bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of medication optimization and recommendations by clinical pharmacists embedded in a memory disorder clinic
Authors: Coli Katherine G. , Lee Monica , Aladeen Traci S. , Mattle Anna G. , Ajtai Bela , Rainka Michelle M. 
Published: December 2022

AbstractIntroductionOlder patients with dementia or mild cognitive impairment (MCI) are particularly vulnerable to adverse effects from potentially inappropriate medications (PIMs). Previous studies demonstrated that pharmacist interventions may reduce PIMs, but the impact of pharmacists embedded in an outpatient memory care clinic has not been adequately studied.ObjectiveTo determine the impact of pharmacist recommendations on PIM reduction in older adults with dementia or MCI.MethodsThis prospective observational study within an outpatient neurology center included patients at least 65 years old diagnosed with dementia or MCI. Pharmacists utilized the American Geriatrics Society Beers Criteria, the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions, and the Anticholinergic Burden Scale (ACB) to identify PIMs and reviewed patient charts to make pharmacologic and nonpharmacologic recommendations to prescribers when appropriate per clinical judgment. Primary outcomes included frequency and prevalence of PIMs before versus after pharmacist intervention and rate of acceptance of pharmacy recommendations. Additional outcomes included ACB scores before versus after intervention.ResultsA total of 180 patients were included. Pharmacists made recommendations for 49% of patients, most commonly laboratory monitoring recommendations and medication discontinuations or substitutions. Out of 192 total pharmacist recommendations, 61 (32%) were accepted by providers within the memory clinic. After pharmacist intervention, the frequency and prevalence of PIMs were reduced from average 1.8 to 1.7 PIMs per patient and from 78% to 74% of patients with at least one PIM (p < 0.05). ACB scores were reduced from average 1.5 to 1.3 (p < 0.01).ConclusionPharmacist intervention resulted in a reduction in PIMs and ACB scores in patients with dementia or MCI. Future studies should incorporate a controlled prospective design with scheduled clinical outcomes assessments such as cognitive testing to examine the clinical benefit of pharmacist intervention and explore methods to improve multidisciplinary collaboration between pharmacists and prescribers.
STAT3/Mitophagy Axis Coordinates Macrophage NLRP3 Inflammasome Activation and Inflammatory Bone Loss
Authors: Zhu Lingxin , Wang Zijun , Sun Xiaoyue , Yu Jingjing , Li Ting , Zhao Huan , Ji Yaoting , Peng Bin , Du Minquan 
Published: December 2022

ABSTRACT
Signal transducer and activator of transcription 3 (STAT3), a cytokine-responsive transcription factor, is known to play a role in immunity and bone remodeling. However, whether and how STAT3 impacts macrophage NLR family pyrin domain containing 3 (NLRP3) inflammasome activation associated with inflammatory bone loss remains unknown. Here, STAT3 signaling is hyperactivated in macrophages in the context of both non-sterile and sterile inflammatory osteolysis, and this was highly correlated with the cleaved interleukin-1β (IL-1β) expression pattern. Strikingly, pharmacological inhibition of STAT3 markedly blocks macrophage NLRP3 inflammasome activation in vitro, thereby relieving inflammatory macrophage-amplified osteoclast formation and bone-resorptive activity. Mechanistically, STAT3 inhibition in macrophages triggers PTEN-induced kinase 1 (PINK1)-dependent mitophagy that eliminates dysfunctional mitochondria, reverses mitochondrial membrane potential collapse, and inhibits mitochondrial reactive oxygen species release, thus inactivating the NLRP3 inflammasome. In vivo, STAT3 inhibition effectively protects mice from both infection-induced periapical lesions and aseptic titanium particle-mediated calvarial bone erosion with potent induction of PINK1 and downregulation of inflammasome activation, macrophage infiltration, and osteoclast formation. This study reveals the regulatory role of the STAT3/mitophagy axis at the osteo-immune interface and highlights a potential therapeutic intervention to prevent inflammatory bone loss. © 2022 American Society for Bone and Mineral Research (ASBMR).
Abstract
Schematic illustration. In both non-sterile and sterile inflammatory osteolysis, macrophage hyperactivated STAT3 is highly correlated with the cleaved IL-1β expression. Targeting STAT3 using stattic blocks macrophage NLRP3 inflammasome activation through triggering PINK1-dependent mitophagy that eliminates dysfunctional mitochondria, thereby relieving inflammatory macrophage-amplified osteoclast formation in vitro and protecting mouse inflammatory osteolysis in vivo.
FK506 binding protein 51: Its role in the adipose organ and beyond
Authors: Galigniana Natalia M. , Ruiz Marina C. , Piwien‐Pilipuk Graciela 
Published: December 2022

AbstractThere is a great body of evidence that the adipose organ plays a central role in the control not only of energy balance, but importantly, in the maintenance of metabolic homeostasis. Interest in the study of different aspects of its physiology grew in the last decades due to the pandemic of obesity and the consequences of metabolic syndrome. It was not until recently that the first evidence for the role of the high molecular weight immunophilin FK506 binding protein (FKBP) 51 in the process of adipocyte differentiation have been described. Since then, many new facets have been discovered of this stress‐responsive FKBP51 as a central node for precise coordination of many cell functions, as shown for nuclear steroid receptors, autophagy, signaling pathways as Akt, p38 MAPK, and GSK3, as well as for insulin signaling and the control of glucose homeostasis. Thus, the aim of this review is to integrate and discuss the recent advances in the understanding of the many roles of FKBP51 in the adipose organ.
Drug repurposing toward the inhibition of RNA‐dependent RNA polymerase of various flaviviruses through computational study
Authors: Murali Aarthy , Kumar Sushil , Akshaya Srinivasan , Singh Sanjeev K. 
Published: December 2022

AbstractNumerous pathogens affecting human is present in the flavivirus family namely west nile, dengue, yellow fever, and zika which involves in development of global burden and distressing the environment economically. Till date, no approved drugs are available for targeting these viruses. The threat which urged the identification of small molecules for the inhibition of these viruses is the spreading of serious viral diseases. The recent outbreak of zika and dengue infections postured a solemn risk to worldwide public well‐being. RNA‐dependent RNA polymerase (RdRp) is the supreme adaptable enzymes of all the RNA viruses which is responsible for the replication and transcription of genome among the structural and nonstructural proteins of flaviviruses. It is understood that the RdRp of the flaviviruses are similar stating that the japanese encephalitis and west nile shares 70% identity with zika whereas the dengue serotype 2 and 3 shares the identity of 76% and 81%, respectively. In this study, we investigated the binding site of four flaviviral RdRp and provided insights into various interaction of the molecules using the computational approach. Our study helps in recognizing the potent compounds that could inhibit the viral protein as a common inhibitor. Additionally, with the conformational stability analysis, we proposed the possible mechanism of inhibition of the identified common small molecule toward RdRp of flavivirus. Finally, this study could be an initiative for the identification of common inhibitors and can be explored further for understanding the mechanism of action through in vitro studies for the study on efficacy.
Characterization of advanced glycation end products and aggregates of irisin: Multispectroscopic and microscopic approaches
Authors: Waseem Rashid , Shamsi Anas , Khan Tanzeel , Anwer Ayesha , Shahid Mohammad , Kazim Syed Naqui , Hassan Md. Imtaiyaz , Islam Asimul 
Published: December 2022

AbstractGlycation of proteins leading to the formation of advanced glycation end products (AGEs) has been demonstrated to contribute to the pathogenesis of several diseases. Irisin is a clinically significant protein, putatively involved in obesity, diabetes, and neurological disorders. This study aimed to monitor the methyl‐glyoxal (MG) induced AGEs and aggregate formation of irisin, as a function of time, employing multispectroscopic and microscopic approaches. ANS fluorescence suggested a molten globule‐like state on Day 6, followed by the formation of irisin AGEs adducts, as confirmed by AGE‐specific fluorescence. Glycation of irisin led to aggregate formation, which was characterized by Thioflavin T fluorescence, CD spectroscopy, and microscopic studies. These aggregates were confirmed by exploiting fluorescence microscopy, confocal, and transmission electron microscopy. Molecular docking was performed to determine the crucial residues of irisin involved in irisin‐MG interaction. Usually, MG is present in trace amounts as a metabolic by‐product in the body, which is found to be elevated in diseased conditions viz. diabetes and Alzheimer's disease. This study characterized the AGEs and aggregates of clinically important protein, irisin; and since MG level has been found to be increased in various pathological conditions, this study provides a clinical perspective. There is a possibility that elevated MG concentrations might glycate irisin resulting in reduced irisin levels as reported in pathological conditions. However, further investigations are required to prove it.
Differential gene expression analysis of RAGE‐S100A6 complex for target selection and the design of novel inhibitors for anticancer drug discovery
Authors: Faruqui Tabrez , Singh Garima , Khan Salman , Khan Mohd Sajid , Akhter Yusuf 
Published: December 2022

AbstractReceptor for advanced glycation end products (RAGE), a member of the immunoglobulin family, interactions with its ligands trigger downstream signaling and induce an inflammatory response linked to diabetes, inflammation, carcinogenesis, cardiovascular disease, and a variety of other human disorders. The interaction of RAGE and S100A6 has been associated with a variety of malignancies. For the control of RAGE‐related illnesses, there is a great demand for more specialized drug options. To identify the most effective target for combating human malignancies associated with RAGE‐S100A6 complex, we conducted single and differential gene expression analyses of S100A6 and RAGE, comparing normal and malignant tissues. Further, a structure‐based virtual screening was conducted using the ZINC15 database. The chosen compounds were then subjected to a molecular docking investigation on the RAGE active site region, recognized by the various cancer‐related RAGE ligands. An optimized RAGE structure was screened against a library of drug‐like molecules. The screening results suggested that three promising compounds were presented as the top acceptable drug‐like molecules with a high binding affinity at the RAGE V‐domain catalytic region. We depicted that these compounds may be potential RAGE inhibitors and could be used to produce a successful medication against human cancer and other RAGE‐related diseases based on their various assorted parameters, binding energy, hydrogen bonding, ADMET characteristics, etc. MD simulation on a time scale of 50 ns was used to test the stability of the RAGE‐inhibitor complexes. Therefore, targeting RAGE and its ligands using these drug‐like molecules may be an effective therapeutic approach.
Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening
Authors: Wang Xin , Ye Cheng‐hao , Li En‐min , Xu Li‐yan , Lin Wang‐qiang , Chen Guang‐hui 
Published: December 2022

AbstractAlthough the aberrant activity of fibroblast growth factor receptor 3 (FGFR3) is implicated in various cancers, the reported kinase inhibitors of FGFR3 tend to cause side effects resulting from the inhibitory activity on vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, it is necessary to find a novel high‐selective inhibitor of FGFR3 over VEGFR2 from the small‐molecule compound database. In this study, integrated virtual screening protocols were established to screen for selective inhibitors of FGFR3 over VEGFR2 in Drugbank and Asinex databases by combining three‐dimensional pharmacophore model, molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations. Finally, it is found that Asinex‐5082, as an octahydropyrrolo[3,2‐b] pyridin derivative, has larger binding free energy with FGFR3 (−39.3 kcal/mol) than reference drug Erdafitinib (−29.9 kcal/mol), while cannot bind with VEGFR2, resulting in considerable inhibitory selectivity. This is because Asinex‐5082, unlike Erdafitinib, has not m‐dimethoxybenzene with large steric hindrance, thus can enter the larger ATP‐binding pocket of FGFR3 with DFG‐in conformation to form hydrophobic interaction with residues Met529, Ile539, and Tyr557 as well as hydrogen bond with Ala558. On the other hand, due to the fact that the benzodioxane and N‐heterocyclic rings are connected by carbonyl (C=O), Asinex‐5082 cannot rotate freely so as to enter the smaller ATP binding pocket of VEGFR2 on the DFG‐out conformation. The lead molecule Asinex‐5082 may facilitate the rational design and development of novel selective inhibitors of FGFR3 over VEGFR2 as anticancer drugs.
Phosphorylation states greatly regulate the activity and gating properties of Cav3.1 T‐type Ca2+ channels
Authors: Jeong Sua , Shim Ji Seon , Sin Seok Kyo , Park Kang‐Sik , Lee Jung‐Ha 
Published: December 2022

AbstractCav3.1 T‐type Ca2+ channels play pivotal roles in neuronal low‐threshold spikes, visceral pain, and pacemaker activity. Phosphorylation has been reported to potently regulate the activity and gating properties of Cav3.1 channels. However, systematic identification of phosphorylation sites (phosphosites) in Cav3.1 channel has been poorly investigated. In this work, we analyzed rat Cav3.1 protein expressed in HEK‐293 cells by mass spectrometry, identified 30 phosphosites located at the cytoplasmic regions, and illustrated them as a Cav3.1 phosphorylation map which includes the reported mouse Cav3.1 phosphosites. Site‐directed mutagenesis of the phosphosites to Ala residues and functional analysis of the phospho‐silent Cav3.1 mutants expressed in Xenopus oocytes showed that the phospho‐silent mutation of the N‐terminal Ser18 reduced its current amplitude with accelerated current kinetics and negatively shifted channel availability. Remarkably, the phospho‐silent mutations of the C‐terminal Ser residues (Ser1924, Ser2001, Ser2163, Ser2166, or Ser2189) greatly reduced their current amplitude without altering the voltage‐dependent gating properties. In contrast, the phosphomimetic Asp mutations of Cav3.1 on the N‐ and C‐terminal Ser residues reversed the effects of the phospho‐silent mutations. Collectively, these findings demonstrate that the multiple phosphosites of Cav3.1 at the N‐ and C‐terminal regions play crucial roles in the regulation of the channel activity and voltage‐dependent gating properties.
Na,K‐ATPase: A murzyme facilitating thermodynamic equilibriums at the membrane‐interface
Authors: Manoj Kelath Murali , Gideon Daniel A. , Bazhin Nikolai M. , Tamagawa Hirohisa , Nirusimhan Vijay , Kavdia Mahendra , Jaeken Laurent 
Published: December 2022

AbstractThe redox metabolic paradigm of murburn concept advocates that diffusible reactive species (DRS, particularly oxygen‐centric radicals) are mainstays of physiology, and not mere pathological manifestations. The murburn purview of cellular function also integrates the essential principles of bioenergetics, thermogenesis, homeostasis, electrophysiology, and coherence. In this context, any enzyme that generates/modulates/utilizes/sustains DRS functionality is called a murzyme. We have demonstrated that several water‐soluble (peroxidases, lactate dehydrogenase, hemogoblin, etc.) and membrane‐embedded (Complexes I–V in mitochondria, Photosystems I/II in chloroplasts, rhodopsin/transducin in rod cells, etc.) proteins serve as murzymes. The membrane protein of Na,K‐ATPase (NKA, also known as sodium‐potassium pump) is the focus of this article, owing to its centrality in neuro‐cardio‐musculo electrophysiology. Herein, via a series of critical queries starting from the geometric/spatio‐temporal considerations of diffusion/mass transfer of solutes in cells to an update on structural/distributional features of NKA in diverse cellular systems, and from various mechanistic aspects of ion‐transport (thermodynamics, osmoregulation, evolutionary dictates, etc.) to assays/explanations of inhibitory principles like cardiotonic steroids (CTS), we first highlight some unresolved problems in the field. Thereafter, we propose and apply a minimalist murburn model of trans‐membrane ion‐differentiation by NKA to address the physiological inhibitory effects of trans‐dermal peptide, lithium ion, volatile anesthetics, confirmed interfacial DRS + proton modulators like nitrophenolics and unsaturated fatty acid, and the diverse classes of molecules like CTS, arginine, oximes, etc. These explanations find a pan‐systemic connectivity with the inhibitions/uncouplings of other membrane proteins in cells.
Topography of pleural epithelial structure enabled by en face isolation and machine learning
Authors: Liu Betty S. , Valenzuela Cristian D. , Mentzer Katherine L. , Wagner Willi L. , Khalil Hassan A. , Chen Zi , Ackermann Maximilian , Mentzer Steven J. 
Published: December 2022

AbstractPleural epithelial adaptations to mechanical stress are relevant to both normal lung function and parenchymal lung diseases. Assessing regional differences in mechanical stress, however, has been complicated by the nonlinear stress–strain properties of the lung and the large displacements with ventilation. Moreover, there is no reliable method of isolating pleural epithelium for structural studies. To define the topographic variation in pleural structure, we developed a method of en face harvest of murine pleural epithelium. Silver‐stain was used to highlight cell borders and facilitate imaging with light microscopy. Machine learning and watershed segmentation were used to define the cell area and cell perimeter of the isolated pleural epithelial cells. In the deflated lung at residual volume, the pleural epithelial cells were significantly larger in the apex (624 ± 247 μm2) than in basilar regions of the lung (471 ± 119 μm2) (p < 0.001). The distortion of apical epithelial cells was consistent with a vertical gradient of pleural pressures. To assess epithelial changes with inflation, the pleura was studied at total lung capacity. The average epithelial cell area increased 57% and the average perimeter increased 27% between residual volume and total lung capacity. The increase in lung volume was less than half the percent change predicted by uniform or isotropic expansion of the lung. We conclude that the structured analysis of pleural epithelial cells complements studies of pulmonary microstructure and provides useful insights into the regional distribution of mechanical stresses in the lung.
Lysosome signaling in cell survival and programmed cell death for cellular homeostasis
Authors: Patra Srimanta , Patil Shankargouda , Klionsky Daniel J. , Bhutia Sujit K. 
Published: December 2022

AbstractRecent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome‐governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization‐associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.
Neural crest cells development and neuroblastoma progression: Role of Wnt signaling
Authors: Ahmad Mir Hilal , Ghosh Balaram , Rizvi Moshahid Alam , Ali Mansoor , Kaur Loveleena , Mondal Amal Chandra 
Published: December 2022

AbstractNeuroblastoma (NB) is one of the most common heterogeneous extracranial cancers in infancy that arises from neural crest (NC) cells of the sympathetic nervous system. The Wnt signaling pathway, both canonical and noncanonical pathway, is a highly conserved signaling pathway that regulates the development and differentiation of the NC cells during embryogenesis. Reports suggest that aberrant activation of Wnt ligands/receptors in Wnt signaling pathways promote progression and relapse of NB. Wnt signaling pathways regulate NC induction and migration in a similar manner; it regulates proliferation and metastasis of NB. Inhibiting the Wnt signaling pathway or its ligands/receptors induces apoptosis and abrogates proliferation and tumorigenicity in all major types of NB cells. Here, we comprehensively discuss the Wnt signaling pathway and its mechanisms in regulating the development of NC and NB pathogenesis. This review highlights the implications of aberrant Wnt signaling in the context of etiology, progression, and relapse of NB. We have also described emerging strategies for Wnt‐based therapies against the progression of NB that will provide new insights into the development of Wnt‐based therapeutic strategies for NB.
miRNA in Parkinson's disease: From pathogenesis to theranostic approaches
Authors: Elangovan Ajay , Venkatesan Dhivya , Selvaraj Priyanka , Pasha Md. Younus , Babu Harysh Winster Suresh , Iyer Mahalaxmi , Narayanasamy Arul , Subramaniam Mohana Devi , Valsala Gopalakrishnan Abilash , Kumar Nachimuthu Senthil , Vellingiri Balachandar 
Published: December 2022

AbstractParkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non‐motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor‐alpha and interleukin‐6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.