition and Disaggregation Activity of A-Type Procyanidins
Authors: Tanaka Taisei , Betkekar Vipul V. , Ohmori Ken , Suzuki Keisuke , Shigemori Hideyuki
Published: November 2021

The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid polypeptide (hIAPP) that aggregates in the pancreas are considered cytotoxic and the cause of the development of AD and T2D, respectively. Thus, inhibiting amyloid polypeptide aggregation and disaggregation existing amyloid aggregates are promising approaches in the therapy and prevention against both diseases. Therefore, in this research, we evaluated the Aβ/hIAPP anti-aggregation and disaggregation activities of A-type procyanidins 1–7 and their substructures 8 and 9, by conducting structure–activity relationship studies and identified the active site. The thioflavin-T (Th-T) assay, which quantifies the degree of aggregation of amyloid polypeptides based on fluorescence intensity, and transmission electron microscopy (TEM), employed to directly observe amyloid polypeptides, were used to evaluate the activity. The results showed that catechol-containing compounds 1–6 exhibited Aβ/hIAPP anti-aggregation and disaggregation activities, while compound 7, without catechol, showed no activity. This suggests that the presence of catechol is important for both activities. Daily intake of foods containing A-type procyanidins may be effective in the prevention and treatment of both diseases.
Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension
Authors: Baranowska-Kuczko Marta , Kozłowska Hanna , Kloza Monika , Kusaczuk Magdalena , Harasim-Symbor Ewa , Biernacki Michał , Kasacka Irena , Malinowska Barbara
Published: November 2021

Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.
Influence of Stabilizer on the Development of Luteolin Nanosuspension for Cutaneous Delivery: An In Vitro and In Vivo Evaluation
Authors: Elmowafy Mohammed , Shalaby Khaled , Al-Sanea Mohammad M. , Hendawy Omnia M. , Salama Ayman , Ibrahim Mohamed F. , Ghoneim Mohammed M.
Published: November 2021

Luteolin is a natural drug used as an antioxidant and anti-inflammatory, but unfortunately, it possesses low water solubility, which hinders its delivery via the skin. The main objective of this study was to prepare a luteolin-loaded nanosuspension by the antisolvent precipitation/sonication technique and study the effects of four stabilizers (two nonionic stabilizers, Pluronic F127 and Tween 80, and two polymeric stabilizers, HPMC and alginate) on the physicochemical properties of the prepared formulations. The selected formulations were incorporated into a gel base to evaluate their skin permeability and anti-inflammatory efficacy. The particle size was in the nanosize range (in the range from 468.1 ± 18.6 nm to 1024.8 ± 15.9 nm), while the zeta potential was negative and in the range from −41.7 ± 6.3 mV to −15.3 ± 1.9 mV. In particular, alginate-stabilized nanosuspensions showed the smallest particle size, the highest zeta potential value, and excellent stability due to the dual stabilizing effects (electrostatic and steric effects). The DSC results revealed a less crystalline structure of luteolin in lyophilized NS2 and NS12. Formulations stabilized by 1% Pluronic (NS2) and 2% alginate (NS12) were incorporated into a carbopol 940 gel base and showed good organoleptic character (homogenous with no evidenced phase separation or grittiness). In vitro dissolution studies showed that NS12 enhanced luteolin release rates, indicating the effect of particle size on the drug release pattern. On the other hand, NS2 showed enhanced skin permeability and anti-inflammatory effect in a carrageenan-induced paw edema model, revealing the surface activity role of the stabilizers. In conclusion, while alginate increased the nanosuspension stability by means of dual stabilizing effects, Pluronic F127 improved the skin delivery and pharmacodynamic efficacy of luteolin.
Liposomal Nanocarriers Designed for Sub-Endothelial Matrix Targeting under Vascular Flow Conditions
Authors: Grimsley Lauren B. , West Phillip C. , McAdams Callie D. , Bush Charles A. , Kirkpatrick Stacy S. , Arnold Joshua D. , Buckley Michael R. , Dieter Raymond A. , Freeman Michael B. , McNally Michael M. , Stevens Scott L. , Grandas Oscar H. , Mountain Deidra J. H.
Published: November 2021

Vascular interventions result in the disruption of the tunica intima and the exposure of sub-endothelial matrix proteins. Nanoparticles designed to bind to these exposed matrices could provide targeted drug delivery systems aimed at inhibiting dysfunctional vascular remodeling and improving intervention outcomes. Here, we present the progress in the development of targeted liposomal nanocarriers designed for preferential collagen IV binding under simulated static vascular flow conditions. PEGylated liposomes (PLPs), previously established as effective delivery systems in vascular cells types, served as non-targeting controls. Collagen-targeting liposomes (CT-PLPs) were formed by conjugating established collagen-binding peptides to modified lipid heads via click chemistry (CTL), and inserting them at varying mol% either at the time of PLP assembly or via micellar transfer. All groups included fluorescently labeled lipid species for imaging and quantification. Liposomes were exposed to collagen IV matrices statically or via hemodynamic flow, and binding was measured via fluorometric analyses. CT-PLPs formed with 5 mol% CTL at the time of assembly demonstrated the highest binding affinity to collagen IV under static conditions, while maintaining a nanoparticle characterization profile of ~50 nm size and a homogeneity polydispersity index (PDI) of ~0.2 favorable for clinical translation. When liposomes were exposed to collagen matrices within a pressurized flow system, empirically defined CT-PLPs demonstrated significant binding at shear stresses mimetic of physiological through pathological conditions in both the venous and arterial architectures. Furthermore, when human saphenous vein explants were perfused with liposomes within a closed bioreactor system, CT-PLPs demonstrated significant ex vivo binding to diseased vascular tissue. Ongoing studies aim to further develop CT-PLPs for controlled targeting in a rodent model of vascular injury. The CT-PLP nanocarriers established here show promise as the framework for a spatially controlled delivery platform for future application in targeted vascular therapeutics.
Citrus Flavanone Narirutin, In Vitro and In Silico Mechanistic Antidiabetic Potential
Authors: Qurtam Ashraf Ahmed , Mechchate Hamza , Es-safi Imane , Al-zharani Mohammed , Nasr Fahd A. , Noman Omar M. , Aleissa Mohammed , Imtara Hamada , Aleissa Abdulmalik M. , Bouhrim Mohamed , Alqahtani Ali S.
Published: November 2021

Citrus fruits and juices have been studied extensively for their potential involvement in the prevention of various diseases. Flavanones, the characteristic polyphenols of citrus species, are the primarily compounds responsible for these studied health benefits. Using in silico and in vitro methods, we are exploring the possible antidiabetic action of narirutin, a flavanone family member. The goal of the in silico research was to anticipate how narirutin would interact with eight distinct receptors implicated in diabetes control and complications, namely, dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), alpha-amylase (AAM), peroxisome proliferator-activated receptor gamma (PPAR-γ), alpha-glucosidase (AGL), while the in vitro study looked into narirutin’s possible inhibitory impact on alpha-amylase and alpha-glucosidase. The results indicate that the studied citrus flavanone interacted remarkably with most of the receptors and had an excellent inhibitory activity during the in vitro tests suggesting its potent role among the different constituent of the citrus compounds in the management of diabetes and also its complications.
Advanced Therapy Medicinal Products for Eye Diseases: Goals and Challenges
Authors: Diebold Yolanda , García-Posadas Laura
Published: November 2021

Advanced therapy medicinal products (ATMPs) are a novel class of medicines with enormous potential to improve treatments for a wide range of diseases, including those affecting eye structures [...]
Inhalable Microparticles Embedding Calcium Phosphate Nanoparticles for Heart Targeting: The Formulation Experimental Design
Authors: Quarta Eride , Sonvico Fabio , Bettini Ruggero , De Luca Claudio , Dotti Alessandro , Catalucci Daniele , Iafisco Michele , Degli Esposti Lorenzo , Colombo Gaia , Trevisi Giovanna , Rekkas Dimitrios M. , Rossi Alessandra , Wong Tin Wui , Buttini Francesca , Colombo Paolo
Published: November 2021

Inhalation of Calcium Phosphate nanoparticles (CaPs) has recently unmasked the potential of this nanomedicine for a respiratory lung-to-heart drug delivery targeting the myocardial cells. In this work, we investigated the development of a novel highly respirable dry powder embedding crystalline CaPs. Mannitol was selected as water soluble matrix excipient for constructing respirable dry microparticles by spray drying technique. A Quality by Design approach was applied for understanding the effect of the feed composition and spraying feed rate on typical quality attributes of inhalation powders. The in vitro aerodynamic behaviour of powders was evaluated using a medium resistance device. The inner structure and morphology of generated microparticles were also studied. The 1:4 ratio of CaPs/mannitol led to the generation of hollow microparticles, with the best aerodynamic performance. After microparticle dissolution, the released nanoparticles kept their original size.
Safety and Efficacy of Combined Low-Dose Lithium and Low-Dose Aspirin: A Pharmacological and Behavioral Proof-of-Concept Study in Rats
Authors: Shvartsur Rachel , Agam Galila , Shnaider Alla , Uzzan Sarit , Nassar Ahmad , Jabarin Adi , Abu-Freha Naim , Meir Karen , Azab Abed N.
Published: November 2021

Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin—all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.
Intranasal Zolmitriptan-Loaded Bilosomes with Extended Nasal Mucociliary Transit Time for Direct Nose to Brain Delivery
Authors: El Taweel Mai M. , Aboul-Einien Mona H. , Kassem Mohammed A. , Elkasabgy Nermeen A.
Published: November 2021

This study aimed at delivering intranasal zolmitriptan directly to the brain through preparation of bilosomes incorporated into a mucoadhesive in situ gel with extended nasal mucociliary transit time. Zolmitriptan-loaded bilosomes were constructed through a thin film hydration method applying Box–Behnken design. The independent variables were amount of sodium deoxycholate and the amount and molar ratio of cholesterol/Span® 40 mixture. Bilosomes were assessed for their entrapment efficiency, particle size and in vitro release. The optimal bilosomes were loaded into mucoadhesive in situ gel consisting of poloxamer 407 and hydroxypropyl methylcellulose. The systemic and brain kinetics of Zolmitriptan were evaluated in rats by comparing intranasal administration of prepared gel to an IV solution. Statistical analysis suggested an optimized bilosomal formulation composition of sodium deoxycholate (5 mg) with an amount and molar ratio of cholesterol/Span® 40 mixture of 255 mg and 1:7.7, respectively. The mucoadhesive in situ gel containing bilosomal formulation had a sol-gel temperature of 34.03 °C and an extended mucociliary transit time of 22.36 min. The gelling system possessed enhanced brain bioavailability compared to bilosomal dispersion (1176.98 vs. 835.77%, respectively) following intranasal administration. The gel revealed successful brain targeting with improved drug targeting efficiency and direct transport percentage indices. The intranasal delivery of mucoadhesive in situ gel containing zolmitriptan-loaded bilosomes offered direct nose-to-brain drug targeting with enhanced brain bioavailability.
Targeting Engineered Nanoparticles for Breast Cancer Therapy
Authors: Ganesan Kumar , Wang Yan , Gao Fei , Liu Qingqing , Zhang Chen , Li Peng , Zhang Jinming , Chen Jianping
Published: November 2021

Breast cancer (BC) is the second most common cancer in women globally after lung cancer. Presently, the most important approach for BC treatment consists of surgery, followed by radiotherapy and chemotherapy. The latter therapeutic methods are often unsuccessful in the treatment of BC because of their various side effects and the damage incurred to healthy tissues and organs. Currently, numerous nanoparticles (NPs) have been identified and synthesized to selectively target BC cells without causing any impairments to the adjacent normal tissues or organs. Based on an exploratory study, this comprehensive review aims to provide information on engineered NPs and their payloads as promising tools in the treatment of BC. Therapeutic drugs or natural bioactive compounds generally incorporate engineered NPs of ideal sizes and shapes to enhance their solubility, circulatory half-life, and biodistribution, while reducing their side effects and immunogenicity. Furthermore, ligands such as peptides, antibodies, and nucleic acids on the surface of NPs precisely target BC cells. Studies on the synthesis of engineered NPs and their impact on BC were obtained from PubMed, Science Direct, and Google Scholar. This review provides insights on the importance of engineered NPs and their methodology for validation as a next-generation platform with preventive and therapeutic effects against BC.