bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice
Authors: Irelan Daniel , Boyd Abigail , Fiedler Edward , Lochmaier Peter , McDonough Will , Aragon Ileana V. , Rachek Lyudmila , Abou Saleh Lina , Richter Wito
Published: February 2023

cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice. Blood glucose levels in postprandial mice increase rapidly upon drug injection, reaching a maximum after ~45 min, and returning to baseline within ~4 h. This transient blood glucose spike is replicated by several structurally distinct PDE4 inhibitors, suggesting that it is a class effect of PDE4 inhibitors. PDE4 inhibitor treatment does not reduce serum insulin levels, and the subsequent injection of insulin potently reduces PDE4 inhibitor-induced blood glucose levels, suggesting that the glycemic effects of PDE4 inhibition are independent of changes in insulin secretion and/or sensitivity. Conversely, PDE4 inhibitors induce a rapid reduction in skeletal muscle glycogen levels and potently inhibit the uptake of 2-deoxyglucose into muscle tissues. This suggests that reduced glucose uptake into muscle tissue is a significant contributor to the transient glycemic effects of PDE4 inhibitors in mice.
PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?
Authors: Pérez-Segura Isaac , Santiago-Balmaseda Alberto , Rodríguez-Hernández Luis Daniel , Morales-Martínez Adriana , Martínez-Becerril Hilda Angélica , Martínez-Gómez Paola A. , Delgado-Minjares Karen M. , Salinas-Lara Citlaltepetl , Martínez-Dávila Irma A. , Guerra-Crespo Magdalena , Pérez-Severiano Francisca , Soto-Rojas Luis O.
Published: February 2023

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.
A Comprehensive Review on the Biological, Agricultural and Pharmaceutical Properties of Secondary Metabolites Based-Plant Origin
Authors: Elshafie Hazem S. , Camele Ippolito , Mohamed Amira A.
Published: February 2023

Natural products are compounds produced by living organisms and can be divided into two main categories: primary (PMs) and secondary metabolites (SMs). Plant PMs are crucial for plant growth and reproduction since they are directly involved in living cell processes, whereas plant SMs are organic substances directly involved in plant defense and resistance. SMs are divided into three main groups: terpenoids, phenolics and nitrogen-containing compounds. The SMs contain a variety of biological capabilities that can be used as flavoring agents, food additives, plant-disease control, strengthen plant defenses against herbivores and, additionally, it can help plant cells to be better adapted to the physiological stress response. The current review is mainly focusing on certain key elements related to the significance, biosynthesis, classification, biochemical characterization and medical/pharmaceutical uses of the major categories of plant SMs. In addition, the usefulness of SMs in controlling plant diseases, boosting plant resistance and as potential natural, safe, eco-friendly substitutes for chemosynthetic pesticides were also reported in this review.
Silicon Application for the Modulation of Rhizosphere Soil Bacterial Community Structures and Metabolite Profiles in Peanut under Ralstonia solanacearum Inoculation
Authors: Deng Quanqing , Liu Hao , Lu Qing , Gangurde Sunil S. , Du Puxuan , Li Haifen , Li Shaoxiong , Liu Haiyan , Wang Runfeng , Huang Lu , Chen Ronghua , Fan Chenggen , Liang Xuanqiang , Chen Xiaoping , Hong Yanbin
Published: February 2023

Silicon (Si) has been shown to promote peanut growth and yield, but whether Si can enhance the resistance against peanut bacterial wilt (PBW) caused by Ralstonia solanacearum, identified as a soil-borne pathogen, is still unclear. A question regarding whether Si enhances the resistance of PBW is still unclear. Here, an in vitro R. solanacearum inoculation experiment was conducted to study the effects of Si application on the disease severity and phenotype of peanuts, as well as the microbial ecology of the rhizosphere. Results revealed that Si treatment significantly reduced the disease rate, with a decrement PBW severity of 37.50% as compared to non-Si treatment. The soil available Si (ASi) significantly increased by 13.62–44.87%, and catalase activity improved by 3.01–3.10%, which displayed obvious discrimination between non-Si and Si treatments. Furthermore, the rhizosphere soil bacterial community structures and metabolite profiles dramatically changed under Si treatment. Three significantly changed bacterial taxa were observed, which showed significant abundance under Si treatment, whereas the genus Ralstonia genus was significantly suppressed by Si. Similarly, nine differential metabolites were identified to involve into unsaturated fatty acids via a biosynthesis pathway. Significant correlations were also displayed between soil physiochemical properties and enzymes, the bacterial community, and the differential metabolites by pairwise comparisons. Overall, this study reports that Si application mediated the evolution of soil physicochemical properties, the bacterial community, and metabolite profiles in the soil rhizosphere, which significantly affects the colonization of the Ralstonia genus and provides a new theoretical basis for Si application in PBW prevention.
Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer
Authors: Dong Jia , Liu Jiang , Zhang Bo , Liang Chen , Hua Jie , Meng Qingcai , Wei Miaoyan , Wang Wei , Yu Xianjun , Xu Jin
Published: February 2023

(1) Background: Pancreatic cancer (PC) is one of the most lethal tumors. Mitochondrial dysfunction has been reported to be involved in cancer development; however, its role in PC has remained unclear. (2) Methods: The differentially expressed NMGs were selected between PC and normal pancreatic tissue. The NMG-related prognostic signature was established by LASSO regression. A nomogram was developed based on the 12-gene signature combined with other significant pathological features. An extensive analysis of the 12 critical NMGs was performed in multiple dimensions. The expression of some key genes was verified in our external cohort. (3) Results: Mitochondria-related transcriptome features was obviously altered in PC compared with normal pancreas tissue. The 12-NMG signature showed good performance in predicting prognosis in various cohorts. The high- and low-risk groups exhibited notable diversity in gene mutation characteristics, biological characteristics, chemotherapy response, and the tumor immune microenvironment. Critical gene expression was demonstrated in our cohort at the mRNA and protein levels and in organelle localization. (4) Conclusions: Our study analyzed the mitochondrial molecular characterization of PC, proving the crucial role of NMGs in PC development. The established NMG signature helps classify patient subtypes in terms of prognosis prediction, treatment response, immunological features, and biological function, providing a potential therapeutic strategy targeting mitochondrial transcriptome characterization.
Effects of Fractionated Radiation Exposure on Vimentin Expression in Cervical Cancers: Analysis of Association with Cancer Stem Cell Response and Short-Term Prognosis
Authors: Zamulaeva Irina , Matchuk Olga , Selivanova Elena , Mkrtchian Liana , Yakimova Anna , Gusarova Victoria , Lipunov Nikita , Krikunova Liudmila , Ivanov Sergey , Kaprin Andrey
Published: February 2023

Elucidation of the mechanisms for the response of cancer stem cells (CSCs) to radiation exposure is of considerable interest for further improvement of radio- and chemoradiotherapy of cervical cancer (CC). The aim of this work is to evaluate the effects of fractionated radiation exposure on the expression of vimentin, which is one of the end-stage markers of epithelial-mesenchymal transition (EMT), and analyze its association with CSC radiation response and short-term prognosis of CC patients. The level of vimentin expression was determined in HeLa, SiHa cell lines, and scrapings from the cervix of 46 CC patients before treatment and after irradiation at a total dose of 10 Gy using real-time polymerase chain reaction (PCR) assay, flow cytometry, and fluorescence microscopy. The number of CSCs was assessed using flow cytometry. Significant correlations were shown between vimentin expression and postradiation changes in CSC numbers in both cell lines (R = 0.88, p = 0.04 for HeLa and R = 0.91, p = 0.01 for SiHa) and cervical scrapings (R = 0.45, p = 0.008). Associations were found at the level of tendency between postradiation increase in vimentin expression and unfavorable clinical outcome 3–6 months after treatment. The results clarify some of the relationships between EMT, CSCs, and therapeutic resistance that are needed to develop new strategies for cancer treatment.
Lipids as Targets for Renal Cell Carcinoma Therapy
Authors: Stepanovska Tanturovska Bisera , Manaila Roxana , Fabbro Doriano , Huwiler Andrea
Published: February 2023

Kidney cancer is among the top ten most common cancers to date. Within the kidney, renal cell carcinoma (RCC) is the most common solid lesion occurring. While various risk factors are suspected, including unhealthy lifestyle, age, and ethnicity, genetic mutations seem to be a key risk factor. In particular, mutations in the von Hippel–Lindau gene (Vhl) have attracted a lot of interest since this gene regulates the hypoxia inducible transcription factors HIF-1α and HIF-2α, which in turn drive the transcription of many genes that are important for renal cancer growth and progression, including genes involved in lipid metabolism and signaling. Recent data suggest that HIF-1/2 are themselves regulated by bioactive lipids which make the connection between lipids and renal cancer obvious. This review will summarize the effects and contributions of the different classes of bioactive lipids, including sphingolipids, glycosphingolipids, eicosanoids, free fatty acids, cannabinoids, and cholesterol to renal carcinoma progression. Novel pharmacological strategies interfering with lipid signaling to treat renal cancer will be highlighted.
D-Amino Acids and Cancer: Friends or Foes?
Authors: Murtas Giulia , Pollegioni Loredano
Published: February 2023

α-amino acids exist in two configurations, named D-(dextro) and L-(levo) enantiomers. L-amino acids are used in protein synthesis and play a central role in cell metabolism. The effects of the L-amino acid composition of foods and the dietary modifications of this composition on the efficacy of cancer therapies have been widely investigated in relation to the growth and reproduction of cancerous cells. However, less is known about the involvement of D-amino acids. In recent decades, D-amino acids have been identified as natural biomolecules that play interesting and specific roles as common components of the human diet. Here, we focus on recent investigations showing altered D-amino acid levels in specific cancer types and on the various roles proposed for these biomolecules related to cancer cell proliferation, cell protection during therapy, and as putative, innovative biomarkers. Notwithstanding recent progress, the relationship between the presence of D-amino acids, their nutritional value, and cancer cell proliferation and survival represents an underrated scientific issue. Few studies on human samples have been reported to date, suggesting a need for routine analysis of D-amino acid content and an evaluation of the enzymes involved in regulating their levels in clinical samples in the near future.
Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium
Authors: Shpakov Alexander O. , Zorina Inna I. , Derkach Kira V.
Published: February 2023

A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer’s disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.
Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells
Authors: Majidipur Amene , Morin-Dewaele Margot , Gaspar Lopes Jeanne , Berry Francois , Fouchet Julien , Bartier Sophie , Dufros Duval Anais , Soyeux Pascale , Huet Eric , Louis Bruno , Coste André , Béquignon Émilie , Saldana Carolina , Le Corvoisier Philippe , Destouches Damien , Pawlotsky Jean-Michel , de la Taille Alexandre , Vacherot Francis , Bruscella Patrice , Firlej Virginie
Published: February 2023

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.
Atomistic Study for the Tantalum and Tantalum–Tungsten Alloy Threshold Displacement Energy under Local Strain
Authors: Bany Salman Mohammad , Park Minkyu , Banisalman Mosab Jaser
Published: February 2023

The threshold displacement energy (TDE) is an important measure of the extent of a material’s radiation damage. In this study, we investigate the influence of hydrostatic strains on the TDE of pure tantalum (Ta) and Ta–tungsten (W) alloy with a W content ranging from 5% to 30% in 5% intervals. Ta–W alloy is commonly used in high-temperature nuclear applications. We found that the TDE decreased under tensile strain and increased under compressive strain. When Ta was alloyed with 20 at% W, the TDE increased by approximately 15 eV compared to pure Ta. The directional-strained TDE (Ed,i) appears to be more influenced by complex ⟨i j k⟩ directions rather than soft directions, and this effect is more prominent in the alloyed structure than in the pure one. Our results suggest that radiation defect formation is enhanced by tensile strain and suppressed by compressive strain, in addition to the effects of alloying.
Pharmacometabolomics for the Study of Lipid-Lowering Therapies: Opportunities and Challenges
Authors: Gianazza Erica , Brioschi Maura , Iezzi Ada , Paglia Giuseppe , Banfi Cristina
Published: February 2023

Lipid-lowering therapies are widely used to prevent the development of atherosclerotic cardiovascular disease (ASCVD) and related mortality worldwide. “Omics” technologies have been successfully applied in recent decades to investigate the mechanisms of action of these drugs, their pleiotropic effects, and their side effects, aiming to identify novel targets for future personalized medicine with an improvement of the efficacy and safety associated with the treatment. Pharmacometabolomics is a branch of metabolomics that is focused on the study of drug effects on metabolic pathways that are implicated in the variation of response to the treatment considering also the influences from a specific disease, environment, and concomitant pharmacological therapies. In this review, we summarized the most significant metabolomic studies on the effects of lipid-lowering therapies, including the most commonly used statins and fibrates to novel drugs or nutraceutical approaches. The integration of pharmacometabolomics data with the information obtained from the other “omics” approaches could help in the comprehension of the biological mechanisms underlying the use of lipid-lowering drugs in view of defining a precision medicine to improve the efficacy and reduce the side effects associated with the treatment.
An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility
Authors: Sheikh Ishfaq Ahmad , Beg Mohd Amin , Hamoda Taha Abo-Almagd Abdel-Meguid , Mandourah Hammam Mahmoud Siraj , Memili Erdogan
Published: February 2023

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger’s induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility.
The Gilded Clot: Review of Metal-Modulated Platelet Activation, Coagulation, and Fibrinolysis
Authors: Nielsen Vance G. , Goff Tanner , Hunsaker Brent D. , Neves Coulter D.
Published: February 2023

The processes of blood coagulation and fibrinolysis that in part maintain the physical integrity of the circulatory system and fluidity of its contents are complex as they are critical for life. While the roles played by cellular components and circulating proteins in coagulation and fibrinolysis are widely acknowledged, the impact of metals on these processes is at best underappreciated. In this narrative review we identify twenty-five metals that can modulate the activity of platelets, plasmatic coagulation, and fibrinolysis as determined by in vitro and in vivo investigations involving several species besides human beings. When possible, the molecular interactions of the various metals with key cells and proteins of the hemostatic system were identified and displayed in detail. It is our intention that this work serve not as an ending point, but rather as a fair evaluation of what mechanisms concerning metal interactions with the hemostatic system have been elucidated, and as a beacon to guide future investigation.
Future Trends in Biomaterials and Devices for Cells and Tissues
Authors: De Bartolo Loredana , Piscioneri Antonella , Ramakrishna Seeram
Published: February 2023

Setting up physiologically relevant in vitro models requires realizing a proper hierarchical cellular structure, wherein the main tissue features are recapitulated [...]
PS II Subunit P in Lilium pumilum (LpPsbP) Confers Saline-Alkali Resistance to the Plant by Scavenging ROS
Authors: Jing Yibo , Song Yu , Ji Shangwei , Zhang Ling , Wang Zongying , Dong Yi , Xu Yang , Jin Shumei
Published: February 2023

(1) Background: The growth of plants is impacted by salinity and alkali, Lilium pumilum (L. pumilum) is an ornamental plant with strong resistance to salinity and alkali, while the LpPsbP gene is helpful to fully understand the Saline-Alkali tolerance of L. pumilum. (2) Methods: Gene cloning, bioinformatics analysis, expression of fusion protein, determination of physiological indices of plant after Saline-Alkali stress, yeast two-hybrid screening, luciferase complementation assay, chromosome walking to obtain the promoter sequence, and then analyzed by PlantCARE. (3) Results: The LpPsbP gene was cloned and the fusion protein was purified. The transgenic plants had higher Saline-Alkali resistance than the wild type. A total of eighteen proteins interacting with LpPsbP were screened, and nine sites in the promoter sequence were analyzed. (4) Conclusion: Under Saline-Alkali or oxidative stress, L. pumilum will promote the expression of LpPsbP, which will then directly scavenge reactive oxygen species (ROS) in order to protect its photosystem II, reduce its damage, and thus improve the Saline-Alkali resistance of the plant. Moreover, according to some of the literature and the following experiments, two additional speculations are developed on the mechanisms of how two newly found objects, namely jasmonic acid (JA) and FoxO protein, could be involved in ROS scavenging processes were made.
Recent Developments in Polymer Nanocomposites for Bone Regeneration
Authors: Abbas Mohamed , Alqahtani Mohammed S. , Alhifzi Roaa
Published: February 2023

Most people who suffer acute injuries in accidents have fractured bones. Many of the basic processes that take place during embryonic skeletal development are replicated throughout the regeneration process that occurs during this time. Bruises and bone fractures, for example, serve as excellent examples. It almost always results in a successful recovery and restoration of the structural integrity and strength of the broken bone. After a fracture, the body begins to regenerate bone. Bone formation is a complex physiological process that requires meticulous planning and execution. A normal healing procedure for a fracture might reveal how the bone is constantly rebuilding as an adult. Bone regeneration is becoming more dependent on polymer nanocomposites, which are composites made up of a polymer matrix and a nanomaterial. This study will review polymer nanocomposites that are employed in bone regeneration to stimulate bone regeneration. As a result, we will introduce the role of bone regeneration nanocomposite scaffolds, and the nanocomposite ceramics and biomaterials that play a role in bone regeneration. Aside from that, recent advances in polymer nanocomposites might be used in a variety of industrial processes to help people with bone defects overcome their challenges will be discussed.
Investigation of Multi-Subunit Mycobacterium tuberculosis DNA-Directed RNA Polymerase and Its Rifampicin Resistant Mutants
Authors: Monama Mokgerwa Zacharia , Olotu Fisayo , Tastan Bishop Özlem
Published: February 2023

Emerging Mycobacterium tuberculosis (Mtb) resistant strains have continued to limit the efficacies of existing antitubercular therapies. More specifically, mutations in the RNA replicative machinery of Mtb, RNA polymerase (RNAP), have been widely linked to rifampicin (RIF) resistance, which has led to therapeutic failures in many clinical cases. Moreover, elusive details on the underlying mechanisms of RIF-resistance caused by Mtb-RNAP mutations have hampered the development of new and efficient drugs that are able to overcome this challenge. Therefore, in this study we attempt to resolve the molecular and structural events associated with RIF-resistance in nine clinically reported missense Mtb RNAP mutations. Our study, for the first time, investigated the multi-subunit Mtb RNAP complex and findings revealed that the mutations commonly disrupted structural–dynamical attributes that may be essential for the protein’s catalytic functions, particularly at the βfork loop 2, β’zinc-binding domain, the β’ trigger loop and β’jaw, which in line with previous experimental reports, are essential for RNAP processivity. Complementarily, the mutations considerably perturbed the RIF-BP, which led to alterations in the active orientation of RIF needed to obstruct RNA extension. Consequentially, essential interactions with RIF were lost due to the mutation-induced repositioning with corresponding reductions in the binding affinity of the drug observed in majority of the mutants. We believe these findings will significantly aid future efforts in the discovery of new treatment options with the potential to overcome antitubercular resistance.
Multi-Omics Approaches for Revealing the Epigenetic Regulation of Histone H3.1 during Spermatogonial Stem Cell Differentiation In Vitro
Authors: Liu Li , Li Haojie , Wang Mengjie , Zhang Xiangzheng , Ren Jie , Yuan Yan , Sha Jiahao , Guo Xuejiang
Published: February 2023

Epigenetic regulation, particularly post-translational modifications (PTMs) of histones, participates in spermatogonial stem cell (SSCs) differentiation. However, there is a lack of systemic studies of histone PTM regulation during the differentiation of SSCs due to its low number in vivo. Herein, we quantified dynamic changes of 46 different PTMs on histone H3.1 by targeted quantitative proteomics using mass spectrometry during SSCs differentiation in vitro, in combination with our RNA-seq data. We identified seven histone H3.1 modifications to be differentially regulated. In addition, we selected H3K9me2 and H3S10ph for subsequent biotinylated peptide pull-down experiments and identified 38 H3K9me2-binding proteins and 42 H3S10ph-binding proteins, which contain several transcription factors, such as GTF2E2 and SUPT5H, which appear to be crucial for epigenetic regulation of SSC differentiation.
Therapeutic Effect of Curcumin on Metabolic Diseases: Evidence from Clinical Studies
Authors: Zeng Yujiao , Luo Yuting , Wang Lijie , Zhang Kun , Peng Jiayan , Fan Gang
Published: February 2023

Metabolic diseases have become a serious threat to human health worldwide. It is crucial to look for effective drugs from natural products to treat metabolic diseases. Curcumin, a natural polyphenolic compound, is mainly obtained from the rhizomes of the genus Curcuma. In recent years, clinical trials using curcumin for the treatment of metabolic diseases have been increasing. In this review, we provide a timely and comprehensive summary of the clinical progress of curcumin in the treatment of three metabolic diseases, namely type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). The therapeutic effects and underlying mechanisms of curcumin on these three diseases are presented categorically. Accumulating clinical evidence demonstrates that curcumin has good therapeutic potential and a low number of side effects for the three metabolic diseases. It can lower blood glucose and lipid levels, improve insulin resistance and reduce inflammation and oxidative stress. Overall, curcumin may be an effective drug for the treatment of T2DM, obesity and NAFLD. However, more high-quality clinical trials are still required in the future to verify its efficacy and determine its molecular mechanisms and targets.
P188 Therapy in In Vitro Models of Traumatic Brain Injury
Authors: Zargari Michael , Meyer Luise J. , Riess Matthias L. , Li Zhu , Barajas Matthew B.
Published: February 2023

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Varied mechanisms of injury contribute to the heterogeneity of this patient population as demonstrated by the multiple published grading scales and diverse required criteria leading to diagnoses from mild to severe. TBI pathophysiology is classically separated into a primary injury that is characterized by local tissue destruction as a result of the initial blow, followed by a secondary phase of injury constituted by a score of incompletely understood cellular processes including reperfusion injury, disruption to the blood-brain barrier, excitotoxicity, and metabolic dysregulation. There are currently no effective pharmacological treatments in the wide-spread use for TBI, in large part due to challenges associated with the development of clinically representative in vitro and in vivo models. Poloxamer 188 (P188), a Food and Drug Administration-approved amphiphilic triblock copolymer embeds itself into the plasma membrane of damaged cells. P188 has been shown to have neuroprotective properties on various cell types. The objective of this review is to provide a summary of the current literature on in vitro models of TBI treated with P188.
Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1
Authors: Herburg Leonie , Rhein Mathias , Kubinski Sabrina , Kefalakes Ekaterini , Levin Greenwald Matar , Gielman Simona , Barak Segev , Frieling Helge , Grothe Claudia
Published: February 2023

Alcohol abuse accounts for 3.3 million deaths annually, rendering it a global health issue. Recently, fibroblast growth factor 2 (FGF-2) and its target, fibroblast growth factor receptor 1 (FGFR1), were discovered to positively regulate alcohol-drinking behaviors in mice. We tested whether alcohol intake and withdrawal alter DNA methylation of Fgf-2 and Fgfr1 and if there is a correlation regarding mRNA expression of these genes. Blood and brain tissues of mice receiving alcohol intermittently over a six-week period were analyzed using direct bisulfite sequencing and qRT-PCR analysis. Assessment of Fgf-2 and Fgfr1 promoter methylation revealed changes in the methylation of cytosines in the alcohol group compared with the control group. Moreover, we showed that the altered cytosines coincided with binding motives of several transcription factors. We also found that Fgf-2 and Fgfr1 gene expression was significantly decreased in alcohol-receiving mice compared with control littermates, and that this effect was specifically detected in the dorsomedial striatum, a brain region involved in the circuitry of the reward system. Overall, our data showed alcohol-induced alterations in both mRNA expression and methylation pattern of Fgf-2 and Fgfr1. Furthermore, these alterations showed a reward system regional specificity, therefore, resembling potential targets for future pharmacological interventions.
New Titanocene (IV) Dicarboxylates with Potential Cytotoxicity: Synthesis, Structure, Stability and Electrochemistry
Authors: Guk Dmitry A. , Gibadullina Karina R. , Burlutskiy Roman O. , Pavlov Kirill G. , Moiseeva Anna A. , Tafeenko Viktor A. , Lyssenko Konstantin A. , Gandalipov Erik R. , Shtil Alexander A. , Beloglazkina Elena K.
Published: February 2023

The search for new anticancer drugs based on biogenic metals, which have weaker side effects compared to platinum-based drugs, remains an urgent task in medicinal chemistry. Titanocene dichloride, a coordination compound of fully biocompatible titanium, has failed in pre-clinical trials but continues to attract the attention of researchers as a structural framework for the development of new cytotoxic compounds. In this study, a series of titanocene (IV) carboxylate complexes, both new and those known from the literature, was synthesized, and their structures were confirmed by a complex of physicochemical methods and X-ray diffraction analysis (including one previously unknown structure based on perfluorinated benzoic acid). The comprehensive comparison of three approaches for the synthesis of titanocene derivatives known from the literature (the nucleophilic substitution of chloride anions of titanocene dichloride with sodium and silver salts of carboxylic acids as well as the reaction of dimethyltitanocene with carboxylic acids themselves) made it possible to optimize these methods to obtain higher yields of individual target compounds, generalize the advantages and disadvantages of these techniques, and determine the substrate frames of each method. The redox potentials of all obtained titanocene derivatives were determined by cyclic voltammetry. The relationship between the structure of ligands, the reduction potentials of titanocene (IV), and their relative stability in redox processes, as obtained in this work, can be used for the design and synthesis of new effective cytotoxic titanocene complexes. The study of the stability of the carboxylate-containing derivatives of titanocene obtained in the work in aqueous media showed that they were more resistant to hydrolysis than titanocene dichloride. Preliminary tests of the cytotoxicity of the synthesised titanocene dicarboxilates on MCF7 and MCF7-10A cell lines demonstrated an IC50 ≥ 100 μM for all the obtained compounds.
The Role of Reactive Oxygen Species in Plant Response to Radiation
Authors: Tan Yuantao , Duan Yaoke , Chi Qing , Wang Rong , Yin Yue , Cui Dongjie , Li Shuang , Wang Aiying , Ma Ruonan , Li Bing , Jiao Zhen , Sun Hao
Published: February 2023

Radiation is widespread in nature, including ultraviolet radiation from the sun, cosmic radiation and radiation emitted by natural radionuclides. Over the years, the increasing industrialization of human beings has brought about more radiation, such as enhanced UV-B radiation due to ground ozone decay, and the emission and contamination of nuclear waste due to the increasing nuclear power plants and radioactive material industry. With additional radiation reaching plants, both negative effects including damage to cell membranes, reduction of photosynthetic rate and premature aging and benefits such as growth promotion and stress resistance enhancement have been observed. ROS (Reactive oxygen species) are reactive oxidants in plant cells, including hydrogen peroxide (H2O2), superoxide anions (O2•−) and hydroxide anion radicals (·OH), which may stimulate the antioxidant system of plants and act as signaling molecules to regulate downstream reactions. A number of studies have observed the change of ROS in plant cells under radiation, and new technology such as RNA-seq has molecularly revealed the regulation of radiative biological effects by ROS. This review summarized recent progress on the role of ROS in plant response to radiations including UV, ion beam and plasma, and may help to reveal the mechanisms of plant responses to radiation.
Functional Study of PgGRAS68-01 Gene Involved in the Regulation of Ginsenoside Biosynthesis in Panax ginseng
Authors: Liu Chang , Wang Kangyu , Yun Ziyi , Liu Wenbo , Zhao Mingzhu , Wang Yanfang , Hu Jian , Liu Tao , Wang Nan , Wang Yi , Zhang Meiping
Published: February 2023

Ginseng (Panax ginseng C. A. Meyer) is a perennial herb from the genus Panax in the family Araliaceae. It is famous in China and abroad. The biosynthesis of ginsenosides is controlled by structural genes and regulated by transcription factors. GRAS transcription factors are widely found in plants. They can be used as tools to modify plant metabolic pathways by interacting with promoters or regulatory elements of target genes to regulate the expression of target genes, thereby activating the synergistic interaction of multiple genes in metabolic pathways and effectively improving the accumulation of secondary metabolites. However, there are no reports on the involvement of the GRAS gene family in ginsenoside biosynthesis. In this study, the GRAS gene family was located on chromosome 24 pairs in ginseng. Tandem replication and fragment replication also played a key role in the expansion of the GRAS gene family. The PgGRAS68-01 gene closely related to ginsenoside biosynthesis was screened out, and the sequence and expression pattern of the gene were analyzed. The results showed that the expression of PgGRAS68-01 gene was spatio-temporal specific. The full-length sequence of PgGRAS68-01 gene was cloned, and the overexpression vector pBI121-PgGRAS68-01 was constructed. The ginseng seedlings were transformed by Agrobacterium rhifaciens-mediated method. The saponin content in the single root of positive hair root was detected, and the inhibitory role of PgGRAS68-01 in ginsenoside synthesis is reported.
Inhibition of Canonical Transient Receptor Potential Channels 4/5 with Highly Selective and Potent Small-Molecule HC-070 Alleviates Mechanical Hypersensitivity in Rat Models of Visceral and Neuropathic Pain
Authors: Jalava Niina , Kaskinoro Janne , Chapman Hugh , Morales Miguel , Metsänkylä Hanna , Heinonen Satu-Maarit , Koivisto Ari-Pekka
Published: February 2023

Transient receptor potential channels C4/C5 are widely expressed in the pain pathway. Here, we studied the putative analgesic efficacy of the highly selective and potent TRPC4/C5 antagonist HC-070 in rats. Inhibitory potency on human TRPC4 was assessed by using the whole-cell manual patch-clamp technique. Visceral pain sensitivity was assessed by the colonic distension test after intra-colonic trinitrobenzene sulfonic acid injection and partial restraint stress. Mechanical pain sensitivity was assessed by the paw pressure test in the chronic constriction injury (CCI) neuropathic pain model. We confirm that HC-070 is a low nanomolar antagonist. Following single oral doses (3–30 mg/kg in male or female rats), colonic hypersensitivity was significantly and dose-dependently attenuated, even fully reversed to baseline. HC-070 also had a significant anti-hypersensitivity effect in the established phase of the CCI model. HC-070 did not have an effect on the mechanical withdrawal threshold of the non-injured paw, whereas the reference compound morphine significantly increased it. Analgesic effects are observed at unbound brain concentrations near the 50% inhibitory concentration (IC50) recorded in vitro. This suggests that analgesic effects reported here are brought about by TRPC4/C5 blocking in vivo. The results strengthen the idea that TRPC4/C5 antagonism is a novel, safe non-opioid treatment for chronic pain.
Inhibitory Effects of a Novel μ-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference
Authors: Ide Soichiro , Iwase Noriaki , Arai Kenichi , Kojima Masahiro , Ushiyama Shigeru , Taniko Kaori , Ikeda Kazutaka
Published: February 2023

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (Ki = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use.
Theoretical Study on the Gas Phase and Gas–Liquid Interface Reaction Mechanism of Criegee Intermediates with Glycolic Acid Sulfate
Authors: Li Lei , Zhang Qingzhu , Wei Yuanyuan , Wang Qiao , Wang Wenxing
Published: February 2023

Criegee intermediates (CIs) are important zwitterionic oxidants in the atmosphere, which affect the budget of OH radicals, amines, alcohols, organic/inorganic acids, etc. In this study, quantum chemical calculation and Born–Oppenheimer molecular dynamic (BOMD) simulation were performed to show the reaction mechanisms of C2 CIs with glycolic acid sulfate (GAS) at the gas-phase and gas–liquid interface, respectively. The results indicate that CIs can react with COOH and OSO3H groups of GAS and generate hydroperoxide products. Intramolecular proton transfer reactions occurred in the simulations. Moreover, GAS acts as a proton donor and participates in the hydration of CIs, during which the intramolecular proton transfer also occurs. As GAS widely exists in atmospheric particulate matter, the reaction with GAS is one of the sink pathways of CIs in areas polluted by particulate matter.
Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA
Authors: Matyugina Elena , Petushkov Ivan , Surzhikov Sergei , Kezin Vasily , Maslova Anna , Ivanova Olga , Smirnova Olga , Kirillov Ilya , Fedyakina Irina , Kulbachinskiy Andrey , Kochetkov Sergey , Khandazhinskaya Anastasia
Published: February 2023

The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC50 values in the range of 20–50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.
Nanoscale Iron-Based Metal–Organic Frameworks: Incorporation of Functionalized Drugs and Degradation in Biological Media
Authors: Christodoulou Ioanna , Lyu Pengbo , Soares Carla Vieira , Patriarche Gilles , Serre Christian , Maurin Guillaume , Gref Ruxandra
Published: February 2023

Metal–organic frameworks (MOFs) attract growing interest in biomedical applications. Among thousands of MOF structures, the mesoporous iron(III) carboxylate MIL-100(Fe) (MIL stands for the Materials of Lavoisier Institute) is among the most studied MOF nanocarrier, owing to its high porosity, biodegradability, and lack of toxicity. Nanosized MIL-100(Fe) particles (nanoMOFs) readily coordinate with drugs leading to unprecedented payloads and controlled release. Here, we show how the functional groups of the challenging anticancer drug prednisolone influence their interactions with the nanoMOFs and their release in various media. Molecular modeling enabled predicting the strength of interactions between prednisolone-bearing or not phosphate or sulfate moieties (PP and PS, respectively) and the oxo-trimer of MIL-100(Fe) as well as understanding the pore filling of MIL-100(Fe). Noticeably, PP showed the strongest interactions (drug loading up to 30 wt %, encapsulation efficiency > 98%) and slowed down the nanoMOFs’ degradation in simulated body fluid. This drug was shown to bind to the iron Lewis acid sites and was not displaced by other ions in the suspension media. On the contrary, PS was entrapped with lower efficiencies and was easily displaced by phosphates in the release media. Noticeably, the nanoMOFs maintained their size and faceted structures after drug loading and even after degradation in blood or serum after losing almost the totality of the constitutive trimesate ligands. Scanning electron microscopy with high annular dark field (STEM-HAADF) in conjunction with X-Ray energy-dispersive spectrometry (XEDS) was a powerful tool enabling the unraveling of the main elements to gain insights on the MOF structural evolution after drug loading and/or upon degradation.