bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling of the Progressive Degradation of the Nigrostriatal Dopaminergic System in Mice to Study the Mechanisms of Neurodegeneration and Neuroplasticity in Parkinson’s Disease
Authors: Kolacheva Anna , Bannikova Alyona , Pavlova Ekaterina , Bogdanov Vsevolod , Ugrumov Michael
Published: January 2023

The fight against neurodegenerative diseases, including Parkinson’s disease (PD), is among the global challenges of the 21st century. The low efficiency of therapy is due to the late diagnosis and treatment of PD, which take place when there is already significant degradation of the nigrostriatal dopaminergic system, a key link in the regulation of motor function. We have developed a subchronic mouse model of PD by repeatedly administering 1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) at gradually increasing doses with a 24 h interval between injections, a period comparable to the time of MPTP metabolism and elimination from the body. This model reproduces the main hallmarks of PD: progressive degeneration of dopaminergic neurons; the appearance of motor disorders with a 70–80% decrease in the level of dopamine in the striatum; an increase in dopamine turnover in the striatum to compensate for dopamine deficiency. When comparing the degradation of the nigrostriatal dopaminergic system and motor disorders in mice in the acute and subchronic models of PD, it has turned out that the resistance of dopaminergic neurons to MPTP increases with its repeated administration. Our subchronic model of PD opens up broad prospects for studying the molecular mechanisms of PD pathogenesis and developing technologies for early diagnosis and preventive treatment.
3D Hierarchical Porous and N-Doped Carbonized Microspheres Derived from Chitin for Remarkable Adsorption of Congo Red in Aqueous Solution
Authors: Cai Taimei , Chen Huijie , Yao Lihua , Peng Hailong
Published: January 2023

A novel adsorbent of N-doped carbonized microspheres were developed from chitin (N-doped CM-chitin) for adsorption of Congo red (CR). The N-doped CM-chitin showed spherical shape and consisted of carbon nanofibers with 3D hierarchical architecture. There were many micro/nano-pores existing in N-doped CM-chitin with high surface area (455.703 m2 g−1). The N element was uniformly distributed on the carbon nanofibers and formed with oxidize-N graphitic-N, pyrrolic-N, and pyridinic-N. The N-doped CM-chitin showed excellent adsorption capability for CR and the maximum adsorption amount was approximate 954.47 mg g−1. The π-π/n-π interaction, hydrogen-bond interactions, and pore filling adsorption might be the adsorption mechanisms. The adsorption of N-doped CM-chitin was considered as a spontaneous endothermic adsorption process, and which well conformed to the pseudo-second-order kinetic and Langmuir isotherm model. The N-doped CM-chitin exhibited an effective adsorption performance for dynamic CR water with good reusability. Therefore, this work provides new insights into the fabrication of a novel N-doped adsorbent from low-cost and waste biomasses.
Regorafenib and Ruthenium Complex Combination Inhibit Cancer Cell Growth by Targeting PI3K/AKT/ERK Signalling in Colorectal Cancer Cells
Authors: Sharma Deepu , Rasool Fayyaz , Bharti Manjri , Vyas Komal M. , Magani Sri Krishna Jayadev
Published: January 2023

Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths annually. As in all other cancers, kinases are one of the major enzymes that play an essential role in the incidence and progression of CRC. Thus, using multi-kinase inhibitors is one of the therapeutic strategies used to counter advanced-stage CRC. Regorafenib is an FDA-approved drug in the third-line therapy of refractory metastatic colorectal cancer. Acquired resistance to cancers and higher toxicity of these drugs are disadvantages to the patients. To counter this, combination therapy is used as a strategy where a minimal dose of drugs can be used to get a higher efficacy and reduce drug resistance development. Ruthenium-based compounds are observed to be a potential alternative to platinum-based drugs due to their significant safety and effectiveness. Formerly, our lab reported Ru-1, a ruthenium-based compound, for its anticancer activity against multiple cancer cells, such as HepG2, HCT116, and MCF7. This study evaluates Ru-1′s activity against regorafenib-resistant HCT116 cells and as a combination therapeutic with regorafenib. Meanwhile, the mechanism of the effect of Ru-1 alone and with regorafenib as a combination is still unknown. In this study, we tested a drug combination (Ru-1 and regorafenib) against a panel of HT29, HCT116, and regorafenib-resistant HCT116 cells. The combination showed a synergistic inhibitory activity. Several mechanisms underlying these numerous synergistic activities, such as anti-proliferative efficacy, indicated that the combination exhibited potent cytotoxicity and enhanced apoptosis induction. Disruption of mitochondrial membrane potential increased intracellular ROS levels and decreased migratory cell properties were observed. The combination exhibited its activity by regulating PI3K/Akt and p38 MAP kinase signalling. This indicates that the combination of REG/Ru-1 targets cancer cells by modulating the PI3K/Akt and ERK signalling.
Mild Hypophosphatemia-Associated Conditions in Children: The Need for a Comprehensive Approach
Authors: Docio Pablo , Llorente-Pelayo Sandra , García-Unzueta María Teresa , Lavin-Gómez Bernardo A. , Puente Nuria , Mateos Fátima , Riancho-Zarrabeitia Leyre , Gonzalez-Lamuño Domingo , Riancho José A.
Published: January 2023

To better understand the causes of hypophosphatemia in children, we evaluated all serum phosphate tests performed in a tertiary hospital with unexpected but persistent temporary or isolated hypophosphatemia over an 18 year period. We collected 29,279 phosphate tests from 21,398 patients, of which 268 (1.2%) had at least one result showing hypophosphatemia. We found that endocrinopathies (n = 60), tumors (n = 10), and vitamin D deficiency (n = 3) were the medical conditions most commonly associated with mild hypophosphatemia, but in many patients the cause was unclear. Among patients with endocrinopathies, those with diabetes mellitus were found to have lower mean serum phosphate levels (mean 3.4 mg/dL) than those with short stature (3.7 mg/dL) or thyroid disorders (3.7 mg/dL). In addition, we found a correlation between glycemia and phosphatemia in patients with diabetes. However, despite the potential relevance of monitoring phosphate homeostasis and the underlying etiologic mechanisms, renal phosphate losses were estimated in less than 5% of patients with hypophosphatemia. In the pediatric age group, malignancies, hypovitaminosis D, and endocrine disorders, mostly diabetes, were the most common causes of hypophosphatemia. This real-world study also shows that hypophosphatemia is frequently neglected and inadequately evaluated by pediatricians, which emphasizes the need for more education and awareness about this condition to prevent its potentially deleterious consequences.
Synthesis, Crystallographic Structure, Theoretical Analysis, Molecular Docking Studies, and Biological Activity Evaluation of Binuclear Ru(II)-1-Naphthylhydrazine Complex
Authors: Eichhorn Thomas , Kolbe Franz , Mišić Stefan , Dimić Dušan , Morgan Ibrahim , Saoud Mohamad , Milenković Dejan , Marković Zoran , Rüffer Tobias , Dimitrić Marković Jasmina , Kaluđerović Goran N.
Published: January 2023

Ruthenium(II)–arene complexes have gained significant research interest due to their possible application in cancer therapy. In this contribution two new complexes are described, namely [{RuCl(η6-p-cymene)}2(μ-Cl)(μ-1-N,N′-naphthyl)]X (X = Cl, 1; PF6, 2), which were fully characterized by IR, NMR, and elemental microanalysis. Furthermore, the structure of 2 in the solid state was determined by a single crystal X-ray crystallographic study, confirming the composition of the crystals as 2·2MeOH. The Hirshfeld surface analysis was employed for the investigation of interactions that govern the crystal structure of 2·2MeOH. The structural data for 2 out of 2·2MeOH was used for the theoretical analysis of the cationic part [{RuCl(η6-p-cymene)}2(μ-Cl)(μ-1-N,N′-naphthyl)]+ (2a) which is common to both 1 and 2. The density functional theory, at B3LYP/6-31+G(d,p) basis set for H, C, N, and Cl atoms and LanL2DZ for Ru ions, was used for the optimization of the 2a structure. The natural bond orbital and quantum theory of atoms in molecules analyses were employed to quantify the intramolecular interactions. The reproduction of experimental IR and NMR spectra proved the applicability of the chosen level of theory. The binding of 1 to bovine serum albumin was examined by spectrofluorimetry and molecular docking, with complementary results obtained. Compound 1 acted as a radical scavenger towards DPPH• and HO• radicals, along with high activity towards cancer prostate and colon cell lines.
Revisiting the Phylogenetic Relationship and Evolution of Gargarini with Mitochondrial Genome (Hemiptera: Membracidae: Centrotinae)
Authors: Li Feng-E , Yang Lin , Long Jian-Kun , Chang Zhi-Min , Chen Xiang-Sheng
Published: January 2023

In this study, we newly sequenced and analyzed the complete mitochondrial genomes of five genera and six species in Gargarini: Antialcidas floripennae, Centrotoscelus davidi, Kotogargara minuta, Machaerotypus stigmosus, Tricentrus fulgidus, and Tricentrus gammamaculatus. The mitochondrial genomes contain 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and a control region. The lengths of the mitochondrial genomes are 15,253 bp to 15,812 bp, and the AT contents of the obtained mitogenomes indicate a strong AT bias, ranging from 75.8% to 78.5%. The start codons of all PCGs show that most start with a typical ATN (ATA/T/G/C) codon and less start with T/GTG; the stop codon TAA is frequently used, and TAG and a single T are less used. In Gargarini mitogenomes, all tRNA genes can be folded into the canonical cloverleaf secondary structure, except for trnaS1, which lacks a stable dihydrouridine (DHU) stem and is replaced by a simple loop. At the same time, the phylogenetic analysis of the tribe Gargarini based on sequence data of 13 PCGs from 18 treehopper species and four outgroups revealed that the 10 Gargarini species form a steady group with strong support and form a sister group with Leptocentrini, Hypsauchenini, Centrotini, and Leptobelini. Diversification within Gargarini is distinguished by a Later Cretaceous divergence that led to the rapid diversification of the species. Moreover, the ancestral state reconstructions analysis showed the absence of the suprahumeral horn, which was confirmed as the ancestor characteristic of the treehopper, which has evolved from simple to complex. Our results shed new light specifically on the molecular and phylogenetic evolution of the pronotum in Gargarini.
Inhibitory Mechanism of IL-6 Production by Orento in Oral Squamous Cell Carcinoma Cell Line CAL27 Stimulated by Pathogen-Associated Molecular Patterns from Periodontopathogenic Porphyromonas gingivalis
Authors: Imamura Yasuhiro , Makita Yoshimasa , Masuno Kazuya , Oh Hourei
Published: January 2023

Orento is a traditional Japanese medicinal kampo preparation that is also prescribed in oral care. In oral squamous cell carcinoma cell line CAL27, orento significantly inhibited periodontopathogenic bacterium Porphyromonas gingivalis lipopolysaccharide (LPS) and lipoproteins (PAMP)-stimulated production of interleukin (IL)-6. This suggests that orento negatively regulates PAMP-mediated toll-like receptor (TLR) signaling. Orento significantly suppressed PAMP-stimulated activation of the IL-6 promoter, indicating that orento may suppress the production of IL-6 by PAMP at the transcriptional level. Orento also suppressed TLR-mediated activation of transcription factor nuclear factor-kappa B (NF-kB) that was stimulated by PAMP. This finding indicates that orento may suppress the function and activation of factors involved in TLR signaling, thereby suppressing NF-kB-dependent expression of various genes. Orento suppressed IL-1 receptor-associated kinase (IRAK4), IRAK1, and c-Jun N-terminal kinase (JNK) phosphorylation in PAMP-stimulated CAL27 cells. This result indicates that orento is involved in the initiation of TLR signaling by PAMP and suppresses the downstream signaling pathways of myeloid differentiation primary response gene 88 (MyD88) such as mitogen-activated protein kinase (MAPK) and NF-kB cascades. These findings suggest that orento has an inhibitory effect on the production of inflammatory cytokines.
Synaptoproteomic Analysis of the Prefrontal Cortex Reveals Spatio-Temporal Changes in SYNGAP1 Following Cannabinoid Exposure in Rat Adolescence
Authors: Qvist Johanna S. , Scherma Maria , Jayaram-Lindström Nitya , Fratta Walter , Kandel Denise B. , Kandel Eric R. , Fadda Paola , Melas Philippe A.
Published: January 2023

The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate; WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N = 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ9-tetrahydrocannabinol; THC) were also found to have increased levels of SYNGAP1 in the PFC. THC exposure also led to a pronounced upregulation of SYNGAP1 in the amygdala, but without any changes in the dorsal striatum, hippocampus, or nucleus accumbens. To our knowledge, this is the first study to uncover a link between cannabinoid exposure and changes in SYNGAP1 that are spatio-temporal and developmental in nature. Future studies are needed to investigate the putative role of SYNGAP1 in the negative behavioral consequences of cannabis use in adolescence.
The Role of Proteolysis in Amyloidosis
Authors: Acquasaliente Laura , De Filippis Vincenzo
Published: January 2023

Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine
Authors: Spekker Eleonóra , Körtési Tamás , Vécsei László
Published: January 2023

Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.
Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis
Authors: Duranti Elisa , Villa Chiara
Published: January 2023

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.
The Management of Ocular Surface Squamous Neoplasia (OSSN)
Authors: Yeoh Clarice H. Y. , Lee Jerome J. R. , Lim Blanche X. H. , Sundar Gangadhara , Mehta Jodhbir S. , Chan Anita S. Y. , Lim Dawn K. A. , Watson Stephanie L. , Honavar Santosh G. , Manotosh Ray , Lim Chris H. L.
Published: January 2023

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.
Plasma Concentration of Cortisol Negatively Associates with Platelet Reactivity in Older Subjects
Authors: Karolczak Kamil , Konieczna Lucyna , Soltysik Bartlomiej , Kostka Tomasz , Witas Piotr Jakub , Kostanek Joanna , Baczek Tomasz , Watala Cezary
Published: January 2023

The interaction of platelets with steroid hormones is poorly investigated. Age is one of the factors that increase the risk of pathological platelet reactivity and thrombosis. The aim of this study was to assess whether there were associations between platelet reactivity and plasma cortisol levels in volunteers aged 60–65 years. For this purpose, impedance aggregometry in whole blood measured after arachidonic acid, collagen, or ADP stimulation was used to estimate platelet reactivity and mass spectrometry was used to measure peripheral plasma cortisol concentration. Statistically significant negative correlations were observed between cortisol concentration and platelet reactivity in response to arachidonic acid and ADP, but not to collagen. The presented results suggest for the very first time that cortisol is a new endogenous modulator of platelet reactivity in the elderly population.
Reovirus μ2 Protein Impairs Translation to Reduce U5 snRNP Protein Levels
Authors: Boudreault Simon , Martineau Carole-Anne , Faucher-Giguère Laurence , Abou-Elela Sherif , Lemay Guy , Bisaillon Martin
Published: January 2023

Mammalian orthoreovirus (MRV) is a double-stranded RNA virus from the Reoviridae family that infects a large range of mammals, including humans. Recently, studies have shown that MRV alters cellular alternative splicing (AS) during viral infection. The structural protein μ2 appears to be the main determinant of these AS modifications by decreasing the levels of U5 core components EFTUD2, PRPF8, and SNRNP200 during infection. In the present study, we investigated the mechanism by which μ2 exerts this effect on the U5 components. Our results revealed that μ2 has no impact on steady-state mRNA levels, RNA export, and protein stability of these U5 snRNP proteins. However, polysome profiling and metabolic labeling of newly synthesized proteins revealed that μ2 exerts an inhibitory effect on global translation. Moreover, we showed that μ2 mutants unable to accumulate in the nucleus retain most of the ability to reduce PRPF8 protein levels, indicating that the effect of μ2 on U5 snRNP components mainly occurs in the cytoplasm. Finally, co-expression experiments demonstrated that μ2 suppresses the expression of U5 snRNP proteins in a dose-dependent manner, and that the expression of specific U5 snRNP core components have different sensitivities to μ2’s presence. Altogether, these results suggest a novel mechanism by which the μ2 protein reduces the levels of U5 core components through translation inhibition, allowing this viral protein to alter cellular AS during infection.
The Association of Glucose Control with Circulating Levels of Red Blood Cell-Derived Vesicles in Type 2 Diabetes Mellitus Patients with Atrial Fibrillation
Authors: Berezin Alexander A. , Obradovic Zeljko , Kopp Kristen , Berezina Tetiana A. , Lichtenauer Michael , Wernly Bernhard , Berezin Alexander E.
Published: January 2023

Hyperglycemia is a trigger for structural alteration of red blood cells (RBCs) and their ability to release extracellular vesicles (EVs). The aim of the study was to elucidate whether glucose control in T2DM patients with concomitant HF and AF affects a circulating number of RBC-derived EVs. We prospectively included 417 T2DM patients with HF, 51 of them had atrial fibrillation and 25 healthy volunteers and 30 T2DM non-HF individuals. Clinical assessment, echocardiography examination and biomarker measures were performed at the baseline of the study. RBC-derived EVs were determined as CD235a+ PS+ particles by flow cytometry. NT-proBNP levels were measured by ELISA. AF patients with glycosylated hemoglobin (HbA1c) < 6.9% had lower levels of CD235a+ PS+ RBC-derived vesicles than those with HbA1c ≥ 7.0%. There were no significant differences in number of CD235a+ PS+ RBC-derived vesicles between patients in entire cohort and in non-AF sub-cohort with HbA1c < 6.9% and HbA1c ≥ 7.0%, respectively. Multivariate linear regression yielded that CD235a+ PS+ RBC-derived vesicles ≥ 545 particles in µL (OR = 1.06; 95% CI = 1.01–1.11, p = 0.044) independently predicted HbA1c ≥ 7.0%. Elevated levels of CD235a+ PS+ RBC-derived EVs independently predicted poor glycaemia control in T2DM patients with HF and AF.
Improvement of Seed Germination under Salt Stress via Overexpressing Caffeic Acid O-methyltransferase 1 (SlCOMT1) in Solanum lycopersicum L.
Authors: Ge Lianjing , Yang Xiaoyu , Liu Yue , Tang Huimeng , Wang Qifang , Chu Shunpeng , Hu Jinxiang , Zhang Ning , Shi Qinghua
Published: January 2023

Melatonin (MT) is a phytohormone-like substance and is profoundly involved in modulating nearly all aspects of plant development and acclimation to environmental stressors. However, there remain no studies about the effects of MT on tomato seed germination under salt stress. Here we reported that the overexpression of caffeic acid O-methyltransferase 1 (SlCOMT1) significantly increased both MT content and salt tolerance in the germinated seeds of a transgenic tomato relative to wild type (WT) samples. Physiological investigation showed higher amylase activity in the stressed overexpression seeds than WT, leading to the promoted starch decomposition and enhanced soluble sugar content. The stimulated production of osmolytes and enhanced activities of SOD, POD, and CAT, together with the significant reduction in H2O2 and O2·− accumulation, were revealed in the stressed overexpression seeds relative to WT, largely accounting for their lower membrane lipid peroxidation. qPCR assay showed that, upon salt stress, the transcript abundance of hub genes related to germination (SlCYP707A1, SlABA1, SlGA3ox2 and SlGA2ox4) and stress tolerance (SlCDPK1, SlWRKY33 and SlMAPK1) were distinctly altered in the overexpression samples when compared to WT, providing a molecular basis for MT-mediated improvement of seed salt tolerance. Altogether, our observations shed new insights into biological functions of SlCOMT1 and could expand its utilization in genetic improvement of tomato salt tolerance in future.
Clinical Pharmacokinetics of Approved RNA Therapeutics
Authors: Jo Seong Jun , Chae Soon Uk , Lee Chae Bin , Bae Soo Kyung
Published: January 2023

RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique targets and prolonged pharmacological effects. Their absorption, distribution, metabolism, and excretion (ADME) have important clinical im-plications, but their pharmacokinetic properties have not been fully understood. Most RNA therapeutics have structural modifications to prevent rapid elimination from the plasma and are administered intravenously or subcutaneously, with some exceptions, for effective distribution to target organs. Distribution of drugs into tissues depends on the addition of a moiety that can be transported to the target and RNA therapeutics show a low volume of distribution because of their molecular size and negatively-charged backbone. Nucleases metabolize RNA therapeutics to a shortened chain, but their metabolic ratio is relatively low. Therefore, most RNA therapeutics are excreted in their intact form. This review covers not only ADME features but also clinical pharmacology data of the RNA therapeutics such as drug–drug interaction or population pharmacokinetic analyses. As the market of RNA therapeutics is expected to rapidly expand, comprehensive knowledge will contribute to interpreting and evaluating the pharmacological properties.
Bone Regeneration Guided by a Magnetized Scaffold in an Ovine Defect Model
Authors: Maglio Melania , Sartori Maria , Gambardella Alessandro , Shelyakova Tatiana , Dediu Valentin Alek , Santin Matteo , Piñeiro Yolanda , López Manuel Bañobre , Rivas Josè , Tampieri Anna , Sprio Simone , Martini Lucia , Gatti Alessandro , Russo Alessandro , Giavaresi Gianluca , Fini Milena
Published: January 2023

The reconstruction of large segmental defects still represents a critical issue in the orthopedic field. The use of functionalized scaffolds able to create a magnetic environment is a fascinating option to guide the onset of regenerative processes. In the present study, a porous hydroxyapatite scaffold, incorporating superparamagnetic Fe3O4 nanoparticles (MNPs), was implanted in a critical bone defect realized in sheep metatarsus. Superparamagnetic nanoparticles functionalized with hyperbranched poly(epsilon-Lysine) peptides and physically complexed with vascular endothelial growth factor (VEGF) where injected in situ to penetrate the magnetic scaffold. The scaffold was fixed with cylindrical permanent NdFeB magnets implanted proximally, and the magnetic forces generated by the magnets enabled the capture of the injected nanoparticles forming a VEGF gradient in its porosity. After 16 weeks, histomorphometric measurements were performed to quantify bone growth and bone-to-implant contact, while the mechanical properties of regenerated bone via an atomic force microscopy (AFM) analysis were investigated. The results showed increased bone regeneration at the magnetized interface; this regeneration was higher in the VEGF-MNP-treated group, while the nanomechanical behavior of the tissue was similar to the pattern of the magnetic field distribution. This new approach provides insights into the ability of magnetic technologies to stimulate bone formation, improving bone/scaffold interaction.
Target-Specific Nanoparticle Polyplex Down-Regulates Mutant Kras to Prevent Pancreatic Carcinogenesis and Halt Tumor Progression
Authors: Smith Jill P. , Chen Wenqiang , Shivapurkar Narayan , Gerber Monica , Tucker Robin D. , Kallakury Bhaskar , Dasa Siva Sai Krishna , Kularatne Ruvanthi N. , Stern Stephan T.
Published: January 2023

Survival from pancreatic cancer is poor because most cancers are diagnosed in the late stages and there are no therapies to prevent the progression of precancerous pancreatic intraepithelial neoplasms (PanINs). Inhibiting mutant KRASG12D, the primary driver mutation in most human pancreatic cancers, has been challenging. The cholecystokinin-B receptor (CCK-BR) is absent in the normal pancreas but becomes expressed in high grade PanIN lesions and is over-expressed in pancreatic cancer making it a prime target for therapy. We developed a biodegradable nanoparticle polyplex (NP) that binds selectively to the CCK-BR on PanINs and pancreatic cancer to deliver gene therapy. PanIN progression was halted and the pancreas extracellular matrix rendered less carcinogenic in P48-Cre/LSL-KrasG12D/+ mice treated with the CCK-BR targeted NP loaded with siRNA to mutant Kras. The targeted NP also slowed proliferation, decreased metastases and improved survival in mice bearing large orthotopic pancreatic tumors. Safety and toxicity studies were performed in immune competent mice after short or long-term exposure and showed no off-target toxicity by histological or biochemical evaluation. Precision therapy with target-specific NPs provides a novel approach to slow progression of advanced pancreatic cancer and also prevents the development of pancreatic cancer in high-risk subjects without toxicity to other tissues.
Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling
Authors: Ji Xiwei , Meng Xiangrui , He Qingfeng , Xiang Xiaoqiang , Shi Yufei , Zhu Xiao
Published: January 2023

This study investigated the antitumor effects of foretinib on triple-negative breast cancer cells MDA-MB-231 xenograft tumors in vivo underlying phosphorylated mesenchymal to epithelial transition (p-MET)/ hepatocyte growth factor (HGF)-related mechanism, as well as its pharmacokinetic characteristics. The MDA-MB-231 human breast cancer cell line was used for in vitro experiments, and the tumor xenograft model was established for in vivo experiments. MDA-MB-231 xenograft mice received oral foretinib (15 or 50 mg/kg/day) or vehicle for 18 days. The xenograft tumors were collected. Protein expressions of p-MET and HGF were examined with Western blotting and immunohistochemical staining. The mRNA expression of MET was examined with real-time PCR. Blood samples were collected from the mice treated with foretinib under different doses of 2, 10, and 50 mg/kg, and the pharmacokinetic profiles of foretinib were evaluated. We found that foretinib treatment caused a significant inhibition in tumor growth in a dose-dependent manner, whereas the continuous administration did not result in weight loss in treated nude mice. In both MDA-MB-231 cells and xenograft tumors, foretinib suppressed the expression of p-MET and HGF. These findings reveal that the decrease of p-MET and HGF may play an important role in the anti-breast cancer properties of foretinib.
The Ethanol Extract of Evodiae Fructus and Its Ingredient, Rutaecarpine, Inhibit Infection of SARS-CoV-2 and Inflammatory Responses
Authors: Lin Shengying , Wang Xiaoyang , Guo Hongsheng , Dai Niyu , Tang Roy Wai-Lun , Lee Hung Chun , Leung Ka Wing , Dong Tina Ting-Xia , Webb Sarah E. , Miller Andrew L. , Tsim Karl Wah-Keung
Published: January 2023

COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications.
A Recent Progress in the Leachate Pretreatment Methods Coupled with Anaerobic Digestion for Enhanced Biogas Production: Feasibility, Trends, and Techno-Economic Evaluation
Authors: Anjum Muzammil , Anees Mobeena , Qadeer Samia , Khalid Azeem , Kumar Rajeev , Barakat Mohamed. A.
Published: January 2023

Landfill leachate (LFL) treatment is a severe challenge due to its highly viscous nature and various complex pollutants. Leachate comprises various toxic pollutants, including inorganic macro/nano components, xenobiotics, dissolved organic matter, heavy metals, and microorganisms responsible for severe environmental pollution. Various treatment procedures are available to achieve better effluent quality levels; however, most of these treatments are nondestructive, so pollutants are merely transported from one phase to another, resulting in secondary contamination. Anaerobic digestion is a promising bioconversion technology for treating leachate while producing renewable, cleaner energy. Because of its high toxicity and low biodegradability, biological approaches necessitate employing other techniques to complement and support the primary process. In this regard, pretreatment technologies have recently attracted researchers’ interest in addressing leachate treatment concerns through anaerobic digestion. This review summarizes various LFL pretreatment methods, such as electrochemical, ultrasonic, alkaline, coagulation, nanofiltration, air stripping, adsorption, and photocatalysis, before the anaerobic digestion of leachate. The pretreatment could assist in converting biogas (carbon dioxide to methane) and residual volatile fatty acids to valuable chemicals and fuels and even straight to power generation. However, the selection of pretreatment is a vital step. The techno-economic analysis also suggested the high economic feasibility of integrated-anaerobic digestion. Therefore, with the incorporation of pretreatment and anaerobic digestion, the process could have high economic viability attributed to bioenergy production and cost savings through sustainable leachate management options.
The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows
Authors: Loizzi Vera , Dellino Miriam , Cerbone Marco , Arezzo Francesca , Cazzato Gerardo , Damiani Gianluca Raffaello , Pinto Vincenzo , Silvestris Erica , Kardhashi Anila , Cicinelli Ettore , Cascardi Eliano , Cormio Gennaro
Published: January 2023

All cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35–40 years in BRCA1 mutation carriers and between 40–45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.
Inhibition of Oncogenic Src Ameliorates Silica-Induced Pulmonary Fibrosis via PI3K/AKT Pathway
Authors: Hao Xiaohui , Jin Yixuan , Zhang Yiyang , Li Shifeng , Cui Jie , He Hailan , Guo Lingli , Yang Fang , Liu Heliang
Published: January 2023

Silicosis is a refractory disease. Previous studies indicate that damaged alveolar epithelial cells act as a driver in pulmonary fibrosis. Our results show that epithelial cells that acquire the mesenchymal phenotype are associated with the pathogenesis of silicosis. c-Src kinase, a non-receptor tyrosine kinase, has been shown to be a positive regulator of organ fibrosis, but specific mechanisms remain unclear and rarely researched in silicosis. The activated Phosphatidylinositol-3 kinases/AKT(PI3K/AKT) pathway promotes fibrosis. We aimed to determine whether c-Src regulates fibrosis via the PI3K/AKT signaling pathway in the development of silicosis. C57/BL mice were intratracheally perfused with 10 mg silica suspension to establish a model of silicosis. In vivo, silica particles induced lung fibrosis. The profibrotic cytokine transforming growth factor-β1 (TGF-β1) exhibited a high expression in pulmonary fibrosis. The phosphorylated c-Src protein was increased and the PI3K/AKT pathway was activated in model lung tissue. In vitro, silica increased the expression of TGF-β1- and TGF-β1-induced mesenchymal phenotype and fibrosis in a mouse epithelial cells line. siRNA-Src inhibited the c-Src, the phosphorylation of the PI3K/AKT pathway, and the mesenchymal phenotype induced by TGF-β1. LY294002, a specific inhibitor of PI3K, suppressed the phosphorylation of PI3K/AKT but did not affect Src activation. SU6656, a selective Src inhibitor, attenuated fibrosis in silicosis model. In summary, c-Src promotes fibrosis via the PI3K/AKT pathway in silica-induced lung fibrosis, and Src kinase inhibitors are potentially effective for silicosis treatment.
Genome-Wide Identification and Expression Analysis of the Xyloglucan Endotransglucosylase/Hydrolase Gene Family in Sweet Potato [Ipomoea batatas (L.) Lam]
Authors: Zhang Jing-Zhen , He Pei-Wen , Xu Xi-Ming , Lü Zun-Fu , Cui Peng , George Melvin Sidikie , Lu Guo-Quan
Published: January 2023

The xyloglucan endotransglucosylase/hydrolase (XET/XEH, also named XTH) family is a multigene family, the function of which plays a significant role in cell-wall rebuilding and stress tolerance in plants. However, the specific traits of the XTH gene family members and their expression pattern in different tissues and under stress have not been carried out in sweet potato. Thirty-six XTH genes were identified in I. batatas, all of which had conserved structures (Glyco_hydro_16). Based on Neighbor-Joining phylogenetic analysis the IbXTHs can be divided into three subfamilies—the I/II, IIIA, and IIIB subfamilies, which were unevenly distributed on 13 chromosomes, with the exception of Chr9 and Chr15. Multiple cis-acting regions related to growth and development, as well as stress responses, may be found in the IbXTH gene promoters. The segmental duplication occurrences greatly aided the evolution of IbXTHs. The results of a collinearity analysis showed that the XTH genes of sweet potato shared evolutionary history with three additional species, including A. thaliana, G. max, and O. sativa. Additionally, based on the transcriptome sequencing data, the results revealed that the IbXTHs have different expression patterns in leaves, stems, the root body (RB), the distal end (DE), the root stock (RS), the proximal end (PE), the initiative storage root (ISR), and the fibrous root (FR), and many of them are well expressed in the roots. Differentially expressed gene (DEG) analysis of FRs after hormone treatment of the roots indicated that IbXTH28 and IbXTH30 are up-regulated under salicylic acid (SA) treatment but down-regulated under methyl jasmonate (MeJA) treatment. Attentionally, there were only two genes showing down-regulation under the cold and drought treatment. Collectively, all of the findings suggested that genes from the XTH family are crucial for root specificity. This study could provide a theoretical basis for further research on the molecular function of sweet potato XTH genes.
Antibacterial Activity on Orthopedic Clinical Isolates and Cytotoxicity of the Antimicrobial Peptide Dadapin-1
Authors: Campoccia Davide , Montanaro Lucio , Ravaioli Stefano , Mariani Valentina , Bottau Giulia , De Donno Andrea , Arciola Carla Renata
Published: January 2023

In orthopedic surgery, biomaterial-associated infections represent a complication of serious concern. Most promising strategies to prevent these infections currently rely on the use of anti-infective biomaterials. Desirably, in anti-infective biomaterials, the antibacterial properties should be achieved by doping, grafting, or coating the material surfaces with molecules that are alternative to conventional antibiotics and exhibit a potent and highly specific activity against bacteria, without altering the biocompatibility. Antimicrobial peptides (AMPs) are among the most interesting candidate molecules for this biomaterial functionalization. Here, the potential expressed by the recently discovered peptide Dadapin-1 was explored by assaying its MIC, MBIC and MBC on clinical strains of relevant bacterial species isolated from orthopedic infections and by assessing its cytotoxicity on the human osteoblast-like MG63 cells. When appropriately tested in diluted Mueller Hinton Broth II (MHB II), Dadapin-1 exhibited significant antibacterial properties. MIC values were in the range of 3.1–6.2 µM for the gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus warneri, and 12.4–24.9 µM for the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Interestingly, the peptide was found non-cytotoxic, with an IC50 exceeding the highest concentration tested of 179 µM. Overall, Dadapin-1 expresses considerable potential for future application in the production of anti-infective biomaterials.
Comprehensive Analysis of Major Latex-Like Protein Family Genes in Cucumber (Cucumis sativus L.) and Their Potential Roles in Phytophthora Blight Resistance
Authors: Kang Yunyan , Tong Jiale , Liu Wei , Jiang Zhongli , Pan Gengzheng , Ning Xianpeng , Yang Xian , Zhong Min
Published: January 2023

Major latex-like proteins (MLPs) play crucial roles in abiotic and biotic stresses. However, little was known about this gene family in cucumbers. In this study, a total of 37 putative cucumber MLP genes were identified on a genome-wide level and classified into three groups by sequence homologous comparison with Arabidopsis thaliana. Chromosome mapping suggested that only tandem duplication occurred in evolution. The multiple regulatory cis-elements related to stress, hormone, light and growth response were found in the promoter region of these CsMLP genes, indicating that CsMLPs might be widely involved in the process of plant growth, development and various stress conditions. Transcriptome analysis indicated a strong reprogramming of MLPs expression in response to Phytophthora melonis infection in cucumber. Knockdown of CsMLP1 reduced the P. melonis tolerance, while transient overexpression of CsMLP1 improved disease tolerance in cucumber. Conversely, the silence of CsMLP5 decreased the lesion area caused by P. melonis in the cotyledons, and overexpression of CsMLP5 promoted lesion expansion. Taken together, our results provide a comprehensive basis for further mining the function of CsMLP members and will also be significant for elucidating the evolutionary relationship in cucumber.
Advances in Biological Control and Resistance Genes of Brassicaceae Clubroot Disease-The Study Case of China
Authors: Zhang Chaoying , Du Chunyu , Li Yuwei , Wang Huiying , Zhang Chunyu , Chen Peng
Published: January 2023

Clubroot disease is a soil-borne disease caused by Plasmodiophora brassicae. It occurs in cruciferous crops exclusively, and causes serious damage to the economic value of cruciferous crops worldwide. Although different measures have been taken to prevent the spread of clubroot disease, the most fundamental and effective way is to explore and use disease-resistance genes to breed resistant varieties. However, the resistance level of plant hosts is influenced both by environment and pathogen race. In this work, we described clubroot disease in terms of discovery and current distribution, life cycle, and race identification systems; in particular, we summarized recent progress on clubroot control methods and breeding practices for resistant cultivars. With the knowledge of these identified resistance loci and R genes, we discussed feasible strategies for disease-resistance breeding in the future.