bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on the Canine Adenovirus Type 1 (CAdV-1) Infection in Domestic Dogs in Southern Italy
Authors: Mira Francesco , Puleio Roberto , Schirò Giorgia , Condorelli Lucia , Di Bella Santina , Chiaramonte Gabriele , Purpari Giuseppa , Cannella Vincenza , Balboni Andrea , Randazzo Vincenzo , Antoci Francesco , Vicari Domenico , Guercio Annalisa
Published: October 2022

Canine adenovirus type 1 (CAdV-1) is the causative agent of a systemic and potentially fatal viral disease of domestic and wild canids. In Italy, CAdV-1 infection has also been occasionally described in dogs, but information on the epidemiology and its genomic features is still limited. A study was conducted on 291 dogs suspected of infectious gastrointestinal disease. Samples collected from dogs in southern Italy between 2017 and 2020 were analyzed. Virological and histopathological assays were carried out. The presence of CAdVs and other canine viral enteropathogens was investigated, and sequence and phylogenetic analyses were performed. CAdV-1 was detected in six (2.1%) dead stray dogs alone or in mixed infections with other viruses. Gross lesions and histopathological findings referred to CAdV infection were observed, also involving the central nervous system tissues. All inoculated samples were successfully isolated. Sequence analysis evidenced divergences with the circulating strains previously described in Italy and a closer relation with older CAdV-1 strains collected from other countries, suggesting a genetic heterogeneity of CAdV-1 in Italy. The evidence of the circulation of CAdV-1 and its genomic features allows us to have more in-depth knowledge of the epidemiology and evolution of the CAdV-1 genomic variants.
First Isolation of Yarrowia lipolytica in a Granulomatous Pneumonia of a Spectacled Caiman, Caiman crocodilus Linnaeus, 1758
Authors: Iurescia Manuela , Santini Andrea , Montagnani Marco , Diaconu Elena Lavinia , Stravino Fiorentino , Agnelli Devid , Vergari Emanuela , Fichi Gianluca , Eleni Claudia
Published: October 2022

Contrary to humans, candidiasis is a rare infection in animals. However, in reptiles, candidiasis can cause gastrointestinal, cutaneous, or rarely systemic infections in stressed animals. The infections due to Yarrowia lipolytica have been increasingly described in human medicine, and hundreds of cases are reported, comprised of granulomatous lung lesions. Herein, granulomatous pneumonia of a spectacled caiman, Caiman crocodilus, was described, and the presence of Y. lipolytica in the lesion was confirmed through histopathology, microbiologic cultures, and molecular methods. The cause of death of the spectacled caiman was ascribed to bacterial shock septicemia consequentially to a traumatic lesion. However, in the right lung, several nodules containing white exudate were evidenced. At mycological and molecular analyses, Y. lipolytica was evidenced, and the histological finding confirmed the presence of a Candida infection in the lung granulomatous lesions. The comparison of ITS sequences with 11 Yarrowia spp. isolates, recently described in green sea turtles, and with a human strain was conducted, and the whole genome of a strain isolated in the spectacled caiman was sequenced. Even though Y. lipolytica is considered a non-pathogenic yeast and has been rarely described in animals, it seems to cause granulomatous lesions in reptiles as in humans.
Neuro–Immune Interactions in Severe COVID-19 Infection
Authors: Rossi Elena , Mutti Luciano , Morrione Andrea , Giordano Antonio
Published: October 2022

SARS-CoV-2 is a new coronavirus that has affected the world since 2019. Interstitial pneumonia is the most common clinical presentation, but additional symptoms have been reported, including neurological manifestations. Severe forms of infection, especially in elderly patients, present as an excessive inflammatory response called “cytokine storm”, which can lead to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Little is known about the relationship between symptoms and clinical outcomes or the characteristics of virus–host interactions. The aim of this narrative review is to highlight possible links between neurological involvement and respiratory damage mediated by pathological inflammatory pathways in SARS-CoV-2 infection. We will focus on neuro–immune interactions and age-related immunity decline and discuss some pathological mechanisms that contribute to negative outcomes in COVID-19 patients. Furthermore, we will describe available therapeutic strategies and their effects on COVID-19 neurological symptoms.
Infection by Salmonella enterica Serovar Typhimurium DT104 Modulates Immune Responses, the Metabolome, and the Function of the Enteric Microbiota in Neonatal Broiler Chickens
Authors: Bescucci Danisa M. , Montina Tony , Boras Valerie F. , Inglis G. Douglas
Published: October 2022

Salmonella enterica serovar Typhimurium incites salmonellosis in many different species including chickens and human beings. Acute salmonellosis was studied in neonatal broiler chicks by orally inoculating 2-day-old chicks with S. Typhimurium DT104. The temporal impact of disease (1, 2, and 4 days post-inoculation) on the structure and function of the enteric microbiota, on the bird’s immune response in the ileum, cecum, and colon, and on the metabolome of digesta, breast muscle, liver, serum, and hippocampus were examined. Substantive histopathologic changes were observed in the small and large intestine, including the colon of chicks inoculated with S. Typhimurium, and increased in magnitude over the experimental time period. A variety of inflammatory genes (IFNγ, IL8, IL10, INOS, MIP1β, TGFβ2, TLR4, and TLR15) were temporally regulated. In addition, the metabolome of ileal digesta, breast muscle, liver, serum, and hippocampus was temporally altered in infected chicks. Although the structure of bacterial communities in digesta was not affected by S. Typhimurium infection, metabolomic analysis indicated that the function of the microbiota was changed. Collectively, the study findings demonstrate that infection of neonatal chicks by S. Typhimurium imparts a temporal and systemic impact on the host, affecting the immune system, the metabolome, and the function of the enteric microbiota.
Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs
Authors: Duthie Malcolm S. , Machado Bruna A. S. , Badaró Roberto , Kaye Paul M. , Reed Steven G.
Published: October 2022

Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. Unfortunately, multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial. The recent maturation of RNA vaccines into licensed products in the context of COVID-19 indicates the likelihood of broader use of the technology. Herein, we discuss the potential benefits provided by RNA technology as an approach to address the bottlenecks encountered for Leishmania vaccines. Further, we outline a variety of strategies that could be used to more efficiently evaluate Leishmania vaccine efficacy, including controlled human infection models and initial use in a therapeutic setting, that could prioritize candidates before evaluation in larger, longer and more complicated field trials.
Seasonal Investigation of Anaplasma marginale Infection in Pakistani Cattle Reveals Hematological and Biochemical Changes, Multiple Associated Risk Factors and msp5 Gene Conservation
Authors: Asif Muhammad , Ben Said Mourad , Vinueza Rommel Lenin , Leon Renato , Ahmad Nadeem , Parveen Asia , Khan Adil , Ejaz Arusa , Ali Muhammad , Khan Asmat Ullah , Baber Muhammad , Iqbal Furhan
Published: October 2022

Bovine anaplasmosis is a tick-borne disease caused by an obligate intercellular Gram-negative bacterium named Anaplasma (A.) marginale. In this study, we report the seasonal prevalence, potentially associated risk factors and phylogeny of A. marginale in cattle of three different breeds from Multan District, Southern Punjab, Pakistan. A total of 1020 blood samples (crossbred, n = 340; Holstein Friesian, n = 340; and Sahiwal breed, n = 340) from apparently healthy cattle were collected on a seasonal basis from March 2020 to April 2021. Based on PCR amplification of the msp5 partial sequence, overall, the A. marginale prevalence rate was estimated at 11.1% (113/1020) of the analyzed cattle samples. According to seasons, the highest prevalence rate was observed in autumn (16.5%), followed by winter (10.6%) and summer (9.8%), and the lowest was recorded in the spring (7.5%). The crossbred and Sahiwal cattle were the most susceptible to A. marginale infection, followed by Holstein Friesian cattle (7.9%). Analysis of epidemiological factors revealed that cattle reared on farms where dairy animals have tick loads, dogs coinhabit with cattle and dogs have tick loads have a higher risk of being infected with A. marginale. In addition, it was observed that white blood cell, lymphocyte (%), monocyte (%), hematocrit, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentrations were significantly disturbed in A. marginale-positive cattle compared with non-infested cattle. Genetic analysis of nucleotide sequences and a phylogenetic study based on msp5 partial sequencing demonstrated that this gene appears to be highly conserved among our isolates and those infecting apparently healthy cattle from geographically diverse worldwide regions. The presented data are crucial for estimating the risk of bovine anaplasmosis in order to develop integrated control policies against bovine anaplasmosis and other tick-borne diseases infecting cattle in the country.
Detection of Anti-Neospora caninum IgG in Blood Serum and Colostrum Samples in Naturally Infected Sheep and in Their Newborn Offspring
Authors: Bezerra Roberto Alves , Lima Brendo Andrade , Alvares Felipe Boniedj Ventura , Rossi Gabriel Augusto Marques , Braga Fabio Ribeiro , de Melo Renata Pimentel Bandeira , Mota Rinaldo Aparecido , Vilela Vinícius Longo Ribeiro , Feitosa Thais Ferreira
Published: October 2022

The aim was to detect correlations of IgG antibodies against N. caninum in serum and colostrum samples from ewes, through the IFAT, and to evaluate the presence of this immunoglobulin in the serum of newborn lambs after colostrum ingestion. Blood samples from 162 ewes that did not show any disease in the general physical examination and from their newborn lambs, not more than five days postpartum, along with 162 colostrum samples and 182 blood samples from the neonates, were analyzed. In total, 27.8% (45/162) of the mothers were positive for anti-N. caninum IgG, among which antibodies were detected in the colostrum in 46.7% (21/45). All the ewes with positive colostrum had reactive offspring. The kappa agreement for the correlation between the serological tests on the ewes and the colostrum results was 0.558. This correlation increased as the antibody titers of the mothers increased, and reached 1.000 from the titer of 1:400 from the mothers. Comparison of the antibody detection results between the offspring’s serum and colostrum showed a kappa agreement of 1.000. In conclusion, there was a good agreement regarding the detection of anti-N. caninum IgG between the colostrum samples and the lambs’ serum; the use of colostrum forms a noninvasive alternative for diagnosing N. caninum in sheep herds.
New Corynebacterium Species with the Potential to Produce Diphtheria Toxin
Authors: Prygiel Marta , Polak Maciej , Mosiej Ewa , Wdowiak Karol , Formińska Kamila , Zasada Aleksandra
Published: October 2022

Only three Corynebacterium species are known to produce a lethal exotoxin called diphtheria toxin. These are C. diphtheriae, C. ulcerans and C. pseudotuberculosis. The diphtheria toxin gene (tox) is carried in a family of closely related corynebacteriophages and therefore the toxin can be produced only through lysogenisation, in which the corynephage encoding tox is stably inserted into the chromosome. However, ‘nontoxigenic tox gene-bearing’ (NTTB) strains, which are genotypically tox-positive but do not express the protein, have been described. The emergence of NTTB strains was first observed during the 1990s diphtheria epidemic in Eastern Europe and nowadays such isolates have been detected in many countries in the world. Recently, novel species of Corynebacterium genus have been described which might have the potential of producing the diphtheria toxin due to the possession of the diphtheria toxin gene but it has not produced toxin in laboratory tests. The circulation of NTTB strains could be related to the increased risk for diphtheria disease arising from the risk of re-emerging toxin expression. The article presents the mechanism of diphtheria toxin expression and action, recently described novel species of NTTB corynebacteria as well as the taxonomic changes within the C. diphtheriae group.
Next Generation Sequencing and Comparative Genomic Analysis Reveal Extreme Plasticity of Two Burkholderia glumae Strains HN1 and HN2
Authors: Wang Sai , Nie Wenhan , Yiming Ayizekeranmu , Wang Peihong , Wu Yan , Huang Jin , Ahmad Iftikhar , Chen Gongyou , Guo Longbiao , Zhu Bo
Published: October 2022

Burkholderia glumae is an important rice pathogen, thus the genomic and evolutionary history may be helpful to control this notorious pathogen. Here, we present two complete genomes of the B. glumae strains HN1 and HN2, which were isolated from diseased rice seed in China. Average nucleotide identity (ANI) analysis shows greater than 99% similarity of the strains HN1 and HN2 with other published B. glumae genomes. Genomic annotation revealed that the genome of strain HN1 consists of five replicons (6,680,415 bp) with an overall G + C content of 68.06%, whereas the genome of strain HN2 comprises of three replicons (6,560,085 bp) with an overall G + C content of 68.34%. The genome of HN1 contains 5434 protein-coding genes, 351 pseudogenes, and 1 CRISPR, whereas the genome of HN2 encodes 5278 protein-coding genes, 357 pseudogenes, and 2 CRISPR. Both strains encode many pathogenic-associated genes (143 genes in HN1 vs. 141 genes in HN2). Moreover, comparative genomic analysis shows the extreme plasticity of B. glumae, which may contribute to its pathogenicity. In total, 259 single-copy genes were affected by positive selection. These genes may contribute to the adaption to different environments. Notably, six genes were characterized as virulence factors which may be an additional way to assist the pathogenicity of B. glumae.
Epidemiological Survey of the Main Tick-Borne Pathogens Infecting Dogs from the Republic of Moldova
Authors: D’Amico Gianluca , Ionică Angela Monica , Györke Adriana , Dumitrache Mirabela Oana
Published: October 2022

Despite the significant burden of tick-borne diseases (TBDs), epidemiologic studies are missing, and TBD awareness is low in the Republic of Moldova. Our study is the first to assess the prevalence of the main tick-borne pathogens (TBPs) infecting dogs in this country and associated risk factors. In this cross-sectional, multi-centre study (June 2018–July 2019), blood samples were collected from dogs presenting in veterinary clinics (Chişinău: N = 30) and hosted in public dog shelters (Cahul: N = 42; Chişinău: N = 48). TBPs were assessed by molecular techniques and risk factors by the logistic regression model. Hepatozoon canis was the most prevalent TBP (15.8% [19/120]), followed by Babesia canis (11.7% [14/120]), Anaplasma phagocytophilum (5.8% [7/120]), and Bartonella spp. (0.8% [1/120]). Blood samples tested negative for Borrelia spp., Rickettsia spp., Francisella tularensis, Anaplasma platys, and Ehrlichia canis. Dogs originating from the veterinary clinics had a higher prevalence of A. phagocytophilum infection than those from the shelters (16.6% versus 2.2%, respectively, p = 0.0292; OR: 27.0 [95%CI: 1.4–521.9]). Dogs from Chișinău had a higher prevalence of Hepatozoon canis infection versus those from Cahul (19.2% versus 9.5%, respectively, p = 0.0295; OR: 3.9 [95%CI: 1.1–13.4]). We recommend routine use of acaricides and deworming of dogs to prevent or/and limit TBD spread. Further TBD surveillance studies are needed.
Hybrid Approach to Identifying Druglikeness Leading Compounds against COVID-19 3CL Protease
Authors: Aqeel Imra , Bilal Muhammad , Majid Abdul , Majid Tuba
Published: October 2022

SARS-CoV-2 is a positive single-strand RNA-based macromolecule that has caused the death of more than 6.3 million people since June 2022. Moreover, by disturbing global supply chains through lockdowns, the virus has indirectly caused devastating damage to the global economy. It is vital to design and develop drugs for this virus and its various variants. In this paper, we developed an in silico study-based hybrid framework to repurpose existing therapeutic agents in finding drug-like bioactive molecules that would cure COVID-19. In the first step, a total of 133 drug-likeness bioactive molecules are retrieved from the ChEMBL database against SARS coronavirus 3CL Protease. Based on the standard IC50, the dataset is divided into three classes: active, inactive, and intermediate. Our comparative analysis demonstrated that the proposed Extra Tree Regressor (ETR)-based QSAR model has improved prediction results related to the bioactivity of chemical compounds as compared to Gradient Boosting-, XGBoost-, Support Vector-, Decision Tree-, and Random Forest-based regressor models. ADMET analysis is carried out to identify thirteen bioactive molecules with the ChEMBL IDs 187460, 190743, 222234, 222628, 222735, 222769, 222840, 222893, 225515, 358279, 363535, 365134, and 426898. These molecules are highly suitable drug candidates for SARS-CoV-2 3CL Protease. In the next step, the efficacy of the bioactive molecules is computed in terms of binding affinity using molecular docking, and then six bioactive molecules are shortlisted, with the ChEMBL IDs 187460, 222769, 225515, 358279, 363535, and 365134. These molecules can be suitable drug candidates for SARS-CoV-2. It is anticipated that the pharmacologist and/or drug manufacturer would further investigate these six molecules to find suitable drug candidates for SARS-CoV-2. They can adopt these promising compounds for their downstream drug development stages.
Ligand Growing Experiments Suggested 4-amino and 4-ureido pyridazin-3(2H)-one as Novel Scaffold for FABP4 Inhibition
Authors: Crocetti Letizia , Floresta Giuseppe , Zagni Chiara , Merugu Divya , Mazzacuva Francesca , de Oliveira Silva Renan Rodrigues , Vergelli Claudia , Giovannoni Maria Paola , Cilibrizzi Agostino
Published: October 2022

Fatty acid binding protein (FABP4) inhibitors are of synthetic and therapeutic interest and ongoing clinical studies indicate that they may be a promise for the treatment of cancer, as well as other diseases. As part of a broader research effort to develop more effective FABP4 inhibitors, we sought to identify new structures through a two-step computing assisted molecular design based on the established scaffold of a co-crystallized ligand. Novel and potent FABP4 inhibitors have been developed using this approach and herein we report the synthesis, biological evaluation and molecular docking of the 4-amino and 4-ureido pyridazinone-based series.
Exploitation and Verification of a Stroma- and Metastasis-Associated Risk Prognostic Signature in Pancreatic Adenocarcinoma
Authors: Zheng Jia-Hao , Yao Hong-Fei , Duan Zong-Hao , Ji Pei-Xuan , Yang Jian , Zhu Yu-Heng , Jia Qin-Yuan , Yang Jian-Yu , Liu De-Jun , Sun Yong-Wei , Chen Peng-Cheng , Shi Pei-Dong , Chen Li
Published: October 2022

Pancreatic adenocarcinoma (PAAD), one of the most malignant tumors, not only has abundant mesenchymal components, but is also characterized by an extremely high metastatic risk. The purpose of this study was to construct a model of stroma- and metastasis-associated prognostic signature, aiming to benefit the existing clinical staging system and predict the prognosis of patients. First, stroma-associated genes were screened from the TCGA database with the ESTIMATE algorithm. Subsequently, transcriptomic data from clinical tissues in the RenJi cohort were screened for metastasis-associated genes. Integrating the two sets of genes, we constructed a risk prognostic signature by Cox and LASSO regression analysis. We then obtained a risk score by a quantitative formula and divided all samples into high- and low-risk groups based on the scores. The results demonstrated that patients with high-risk scores have a worse prognosis than those with low-risk scores, both in the TCGA database and in the RenJi cohort. In addition, tumor mutation burden, chemotherapeutic drug sensitivity and immune infiltration analysis also exhibited significant differences between the two groups. In exploring the potential mechanisms of how stromal components affect tumor metastasis, we simulated different matrix stiffness in vitro to explore its effect on EMT key genes in PAAD cells. We found that cancer cells stimulated by high matrix stiffness may trigger EMT and promote PAAD metastasis.
In Vivo Treatment with a Standardized Green Tea Extract Restores Cardiomyocyte Contractility in Diabetic Rats by Improving Mitochondrial Function through SIRT1 Activation
Authors: Vilella Rocchina , Izzo Simona , Naponelli Valeria , Savi Monia , Bocchi Leonardo , Dallabona Cristina , Gerra Maria Carla , Stilli Donatella , Bettuzzi Saverio
Published: October 2022

Background. Green tea catechins are known to promote mitochondrial function, and to modulate gene expression and signalling pathways that are altered in the diabetic heart. We thus evaluated the effectiveness of the in vivo administration of a standardized green tea extract (GTE) in restoring cardiac performance, in a rat model of early streptozotocin-induced diabetes, with a focus on the underlying mechanisms. Methods. Twenty-five male adult Wistar rats were studied: the control (n = 9), untreated diabetic animals (n = 7) and diabetic rats subjected to daily GTE administration for 28 days (n = 9). Isolated ventricular cardiomyocytes were used for ex vivo measurements of cell mechanics and calcium transients, and molecular assays, including the analysis of functional protein and specific miRNA expression. Results. GTE treatment induced an almost complete recovery of cardiomyocyte contractility that was markedly impaired in the diabetic cells, by preserving mitochondrial function and energy availability, and modulating the expression of the sarcoplasmic reticulum calcium ATPase and phospholamban. Increased Sirtuin 1 (SIRT1) expression and activity substantially contributed to the observed cardioprotective effects. Conclusions. The data supported the hypothesis that green tea dietary polyphenols, by targeting SIRT1, can constitute an adjuvant strategy for counteracting the initial damage of the diabetic heart, before the occurrence of diabetic cardiomyopathy.
Effects of Oleacein, a New Epinutraceutical Bioproduct from Extra Virgin Olive Oil, in LPS-Activated Murine Immune Cells
Authors: Muñoz-García Rocío , Sánchez-Hidalgo Marina , Montoya Tatiana , Alcarranza Manuel , Ortega-Vidal Juan , Altarejos Joaquín , Alarcón-de-la-Lastra Catalina
Published: October 2022

The present study was designed to evaluate the immunomodulatory effects of the secoiridoid from extra virgin olive oil, oleacein (OLA), deepening into the possible signaling pathways involved in LPS-activated murine peritoneal macrophages. Moreover, we have explored OLA-induced epigenetic changes in histone markers and related cytokine production in murine LPS-stimulated murine splenocytes. Murine cells were treated with OLA in the presence or absence of LPS (5 μg/mL) for 18 or 24 h. OLA modulated the oxidative stress and the inflammatory response produced by LPS stimulation in murine peritoneal macrophages, by the inhibition of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ, IL-17 and IL-18) and ROS production and the expression of pro-inflammatory enzymes such as iNOS, COX-2 and m-PGES1. These protective effects could be due to the activation of the Nrf-2/HO-1 axis and the inhibition of JAK/STAT, ERK and P38 MAPKs and inflammasome canonical and non-canonical signaling pathways. Moreover, OLA modulated epigenetic modifications throughout histone methylation deacetylation (H3K18ac) and (H3K9me3 and H3K27me) in LPS-activated spleen cells. In conclusion, our data present OLA as an interesting anti-inflammatory and antioxidant natural compound that is able to regulate histone epigenetic markers. Nevertheless, additional in vivo studies are required to further investigate the beneficial effects of this EVOO secoiridoid, which might be a promising epinutraceutical bioproduct for the management of immune-related inflammatory diseases.
Recent Advances in Hepatocellular Carcinoma Treatment with Radionuclides
Authors: Liu Ruiqi , Li Hong , Qiu Yihua , Liu Hongguang , Cheng Zhen
Published: October 2022

As the third leading cause of cancer death worldwide, hepatocellular carcinoma (HCC) is characterized by late detection, difficult diagnosis and treatment, rapid progression, and poor prognosis. Current treatments for liver cancer include surgical resection, radiofrequency ablation, liver transplantation, chemotherapy, external radiation therapy, and internal radionuclide therapy. Radionuclide therapy is the use of high-energy radiation emitted by radionuclides to eradicate tumor cells, thus achieving the therapeutic effect. Recently, with the continuous development of biomedical technology, the application of radionuclides in treatment of HCC has progressed steadily. This review focuses on three types of radionuclide-based treatment regimens, including transarterial radioembolization (TARE), radioactive seed implantation, and radioimmunotherapy. Their research progress and clinical applications are summarized. The advantages, limitations, and clinical potential of radionuclide treatment of HCC are discussed.
Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules
Authors: Tassone Giusy , Mazzorana Marco , Pozzi Cecilia
Published: October 2022

Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90.
Combined Effects of Methyldopa and Baicalein or Scutellaria baicalensis Roots Extract on Blood Pressure, Heart Rate, and Expression of Inflammatory and Vascular Disease-Related Factors in Spontaneously Hypertensive Pregnant Rats
Authors: Szulc Michał , Kujawski Radosław , Mikołajczak Przemysław Ł. , Bogacz Anna , Wolek Marlena , Górska Aleksandra , Czora-Poczwardowska Kamila , Ożarowski Marcin , Gryszczyńska Agnieszka , Baraniak Justyna , Kania-Dobrowolska Małgorzata , Adamczak Artur , Iwańczyk-Skalska Ewa , Jagodziński Paweł P. , Czerny Bogusław , Kamiński Adam , Uzar Izabela , Seremak-Mrozikiewicz Agnieszka
Published: October 2022

The aim of the study was to investigate the effect of baicalein or Scutellaria baicalensis root extract interaction with methyldopa in pregnant spontaneously hypertensive rats (SHR) at the pharmacodynamic, molecular, and biochemical levels. The rats, after confirming pregnancy, received baicalein (200 mg/kg/day, p.o.) and extract (1000 mg/kg/day, p.o.), in combination with methyldopa (400 mg/kg/day; p.o.), for 14 consecutive days, 1 h before blood pressure and heart rate measurements. In the heart and placenta from mothers after giving birth to their offspring, mRNA expression of factors related to inflammatory processes (TNF-α, Il-1β, IL-6) and vascular diseases (TGF-β, HIF-1α, VEGF, PlGF) was measured. Levels of markers of oxidative stress (superoxide dismutase and malondialdehyde) in the placenta and indicators of myocardial damage (troponin cTnC and cTnI, creatine kinase, myoglobin, and lactate dehydrogenase) in the heart were also assessed. Baicalein co-administered with methyldopa was associated with reduced blood pressure, especially during the first three days. The interactions were more pronounced for such factors as TGF-β, HIF-1α, VEGF, and PlGF than TNF-α, Il-1β, and IL-6. Combined application of baicalein and extract with methyldopa may be of value in the development of a new antihypertensive medication intended for patients suffering from preeclampsia or pregnancy-induced hypertension.
Central Composite Design Implemented Azilsartan Medoxomil Loaded Nanoemulsion to Improve Its Aqueous Solubility and Intestinal Permeability: In Vitro and Ex Vivo Evaluation
Authors: Kumar Girish , Virmani Tarun , Pathak Kamla , Kamaly Omkulthom Al , Saleh Asmaa
Published: October 2022

The present research attempted to design and develop a nanoemulsion formulation of azilsartan medoxomil to improve its aqueous solubility and intestinal permeability. Based on the solubility profile, ethyl oleate, tween 80, and Transcutol P were selected as the oil phase, surfactant, and co-surfactant, respectively. Central composite design (CCD) suggested an optimized azilsartan medoxomil- nanoemulsion formulation (optimized AZL-NE formulation) with 1.25% oil, 15.73% Smix, and 90 s ultrasonication time; it was found to have the droplet size, percentage transmittance, and % cumulative drug release (%CDR) of 71.5 nm, 93.46 ± 1.13%, and 90.14 ± 0.94%, respectively. Furthermore, it exhibited a 0.141 polydispersity index, 34.05 mV zeta potential, a 1.413 ± 0.03 refractive index, 6.68 ± 0.22 pH, 28.17 ± 0.52 cps viscosity, and a 96.98 ± 0.94% percentage drug content. Transmission electron microscopy (TEM) assessed the nano-sized spherical shape, and a differential scanning calorimeter (DSC) assessed the solubilization of the drug in the optimized formulation. The %CDR was 1.71 times higher and the % cumulative drug permeation was 2.1 times higher for the optimized AZL-NE formulation than for the drug suspension through an intestinal segment of a rat, which was also supported by confocal laser scanning microscopy (CLSM) studies. Thus, the nanoemulsion formulation of azilsartan medoxomil ensured the enhancement of the drug availability in the body.
The Role of Anthocyanin in Modulating Diabetic Cardiovascular Disease and Its Potential to Be Developed as a Nutraceutical
Authors: Sapian Syaifuzah , Taib Izatus Shima , Katas Haliza , Latip Jalifah , Zainalabidin Satirah , Hamid Zariyantey Abd , Anuar Nur Najmi Mohamad , Budin Siti Balkis
Published: October 2022

Cardiovascular disease (CVD) is directly linked to diabetes mellitus (DM), and its morbidity and mortality are rising at an alarming rate. Individuals with DM experience significantly worse clinical outcomes due to heart failure as a CVD consequence than non-diabetic patients. Hyperglycemia is the main culprit that triggers the activation of oxidative damage, inflammation, fibrosis, and apoptosis pathways that aggravate diabetic CVD progression. In recent years, the development of phytochemical-based nutraceutical products for diabetic treatment has risen due to their therapeutic properties. Anthocyanin, which can be found in various types of plants, has been proposed for preventing and treating various diseases, and has elicited excellent antioxidative, anti-inflammation, anti-fibrosis, and anti-apoptosis effects. In preclinical and clinical studies, plants rich in anthocyanin have been reported to attenuate diabetic CVD. Therefore, the development of anthocyanin as a nutraceutical in managing diabetic CVD is in demand. In this review, we unveil the role of anthocyanin in modulating diabetic CVD, and its potential to be developed as a nutraceutical for a therapeutic strategy in managing CVD associated with DM.
Network Pharmacology of Ginseng (Part III): Antitumor Potential of a Fixed Combination of Red Ginseng and Red Sage as Determined by Transcriptomics
Authors: Panossian Alexander , Abdelfatah Sara , Efferth Thomas
Published: October 2022

Background: This study aimed to assess the effect of a fixed combination of Red Ginseng and Red Sage (RG–RS) on the gene expression of neuronal cells to evaluate the potential impacts on cellular functions and predict its relevance in the treatment of stress and aging-related diseases and disorders. Methods: Gene expression profiling was conducted by transcriptome-wide mRNA microarray analyses of murine HT22 hippocampal cell culture after treatment with RG–RS preparation. Ingenuity pathway analysis (IPA) was performed with datasets of significantly upregulated or downregulated genes and the expected effects on the physiological and cellular function and the diseases were identified. Results: RG–RS deregulates 1028 genes associated with cancer and 139 with metastasis, suggesting a predicted decrease in tumorigenesis, the proliferation of tumor cells, tumor growth, metastasis, and an increase in apoptosis and autophagy by their effects on the various signaling and metabolic pathways, including the inhibition of Warburg’s aerobic glycolysis, estrogen-mediated S-phase entry signaling, osteoarthritis signaling, and the super-pathway of cholesterol biosynthesis. Conclusion: The results of this study provide evidence of the potential efficacy of the fixed combination of Red Ginseng (Panax ginseng C.A. Mey.) and Red Sage/Danshen (Salvia miltiorrhiza Bunge) in cancer. Further clinical and experimental studies are required to assess the efficacy and safety of RG–RS in preventing the progression of cancer, osteoarthritis, and other aging-related diseases.
Correction: Nguyen et al. Oligonucleotide Solid Nucleolipid Nanoparticles against Antibiotic Resistance of ESBL-Producing Bacteria. Pharmaceutics 2022, 14, 299
Authors: Nguyen Phuoc Vinh , Aubry Clémentine , Boudaoud Narimane , Gaubert Alexandra , Langlois Marie-Hélène , Marchivie Mathieu , Gaudin Karen , Arpin Corinne , Barthélémy Philippe , Kauss Tina
Published: October 2022

In the original publication [...]
Investigation of a Minocycline-Loaded Nanoemulgel for the Treatment of Acne Rosacea
Authors: Siddiqui Ayesha , Jain Pooja , Alex Thompson Santosh , Ali Mohammed Asgar , Hassan Nazia , Haneef Jamshed , Naseef Punnoth Poonkuzhi , Kuruniyan Mohamed Saheer , Mirza Mohd. Aamir , Iqbal Zeenat
Published: October 2022

In the present investigation, a nanoemulgel of minocycline was formulated and optimized for an improved drug delivery and longer retention time in the targeted area. Combining eucalyptus oil, Tween 20, and Transcutol HP, different o/w nanoemulsions were formulated by the oil phase titration method and optimized by pseudo-ternary phase diagrams. The morphology, droplet size, viscosity, and refractive index of the thermodynamically stable nanoemulsion were determined. Furthermore, optimized nanoemulsion was suspended in 1.0% w/v of Carbopol 940 gel to formulate the nanoemulgel, and for this, pH, viscosity, and spreadability were determined and texture analysis was performed. To compare the extent of drug penetration between nanoemulsion and nanoemulgel, ex vivo skin permeation studies were conducted with Franz diffusion cell using rat skin as the permeation membrane, and the nanoemulgel exhibited sustained-release behavior. It can be concluded that the suggested minocycline-containing naoemulgel is expected to treat acne rosacea more effectively.
Evaluation and Validation of the Limited Sampling Strategy of Polymyxin B in Patients with Multidrug-Resistant Gram-Negative Infection
Authors: Li Xueyong , Zhang Bingqing , Cheng Yu , Chen Maohua , Lin Hailing , Huang Binglin , Que Wancai , Liu Maobai , Zhou Lili , Weng Qinyong , Zhang Hui , Qiu Hongqiang
Published: October 2022

Polymyxin B (PMB) is the final option for treating multidrug-resistant Gram-negative bacterial infections. The acceptable pharmacokinetic/pharmacodynamic target is an area under the concentration–time curve across 24 h at a steady state (AUCss,24h) of 50–100 mg·h/L. The limited sampling strategy (LSS) is useful for predicting AUC values. However, establishing an LSS is a time-consuming process requiring a relatively dense sampling of patients. Further, given the variability among different centers, the predictability of LSSs is frequently questioned when it is extrapolated to other clinical centers. Currently, limited data are available on a reliable PMB LSS for estimating AUCss,24h. This study assessed and validated the practicability of LSSs established in the literature based on data from our center to provide reliable and ready-made PMB LSSs for laboratories performing therapeutic drug monitoring (TDM) of PMB. The influence of infusion and sampling time errors on predictability was also explored to obtain the optimal time points for routine PMB TDM. Using multiple regression analysis, PMB LSSs were generated from a model group of 20 patients. A validation group (10 patients) was used to validate the established LSSs. PMB LSSs from two published studies were validated using a dataset of 30 patients from our center. A population pharmacokinetic model was established to simulate the individual plasma concentration profiles for each infusion and sampling time error regimen. Pharmacokinetic data obtained from the 30 patients were fitted to a two-compartment model. Infusion and sampling time errors observed in real-world clinical practice could considerably affect the predictability of PMB LSSs. Moreover, we identified specific LSSs to be superior in predicting PMB AUCss,24h based on different infusion times. We also discovered that sampling time error should be controlled within −10 to 15 min to obtain better predictability. The present study provides validated PMB LSSs that can more accurately predict PMB AUCss,24h in routine clinical practice, facilitating PMB TDM in other laboratories and pharmacokinetics/pharmacodynamics-based clinical studies in the future.
A Simple, Safe, and Effective Method for Preparing Autologous Bio-Based Fibrin Glue for Ophthalmic Use
Authors: Fernández-Vega-Cueto Luis , Persinal-Medina Mairobi , Vázquez Natalia , Chacón Manuel , Alfonso-Bartolozzi Belén , Alonso-Alonso Sergio , Sánchez Teresa , Berisa-Prado Silvia , Martínez-López Laura María , Merayo-Lloves Jesús , Meana Álvaro
Published: October 2022

This study proposes a method to prepare autologous bio-based fibrin glue (FG) for use in ophthalmic surgery. FGs containing three fibrinogen concentrations and a thrombin concentrate were prepared using human blood from five donors (FG1: physiological fibrinogen concentration; FG2 and FG3: concentrated fibrinogen). The adhesion strength was tested, and the clinical safety and efficacy were studied in rabbit eyes in conjunctival surgery. A commercial FG was used as a control. From each donor, 2 mL of FG was prepared, containing 1 mL of 3.49 ± 0.78 (FG1), 17.74 ± 4.66 (FG2), or 47.46 ± 9.36 mg/mL (FG3) of fibrinogen and 1 mL of 2248.12 ± 604.20 UI/mL of thrombin. The average adhesion strength increased with the fibrinogen concentration, from 1.49 ± 0.39 kPa (FG1) to 3.14 ± 1.09 kPa (FG3). FG1 showed poor results when used for autograft adhesion. In contrast, the conjunctival autografts were successfully grafted using FG2 and FG3, revealing equivalent adhesion properties compared with commercial FG, but with less inflammation. In conclusion, FGs could be prepared on demand within minutes from small volumes of human blood, using a method that results in FGs which exhibit good adhesion capacity and are also safe and effective in a preclinical study.
Chondrogenic Differentiation of Human Mesenchymal Stem Cells via SOX9 Delivery in Cationic Niosomes
Authors: Carballo-Pedrares Natalia , Sanjurjo-Rodriguez Clara , Señarís Jose , Díaz-Prado Silvia , Rey-Rico Ana
Published: October 2022

Gene transfer to mesenchymal stem cells constitutes a powerful approach to promote their differentiation into the appropriate cartilage phenotype. Although viral vectors represent gold standard vehicles, because of their high efficiency, their use is precluded by important concerns including an elevated immunogenicity and the possibility of insertional mutagenesis. Therefore, the development of new and efficient non-viral vectors is under active investigation. In the present study, we developed new non-viral carriers based on niosomes to promote the effective chondrogenesis of human MSCs. Two different niosome formulations were prepared by varying their composition on non-ionic surfactant, polysorbate 80 solely (P80), or combined with poloxamer 407 (P80PX). The best niosome formulation was proven to transfer a plasmid, encoding for the potent chondrogenic transcription factor SOX9 in hMSC aggregate cultures. Transfection of hMSC aggregates via nioplexes resulted in an increased chondrogenic differentiation with reduced hypertrophy. These results highlight the potential of niosome formulations for gene therapy approaches focused on cartilage repair.
The Translational Landscape Revealed the Sequential Treatment Containing ATRA plus PI3K/AKT Inhibitors as an Efficient Strategy for AML Therapy
Authors: Wang Ke , Ou Ziyao , Deng Ge , Li Shufang , Su Jingjing , Xu Yayun , Zhou Renpeng , Hu Wei , Chen Feihu
Published: October 2022

The present study aimed to better understand the possibility of utilizing all-trans retinoic acids (ATRA) in acute myeloid leukemia (AML). We found that ATRA significantly suppressed global translation and protein synthesis in AML cells. The efficacy of ATRA in treating AML required its translational regulatory functions, as shown by the fact that the decrease in the universal eukaryotic initiation factor 4E (eIF4E) was essential to maintain the induction of cell growth arrest and differentiation by ATRA. By establishing a specific translational landscape, we suggested that transcripts with simple 5′UTR gained a translational advantage in AML cells during ATRA stress. Based on that, the genes translationally regulated by ATRA were mainly enriched in phosphatidylinositol-3-kinase/Akt (PI3K/AKT) signaling; we subsequently revealed that PI3K/AKT activation was required for ATRA to effectively induce AML cell differentiation. However, PI3K/AKT has been reported to promote the stemness of AML cells. As such, we further suggested that sequential treatment including ATRA and PI3K/AKT inhibitor induced robust apoptosis, extremely inhibited the clonality of AML cells, and suppressed the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-driven transformation of CD34+ hematopoietic stem/progenitor cells. Future clinical studies are warranted to further support the clinical application of the sequential strategy for the effective treatment of AML.
Structural Optimization of Platinum Drugs to Improve the Drug-Loading and Antitumor Efficacy of PLGA Nanoparticles
Authors: Sokol Maria B. , Chirkina Margarita V. , Yabbarov Nikita G. , Mollaeva Mariia R. , Podrugina Tatyana A. , Pavlova Anna S. , Temnov Viktor V. , Hathout Rania M. , Metwally Abdelkader A. , Nikolskaya Elena D.
Published: October 2022

Currently, molecular dynamics simulation is being widely applied to predict drug–polymer interaction, and to optimize drug delivery systems. Our study describes a combination of in silico and in vitro approaches aimed at improvement in polymer-based nanoparticle design for cancer treatment. We applied the PASS service to predict the biological activity of novel carboplatin derivatives. Subsequent molecular dynamics simulations revealed the dependence between the drug–polymer binding energy along with encapsulation efficacy, drug release profile, and the derivatives’ chemical structure. We applied ICP-MS analysis, the MTT test, and hemolytic activity assay to evaluate drug loading, antitumor activity, and hemocompatibility of the formulated nanoparticles. The drug encapsulation efficacy varied from 0.2% to 1% and correlated with in silico modelling results. The PLGA nanoparticles revealed higher antitumor activity against A549 human non-small-cell lung carcinoma cells compared to non-encapsulated carboplatin derivatives with IC50 values of 1.40–23.20 µM and 7.32–79.30 µM, respectively; the similar cytotoxicity profiles were observed against H69 and MCF-7 cells. The nanoparticles efficiently induced apoptosis in A549 cells. Thus, nanoparticles loaded with novel carboplatin derivatives demonstrated high application potential for anticancer therapy due to their efficacy and high hemocompatibility. Our results demonstrated the combination of in silico and in vitro methods applicability for the optimization of encapsulation and antitumor efficacy in novel drug delivery systems design.
Discovery of Novel Thiosemicarbazides Containing 1,3,5-Triazines Derivatives as Potential Synergists against Fluconazole-Resistant Candida albicans
Authors: Xie Fei , Hao Yumeng , Liu Jiacun , Bao Junhe , Ni Tingjunhong , Liu Yu , Chi Xiaochen , Wang Ting , Yu Shichong , Jin Yongsheng , Li Liping , Zhang Dazhi , Yan Lan
Published: October 2022

The clinical prevalence of antifungal drug resistance has been increasing over recent years, resulting in the failure of treatments. In an attempt to overcome this critical problem, we sought novel synergistic enhancers to restore the effectiveness of fluconazole against resistant Candida albicans. Based on the structural optimization of hit compound 8 from our in-house library, a series of novel 1,3,5-triazines derivatives was designed, synthesized, and biologically evaluated for synergistic activity in combination with fluconazole. Among them, compounds 10a–o, which contain thiosemicarbazides side chains, exhibited excellent in vitro synergistic antifungal potency (MIC80 = 0.125–2.0 μg/mL, FICI range from 0.127 to 0.25). Interestingly, compound 10l exhibited moderate C. albicans activity as monotherapy with an MIC80 value of 4.0 μg/mL, and also on several Cryptococcus strains (MIC80 ranging from ≤ 0.125–0.5 μg/mL) and C. glabrata (MIC80 ≤ 0.125 μg/mL). These effects were fungal-selective, with much lower levels of cytotoxicity towards human umbilical vein endothelial cells. Here, we report a series of thiosemicarbazides containing 1,3,5-triazines derivatives as potent synergists with fluconazole, and have preliminarily validated compound 10l as a promising antifungal lead for further investigation.