bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis, Anticancer Activity, Docking Calculations and Hydrolytic
Stability Studies of Bioconjugates of Monofluorenated Analogue of BIM-
23052
Authors: Danalev Dancho , Iliev Ivan , Borisova Dessislava , Dzimbova Tatyana , Pajpanova Tamara , Zaharieva Zdravka , Karadjova Veronika , Foteva Tsvetelina , Naydenova Emilia 
Published: May 2022

Background:
The fight against cancer has started since its discovery and has not
subsided to nowadays. Currently, the hybrid molecules have become a promising alternative to the
standard chemotherapeutics for the treatment of multi-causal diseases, including cancers.

Objective:
Herein, we report the synthesis, biological evaluation, mathematical docking calculations
and hydrolytic stability of the new bioconjugates of monofluorinated analogues of BIM-23052,
containing second pharmacophore naphthalimide, caffeic acid or the tripeptide Arg-Gly-Asp.

Method:
All new molecules are obtained using standard peptide synthesis on solid support.
Anticancer potential is studied against a panel of tumor cell lines included human mammary
carcinoma cell lines MCF-7 (ER+, PR+ and Her-2-); MDA-MB-231 (ER-, PR- and Her-2-), as well
as cell lines BALB 3T3 (mouse embryonic fibroblasts) and MCF-10A (human breast epithelial cell
line).

Results:
The IC50 values found in the MCF-10A cell line assay were used to calculate the selective
index (SI). The highest SI relative to MCF-7, with a value of 2.62 is shown by the compound Npht-
Gly-D-Phe-Phe(4-F)-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2. In MCF-10 cells, the weakest antiproliferative
effect was caused by the same compound (IC50 = 622.9 ± 23.91 μM), which makes this
analogue a good candidate for the new anticancer medical drug. Unfortunately, the hydrolytic
stability studies reveal that this bioconjugate is the most unstable of hydrolysis under physiological
conditions in the body.

Conclusion:
Even with lower anticancer activity and selectivity in comparison with Npht-Gly-DPhe-
Phe(4-F)-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2, the compound Arg-Gly-Asp-D-Phe-Phe(4-F)-Phe-
D-Trp-Lys-Thr-Phe-Thr-NH2 is the best candidate between three investigated bioconjugates for
practical application due to combination of activity and stability profiles. Mathematical docking
calculation also reveals that synthesized bioconjugates show selectivity according to different
somatostatin receptors on the surface of different cell lines.
Applications of Gold Nanoparticles in Brain Diseases across the
Blood-Brain Barrier
Authors: Zhang Jun , Yang Ting , Huang Wan , Yu Yao , Sun Taolei 
Published: May 2022

Abstract:
Brain diseases, including Alzheimer's disease (AD), brain tumors and Parkinson's
disease (PD), pose heavy pressure on the public healthcare system. The main obstacle
to vanquish brain diseases is the blood-brain barrier (BBB), which is a selective barrier
mainly formed by brain endothelial cells. BBB prevents almost all drugs from reaching
the brain, thereby hindering drug delivery. Over the past few decades, considerable
signs of progress have been made in crossing the BBB and treating brain diseases. Gold
nanoparticles (AuNPs) demonstrate the characteristics of adjustable size, unique optical
properties, flexible surface modification, and good biocompatibility, which all contribute
AuNPs as a promising candidate in biomedical fields. This article reviews the structure
and properties of BBB, and discusses main transport routes through the BBB. Besides,
nanoparticles, specially AuNPs applied in brain diseases as main drug delivery platforms,
are systematically summarized, emphasizing several methods to modify AuNPs,
including tuning particle size and surface modification, which are aimed at promoting
BBB penetration or prolonging circulation time of AuNPs. In addition, AuNPs utilized in
brain diseases are introduced in detail from the aspects of brain imaging, AD, brain tumors,
and PD. Prospects and challenges that need to be considered in further investigations
and clinical transformation of AuNPs used in brain diseases are also included, hoping
to bring new insights into the applications of AuNPs in brain diseases.
A Global Analysis of Alternative Splicing of Dichocarpum Medicinal
Plants, Ranunculales
Authors: Hao Da-Cheng , Jiang Tao , Chen Hao , Xiao Pei-Gen 
Published: May 2022

Background:
The multiple isoforms are often generated from a single gene via alternative splicing (AS) in plants, and the functional diversity of plant genome is significantly increased. Despite well studied gene functions, the specific functions of isoforms are little known, therefore the accurate prediction of isoform functions is exceedingly wanted.

Methods:
Here we perform the first global analysis of AS of Dichocarpum, a medicinal genus of Ranunculales, by utilizing full-length transcriptome datasets of five Chinese endemic Dichocarpum taxa. Multiple softwares were used to identify AS events, the gene function was annotated based on seven databases, and the protein coding sequence of each AS isoform was translated into an amino acid sequence. The self-developed software DIFFUSE was used to predict the functions of AS isoforms.

Results:
Among 8,485 genes with AS events, the genes with two isoforms were the most (6,038), followed by those with three isoforms and four isoforms. Retained intron (RI, 551) was predominant among 1,037 AS events, and alternative 3' splice sites and alternative 5' splice sites were second. The software DIFFUSE was effective in predicting functions of Dichocarpum isoforms, which have not been unearthed. When compared with the sequence alignment-based database annotations, DIFFUSE performed better in differentiating isoform functions. The DIFFUSE predictions on the terms GO:0003677 (DNA binding) and GO: 0010333 (terpene synthase activity) agreed with biological features of transcript isoforms.

Conclusion:
Numerous AS events were for the first time identified from full-length transcriptome datasets of five Dichocarpum taxa, and functions of AS isoforms were successfully predicted by the self-developed software DIFFUSE. The global analysis of Dichocarpum AS events and predicting isoform functions can help understand metabolic regulations of medicinal taxa and their pharmaceutical explorations.
Caralluma edulis (Apocynaceae): A Comprehensive Review on its Traditional
Uses, Phytochemical Profile and Pharmacological Effects
Authors: Ansari Bushra , Behl Tapan , Pirzada Abdul Saboor , Khan Haroon 
Published: May 2022

Abstract:
Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional sys-tem of treatment. It has been recommended for the treatment of a number medical disorders such as hypertension, Alzheimer’s disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological ef-fects of C. edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant, and analgesic activity against inflammation as well as xylene-mediated ear edema as topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in the rabbit model at test doses. These pharmacological effects are strong-ly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C. edulis is a very po-tential member of the genus Caralluma with strong traditional history, phytochemistry and phyto-pharmacology, and needs further exploration for clinically used lead compounds. In this review, we have focused on combining different reported data on the traditional uses of the plant, its phyto-chemical profile and pharmacological effects in different experimental assay along with subsequent future prospects.
Gm15886-Hipk1 Signaling Pathway Plays Important Roles in the Pathogenesis
of Bronchopulmonary Dysplasia Mice
Authors: Zhu Haiyan , Wu Chantong , Bao Tianping , Tian Zhaofang , Cheng Huaiping , Wang Huifang , Wang Wei , Zheng Yafei 
Published: May 2022

Background:
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in the
respiratory system of premature infants. Gm15886, as a lncRNA, is highly expressed in lung tissue of
BPD newborn mice.

Aims:
This study aimed to clarify the roles of the Gm15886 gene in the pathogenesis of BPD mice by
determining the expression of Gm15886 and Hipk1 in lung tissues.

Methods:
Sequence and localization of the Gm15886 gene and the related information of its adjacent
genes were obtained using the UCSC browsing tool. The targeting gene of the Gm15886 was predicted
using the Ensemble database and double luciferase assay. Neonatal C57BL/6J mice were exposed to 95%
hyperoxia for 7 days to generate the hyperoxia-induced BPD mouse model. RT-PCR assay was used to
detect Gm15886, Hipk1, and VEGF gene transcriptions in lung tissues in the development process of
BPD (0, 3, 5, and 7 days). The pathological changes in lung tissues and Hipk1/VEGF gene transcription
in lung tissues were detected in the Gm15886 gene silenced BPD mice.

Results:
Gm15886 gene transcription in lung tissues was significantly increased in mice of the hyperoxia
model group compared to that in the air control group (p<0.05). Gm15886 gene could completely bind
and interact with the base sequence within the second exon of the Hipk1 gene. Hipk1 was a targeting gene
for Gm15886. Gene transcription and expression of Hipk1 were remarkably enhanced in mice of the hyperoxia
model group compared to that in the air control group (p<0.05). The silencing of the Gm15886
gene improved alveolar morphology and markedly downregulated Hipk1 and upregulated VEGF gene
transcription compared to those in the Blank vector BPD group (p<0.05).

Conclusions:
Gm15886-Hipk1 signaling pathway plays a critical role in the pathogenesis of BPD through
modulating Hipk1 and VEGF gene transcription. This study might provide a theoretical basis for the
treatment of BPD.
Identification of Novel Nontoxic Mutants of Diphtheria Toxin Unable to
ADP-ribosylate EF2 Using Molecular Dynamics Simulations and Free
Energy Calculations
Authors: Tarahomjoo Shirin , Ghaderi Soheila , Esmaelizad Majid , Noofeli Mojtaba , Bozorgmehr Mohammad Reza 
Published: May 2022

Introduction:
The Diphtheria vaccine is currently manufactured by chemical inactivation of
Diphtheria toxin (DT) following large-scale cultivation of the pathogenic Corynebacterium diphtheriae.
The development of non-toxic variants of DT in non-pathogenic recombinant hosts improves the process
safety aspects considerably and is therefore desirable. The cytotoxicity of DT was exerted through ADPribosylation
of elongation factor 2 (EF2) by the catalytic (C) domain of DT using NAD as the ADP donor.

Aim:
We, therefore, aim to design DT variants unable to perform ADP-ribosylation of EF2.

Methods:
We used molecular dynamics simulations (MDS) for docking of the C-domain of DT onto EF2
to identify interacting amino acid fluctuations using the root mean square fluctuation (RMSF). Amino
acids of the C domain possessing low fluctuations and hence low flexibility were then specified and used
for the mutant design. The C domain and the mutants were docked with NAD and ADENYLYL-3'-5'-
PHOSPHO-URIDINE3'-MONOPHOSPHATE (APU) as a C domain inhibitor. G52E showing negligible
NAD binding was also included in our study. Free binding energies of the complexes were calculated and
used to select the desired mutants. Moreover, contact maps of the C domain and the selected mutants
were compared to elucidate their structural differences. The SCRATCH tool was used to estimate their
solubility upon recombinant expression in E. coli. ElliPro was further used to determine their B-cell
epitopes.

Results:
Our results indicated that amino acids Y20, V80, V81, V83, and Y149 within the C domain
showed low flexibility. The constructed mutants, including Y20E and Y80E were able to bind APU,
whereas Y149E was not able to bind it. Both Y20E and Y149E were unable to bind NAD. Thus, these
mutants did not have ADP-ribosylation activity and were nontoxic. These were structurally different from
the C domain. However, their solubility in E. coli and their conformational B-cell epitopes were similar to
those of the C domain.

Conclusion:
Therefore, Y20E and Y149E are applicable for the vaccine design with DT using a much
safer process compared to the commercial process.
A Review on the Recent Multicomponent Synthesis of 4H-Pyran Derivatives
Authors: El-Bana Ghada G. , Salem Mohammed A. , Helal Mohamed H. , Alharbi Osama , Gouda Moustafa A. 
Published: May 2022

Abstract:
4H-Pyran is a well-known moiety, which appears in various natural and synthetic products. These compounds include various biological activities like anti-hepatotoxic, antitumor, anti-inflammatory, antioxidant, anti-spasmolytic, diuretic, estrogenic, anticoagulant, antifungal, antiviral, anti-helminthic, antimicrobial, hypothermal, anti-tubercular, anti-HIV, herbicidal, anticonvulsant and analgesic activity. This review has summarized an overview of general strategies that allow the design of 4H-pyran derivatives via catalyzed one-pot multicomponent reactions.
Case Report on Pulmonary Involvement in a Patient with Adult Still’s Disease
Authors: Rachina Svetlana , Dvoretsky Leonid , Torgashina Anna , Dubrovskaya Nelli , Hewathanthirige Girindu 
Published: May 2022

Background:
Pulmonary manifestations and lung impairment are rarely associated with
the Adult Still's Disease and are reported in less than 5%.

Case Presentation:
The present clinical case describes the Adult Still's Disease with pulmonary involvement
in a 45- year-old male. The main clinical manifestations included continuous fever, failure
to respond to antibiotic therapy, skin rashes, musculoskeletal syndrome and pharyngitis. Additionally,
bronchopulmonary lymphadenopathy, interstitial changes and dense foci with clear contours
were detected in the lungs. Laboratory abnormalities included neutrophilic leukocytosis, increased
ALT, AST, and elevated serum inflammatory marker levels. A cyclical course characterised
the disease with strictly defined time intervals between flare-ups and remissions. After the prescription
of methylprednisolone with the subsequent addition of methotrexate, complete regression of
clinical symptoms, normalization of laboratory tests, and partial regression of computed tomography
findings in the lungs were observed.

Conclusions:
Despite the low incidence, pulmonary involvement is an unfavorable manifestation of
Adult Still's Disease. An individual feature of this case report was the asymptomatic lung involvement
manifested only by changes revealed through computed tomography. For a long time, flareups
of the disease were considered bacterial infections of unclear nature requiring systemic antibiotics.
Effect of Postharvest Treatments on the Biosynthesis of Fruit Volatile
Compounds: A Literature Review
Authors: Magalhães Hilton César Rodrigues , Garruti Deborah dos Santos , Gandra Eliezer Ávila , Purgatto Eduardo 
Published: May 2022

Abstract:
Fruits have different aromatic profiles according to their stage of ripeness, therefore, volatile compounds profile is an important quality attribute, which also determines flavor and aroma characteristics, making this profile a perfect option to guide the optimization of postharvest treatment of fruits. In this context, the objective was to discuss the effects of postharvest treatments, associating them with the biosynthesis of volatile compounds in fruits. There are three major groups of fruit flavor precursors: carbohydrates, amino acids, and fatty acids. The biosynthesis of volatile compounds is directly related to metabolic changes that occur according to the fruit ripening stage. This process occurs under the regulation of hormones, which have ethylene as one of the main agents. Several hormones are also part of this complex mechanism and interact by regulating ethylene levels positively or negatively to form a fine adjustment. Therefore, hormonal treatments have an impact on the biosynthesis of volatile compounds in different ways. Other postharvest treatments such as cold storage, controlled atmosphere, and UV radiation can also impact the volatile compounds biosynthesis, but are generally used synergistically, which circumvents the negative effects on the aromatic profile of the fruits.
UPLC-MS-based Method Development, Validation, and Optimization of
Dissolution Using Quality by Design Approach for Low Dose Digoxin: A
Novel Strategy
Authors: Kumar Pramod , Patel Hitesh B. , P.R. Hemanth Vikram , Beeraka Narasimha M. , Gurupadayya B.M. 
Published: May 2022

Background:
Digoxin, a cardiac glycoside is the one of the most significant drugs of choice for the congestive heart failure treatment. As Digoxin is a BCS class IV drug, the dissolution is a critical quality attribute for its tablet formulation.

Methods:
Current work aims to quantify the dissolution drug release for low dosage digoxin of 0.0625mg tablets with targeted drug release of more than 80% at 60 minutes by highly sensitive, fast, and versatile UPLC-MS technique. UPLC-MS method operated by positive ionization mode with ACQUITY UPLC C18 (2.1 cm x 100 mm, 1.8 µm) column and flow rate of 0.3ml/min has been developed and validated for parameters like linearity, precision, accuracy, ruggedness, limit of detection (LOD) and limit of quantification (LOQ) as per the ICH guidelines.

Results:
LOD was found to be 21 ng/mL. Collision energy for digoxin was observed as 35eV for QDa mass detector along with 803.5m/z precursor ion and 651m/z daughter ion. An optimal custom experimental design was employed to optimize the final dissolution conditions. The critical dissolution factors selected for optimization were pH of dissolution media, dissolution media volume, rpm (rotations per minute). The %drug release (DR) was selected as a critical quality attribute with the desired response of drug release >80% at 60minutes. Outcomes of the design were further evaluated by statistical tools including ANOVA. The final optimized dissolution method consists of 500mL of pH 7.4 buffer with a USP apparatus of I (Basket) rotating at 120 rpm.

Conclusion:
In this current work, we have optimized the dissolution conditions by QbD, and developed a sensitive UPLC-MS method for quantification of digoxin, that can be used in routine quality control purposes efficiently in dissolution testing and quantification of batches of low dose digoxin tablets.
Microwave-induced Facile Synthesis of Highly Strained Three-membered Ring Compounds and Some of Their Reactions
Authors: Banik Bimal Krishna , Kaur Manpreet 
Published: May 2022

Abstract:Compounds with three membered rings experience greater strain than those with other ring systems. In general, the synthesis of small ring compounds, particularly three-membered molecules, faces major challenges because of the severe strain in this system. Moreover, microwaveassisted method creates a higher temperature due to the heat and radiation of a reaction mixture more rapidly than conventional methods. This paper reports the successful synthesis of threemembered heterocyclic compounds via microwave-assisted reactions. Microwaves have assisted in making three-membered compounds while inducing high energy to the reaction mixtures. No reviews have reported the synthesis of these types of molecules either by microwave or conventional procedure. In addition, the reaction of a few three-membered ring compounds to other products through the ring rupture method is also included. On this basis of the chemistry (formation and breakage) of three-membered compounds described here, this report can be considered novel, timely, and highly significant. This review may help numerous researchers for further study in this field as the synthesis and cleavage of three-membered ring structures using a microwave is a challenging objective.
Molnupiravir in COVID-19: A Scoping Review
Authors: Atal Shubham , Kaore Shilpa 
Published: May 2022

Background:
COVID-19, first detected in Wuhan, China, has evolved into a lifethreatening
pandemic spread across six continents, with the global case count being more than 243
million, and mortality over 4.95 million, along with causing significant morbidity. It has initiated
an era of research on repurposed drugs such as hydroxychloroquine, lopinavir/ritonavir,
corticosteroids, remedesivir, ivermectin, alongside selective antivirals to treat or prevent COVID-
19. Molnupiravir is an orally available emerging antiviral drug considered highly promising for
COVID-19.

Methods and results:
We have performed a scoping review for the use of molnupiravir against
SARS-CoV-2 and COVID-19. It acts by inhibiting RNA-dependent RNA polymerase (RdRp), and
exhibits broad-spectrum antiviral activity. Preclinical studies have evaluated the therapeutic efficacy
as well as prophylactic activity of molnupiravir against SARS CoV-2 in various animal models
that include ferrets, hamsters, mice, immunodeficient mice implanted with human lung tissue and
cell cultures, in various doses ranging from 5-300 mg/kg, and results have been encouraging. Initial
evidence of safety and efficacy from early phase clinical studies has been encouraging too, and
recent results from a large phase 3 global trial have shown significant benefits among symptomatic
outpatients. Other late-phase clinical trials are still underway with the aim of establishing molnulpiravir
as a therapeutic option for COVID-19, particularly for non-hospitalized patients.

Conclusions and Relevance:
On the basis of the limited evidence available as of now, molnupiravir
could prove to be a promising oral therapy, worthy of further exploration of its utility for both
treatment and prevention of COVID-19 in humans. Elaborate clinical evaluation is further warranted
to confirm whether the results are replicable to the clinical scenario among outpatients to
reduce the chance of progression to more severe disease.
Genetic Association of VDR gene Apa1 and Taq1 Variants with Scleroderma in an Iranian Northeast Population
Authors: Mehrad-Majd Hassan , Mirfeizi Seyedeh Zahra , Nabizadeh-Marvast Majid , Jokar Mohammad-Hassan , Rafatpanah Houshang , Hashemzadeh Kamila 
Published: May 2022

Background:Despite vigorous research efforts, the etiology of scleroderma (systemic sclerosis (SSc)) remains still unclear and both genetic and environmental factors clearly contribute to the pathogenesis of scleroderma. Reports of aberrant vitamin D status in scleroderma patients suggest a need for considering the genotype and allele frequencies of VDR gene polymorphisms. This case-control study aimed to investigate the possible association of two common polymor-phisms of the VDR gene (ApaI, and TaqI) with susceptibility to scleroderma in an Iranian popula-tion.Methods:Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), ApaI and TaqI polymorphisms in the VDR region were genotyped in 51 patients with scle-roderma and 50 healthy controls. Logistic regression analysis was performed to calculate the geno-types odds ratios (ORs) as a measure of association with the presence of scleroderma. Haplotype and linkage disequilibrium analyses were also performed on the detected genotypes.Results:No significant differences were found for the allelic and genotype distributions of ApaI and TaqI polymorphisms between patients with scleroderma and healthy controls (p>0.05). In hap-lotype analysis, three haplotypes TA, CA, and TC, with a frequency greater than 1% were identi-fied. However, none of them was associated with the risk of scleroderma.Conclusion:Our preliminary study showed no evidence of an association between ApaI and TaqI polymorphisms and scleroderma. As the association between VDR polymorphisms and autoimmune diseases varies across the different ethnic populations, further large cohort studies are necessary to confirm the results.