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International Journal of Molecular... May 2024A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological...
A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic β-amyloid (Aβ42) species in human neuronal cells in response to treatment. Among the most promising compounds were and , which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.
Topics: Donepezil; Alzheimer Disease; Animals; Humans; Mice; Melatonin; Amyloid beta-Peptides; Neuroprotective Agents; Male; Antioxidants; Cholinesterase Inhibitors; Indans; Disease Models, Animal; Neurons; Piperidines
PubMed: 38892154
DOI: 10.3390/ijms25115969 -
International Journal of Molecular... May 2024MicroRNAs (miRNAs) are small RNA molecules that regulate more than 30% of genes in humans. Recent studies have revealed that miRNAs play a crucial role in tumorigenesis.... (Review)
Review
MicroRNAs (miRNAs) are small RNA molecules that regulate more than 30% of genes in humans. Recent studies have revealed that miRNAs play a crucial role in tumorigenesis. Large sets of miRNAs in human tumors are under-expressed compared to normal tissues. Furthermore, experiments have shown that interference with miRNA processing enhances tumorigenesis. Multiple studies have documented the causal role of miRNAs in cancer, and miRNA-based anticancer therapies are currently being developed. This review primarily focuses on two key points: (1) miRNAs and their role in human cancer and (2) the regulation of tumor suppressors by miRNAs. The review discusses (a) the regulation of the tumor suppressor p53 by miRNA, (b) the critical role of the miR-144/451 cluster in regulating the Itch-p63-Ago2 pathway, and (c) the regulation of PTEN by miRNAs. Future research and the perspectives of miRNA in cancer are also discussed. Understanding these pathways will open avenues for therapeutic interventions targeting miRNA regulation.
Topics: Humans; MicroRNAs; Neoplasms; Gene Expression Regulation, Neoplastic; Animals; PTEN Phosphohydrolase; Tumor Suppressor Protein p53
PubMed: 38892054
DOI: 10.3390/ijms25115865 -
International Journal of Molecular... May 2024Neuroblastoma is the most common malignant extracranial solid tumor of childhood. Recent studies involving the application of advanced high-throughput "omics" techniques... (Review)
Review
Neuroblastoma is the most common malignant extracranial solid tumor of childhood. Recent studies involving the application of advanced high-throughput "omics" techniques have revealed numerous genomic alterations, including aberrant coding-gene transcript levels and dysfunctional pathways, that drive the onset, growth, progression, and treatment resistance of neuroblastoma. Research conducted in the past decade has shown that long non-coding RNAs, once thought to be transcriptomic noise, play key roles in cancer development. With the recent and continuing increase in the amount of evidence for the underlying roles of long non-coding RNAs in neuroblastoma, the potential clinical implications of these RNAs cannot be ignored. In this review, we discuss their biological mechanisms of action in the context of the central driving mechanisms of neuroblastoma, focusing on potential contributions to the diagnosis, prognosis, and treatment of this disease. We also aim to provide a clear, integrated picture of future research opportunities.
Topics: Humans; Neuroblastoma; RNA, Long Noncoding; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Animals; Prognosis; Molecular Targeted Therapy
PubMed: 38891878
DOI: 10.3390/ijms25115690 -
International Journal of Molecular... May 2024Bioproducts derived from platelets have been extensively used across various medical fields, with a recent notable surge in their application in dermatology and... (Review)
Review
Bioproducts derived from platelets have been extensively used across various medical fields, with a recent notable surge in their application in dermatology and aesthetic procedures. These products, such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF), play crucial roles in inducing blood vessel proliferation through growth factors derived from peripheral blood. PRP and PRF, in particular, facilitate fibrin polymerization, creating a robust structure that serves as a reservoir for numerous growth factors. These factors contribute to tissue regeneration by promoting cell proliferation, differentiation, and migration and collagen/elastin production. Aesthetic medicine harnesses these effects for diverse purposes, including hair restoration, scar treatment, striae management, and wound healing. Furthermore, these biological products can act as adjuvants with other treatment modalities, such as laser therapy, radiofrequency, and microneedling. This review synthesizes the existing evidence, offering insights into the applications and benefits of biological products in aesthetic medicine.
Topics: Humans; Platelet-Rich Plasma; Regenerative Medicine; Platelet-Rich Fibrin; Wound Healing; Blood Platelets; Animals; Regeneration; Cell Proliferation
PubMed: 38891792
DOI: 10.3390/ijms25115604 -
International Journal of Molecular... May 2024Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC)....
Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Abiraterone Acetate; Pilot Projects; Aged; MicroRNAs; Biomarkers, Tumor; Middle Aged; Gene Expression Regulation, Neoplastic; PTEN Phosphohydrolase; Circulating MicroRNA; Neoplasm Metastasis; Homeodomain Proteins; Aged, 80 and over
PubMed: 38891761
DOI: 10.3390/ijms25115573 -
Healthcare (Basel, Switzerland) Jun 2024Tuberculosis (TB) is the top infectious killer in the world despite efforts to eliminate it. Pharmaceutical care roles are pillars of pharmacy practice, and pharmacists... (Review)
Review
Tuberculosis (TB) is the top infectious killer in the world despite efforts to eliminate it. Pharmaceutical care roles are pillars of pharmacy practice, and pharmacists are well equipped to serve a unique role in the pathway to provide education about TB. Previous systematic reviews emphasize pharmacists' role in treating TB; however, pharmacists can and do play much broader roles in overall TB elimination efforts. Five researchers searched five electronic databases (PubMed, PsychInfo, CINAHL, Academic Search Premier, and Embase). Search terms included pharmacy, pharmacist, tuberculosis, antitubercular agents, supply, distribution, and drug therapy. Inclusion criteria were studies published from 2010 through March 2023, in English or Spanish, addressed a specific TB-related role for pharmacists/pharmacies, and were peer-reviewed. Exclusion criteria included pharmacology, pharmacokinetics, clinical trials on drug efficacy, and editorials. Two researchers conducted each level of review; for discordance, a third researcher reviewed, and a decision was reached by consensus. Roles were extracted and cross-referenced with traditional pharmaceutical care steps. Of the initial 682 hits, 133 were duplicates. After further review, we excluded 514 records, leaving 37 articles for full extraction. We found nine roles for pharmacists in TB prevention and classified them as implemented, not implemented, or recommended. These roles were: (1) TB symptom screening; (2) Referring to TB care systems; (3) TB testing; (4) Dispensing TB medication correctly and/or directly observed therapy; (5) Counseling; (6) Looking to reduce socioeconomic barriers; (7) Procurement of TB medications; (8) Quality assurance of TB medications; (9) Maintaining and using pharmacy data systems. Pharmacists are well situated to play a vital role in the global fight against TB. Findings suggested pharmacists in many settings have already expanded their roles related to TB elimination beyond traditional pharmaceutical care. Still others need to increase the understanding of TB procurement and treatment, their power to improve TB care, and their contributions to data systems that serve population health. Pharmacy curricula should increase TB-related training to better equip future pharmacists to contribute to TB elimination.
PubMed: 38891212
DOI: 10.3390/healthcare12111137 -
Cells Jun 2024Ferroptosis hallmarked by lipid peroxidation and iron homeostasis imbalance is involved in the occurrence and development of various diseases. The plant growth regulator...
Ferroptosis hallmarked by lipid peroxidation and iron homeostasis imbalance is involved in the occurrence and development of various diseases. The plant growth regulator chlormequat chloride (CCC) can contribute to the causality and exacerbation of reproductive disorders. However, the mechanism by which CCC may cause Leydig cell attenuation remains poorly understood. In this study, TM3 Leydig cells were used to investigate the inhibitory effect of CCC on cell growth and its possible mechanism. The results showed that CCC caused apoptosis, pyroptosis, ferroptosis and necroinflammation in TM3 cells. By comparing the effects of ferroptosis inhibitor Ferrostatin-1 (Fer-1) and pan-Caspase inhibitor Z-VAD-FMK (ZVF) on lipid peroxidation and Caspase-mediated regulated cell death (RCD), we found that Fer-1 was better at rescuing the growth of TM3 cells than ZVF. Although ZVF reduced mitochondrial ROS level and inhibited the activation of Caspase3 and Caspase1, it could not significantly ameliorate lipid peroxidation and the levels of IL-1β and HMGB1 like Fer-1. Therefore, ferroptosis might be a key non apoptotic RCD mode responsible for CCC-driven inflammation, leading to weakened viability and proliferation of TM3 cells. In addition, overexpression of ferritin light chain (FTL) promoted the resistance of TM3 cells to CCC-induced ferroptosis-mediated inflammation and to some extent improved the inhibition of viability and proliferation. Altogether, ferroptosis-initiated inflammation might play a key role in CCC-impaired TM3 cell growth.
Topics: Ferroptosis; Animals; Male; Mice; Leydig Cells; Inflammation; Cell Proliferation; Lipid Peroxidation; Reactive Oxygen Species; Cell Line; Apoptosis; Mitochondria; Amino Acid Chloromethyl Ketones; Cyclohexylamines; Phenylenediamines
PubMed: 38891111
DOI: 10.3390/cells13110979 -
Cells May 2024Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs)...
Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment resistance and tumor relapse, emphasizing the need to comprehend the mechanisms regulating these cells. Also, their multifaceted contributions to the tumor microenvironment (TME) underline their significance, driven by their unique properties. This study aimed to characterize glioblastoma stem cells (GSCs), specifically slow-cycling cells (SCCs), in an immunocompetent murine GBM model to explore their similarities with their human counterparts. Using the KR158 mouse model, we confirmed that SCCs isolated from this model exhibited key traits and functional properties akin to human SCCs. KR158 murine SCCs, expanded in the gliomasphere assay, demonstrated sphere forming ability, self-renewing capacity, positive tumorigenicity, enhanced stemness and resistance to chemotherapy. Together, our findings validate the KR158 murine model as a framework to investigate GSCs and SCCs in GBM pathology, and explore specifically the SCC-immune system communications, understand their role in disease progression, and evaluate the effect of therapeutic strategies targeting these specific connections.
Topics: Animals; Mice; Neoplastic Stem Cells; Spheroids, Cellular; Humans; Brain Neoplasms; Glioma; Cell Line, Tumor; Glioblastoma; Immunocompetence; Tumor Microenvironment; Disease Models, Animal; Neoplasm Grading
PubMed: 38891070
DOI: 10.3390/cells13110938 -
Implementation Science Communications Jun 2024Intensive manual therapy is important for improving lifelong upper limb motor outcomes for infants and toddlers with cerebral palsy. This play-based therapy is delivered...
BACKGROUND
Intensive manual therapy is important for improving lifelong upper limb motor outcomes for infants and toddlers with cerebral palsy. This play-based therapy is delivered by caregivers who are coached by occupational therapists. However, access to this therapy is very limited for Canadian children with cerebral palsy younger than two years old. This project aims to first identify barriers and facilitators and then design implementation strategies to support early intensive manual therapy delivery for infants and toddlers with cerebral palsy across Canada.
METHODS
A mixed-methods sequential explanatory design will be used with four consecutive phases. The updated Consolidated Framework for Implementation Research will guide the study. Quantitative data will be collected from a survey in Phase One. Participants will be recruited from three groups: (1) Caregivers of children with cerebral palsy six years old and younger who are eligible for manual therapy; (2) occupational therapists who treat children with cerebral palsy; and (3) healthcare administrators or people responsible for managing pediatric occupational therapy programs. In Phase Two, quantitative data from the survey will be used to map to implementation strategies known to be effective at addressing the identified modifiable barriers and facilitators. Phase Three will collect qualitative data from semi-structured interviews for the purpose of explaining Phase One quantitative findings in greater depth, and for understanding the appropriateness of strategies identified in Phase Two. The participant recruitment strategy and interview guide content for Phase Three will be informed by results of Phase One. Phase Four will use a modified nominal group technique to refine and prioritize an implementation strategy toolbox. Results will be widely disseminated to knowledge users to provide them with tailorable strategies to increase delivery of early intensive manual interventions.
DISCUSSION
This study will provide a comprehensive understanding of the barriers and facilitators to implementation of early intensive manual therapy for young children with cerebral palsy in Canada. A toolbox of evidence-based and tailorable implementation strategies will be disseminated nationally to support uptake of early intensive manual therapy into clinical practice for young children with cerebral palsy.
PubMed: 38890681
DOI: 10.1186/s43058-024-00602-y -
Journal of Science and Medicine in Sport May 2024Explore if implementing an individualised Sub-Symptom Heart Rate Threshold (SSHeRT) rehabilitation program within 48 hours versus physical rest for 14 days affects...
A controlled early-exercise rehabilitation program commencing within 48 hours of a Sports-Related Concussion improves recovery in UK student-athletes: A prospective cohort study.
OBJECTIVES
Explore if implementing an individualised Sub-Symptom Heart Rate Threshold (SSHeRT) rehabilitation program within 48 hours versus physical rest for 14 days affects recovery following SRC in university-aged student-athletes.
DESIGN
Prospective, observational cohort study.
METHODS
Two UK university-aged student-athlete rugby union cohorts were compared (Physical Rest Group (PRG), n = 140, July 2019-March 2020 and Controlled Early-Exercise Group (CEG), n = 167, July 2021-April 2023). Both groups completed the test battery (Post-Concussion Symptom Scale (PCSS), Immediate Post-Concussion and Cognitive Test (ImPACT), Vestibular-Ocular Motor Screening Tool (VOMS)) during pre-season to provide a baseline and within 48 hours, at 4, 8, 14-days post-SRC and at Return to Play (RTP). The PRG (n = 42) physically rested for 14 days as per the nationwide community guidelines. The CEG (n = 52) followed the SSHeRT rehabilitation program. Individual change to baseline was used in all analyses.
RESULTS
The CEG performed better on ImPACT's verbal memory at 4 (PRG; -5.5 (-10.8-0.0), CEG; 1.0 (-2.0-10.5), p = 0.05) and 14 days (PRG; -2.0 (-10.0-3.0), CEG; 4.0 (-1.0-11.0), p = 0.05) and on the VOMS at 4 (PRG; 3.0 (0.0-12.0), CEG; 0.0 (0.0-5.0), p = 0.03, OR; 2.910) and 14-days post-SRC (PRG; 0.0 (0.0-1.0), CEG; 0.0 (0.0-0.0), OR; 5.914). Near point convergence was better at all time points for the CEG. The CEG was 26.7 % more likely to have RTP within 30 days, and 6.7 and 5.1 times more likely to have resumed non-contact and contact academic activities by 4 days.
CONCLUSIONS
SSHeRT is safe, can be used within 48 hours of a SRC and may hasten university-aged student-athletes recovery following an SRC.
PubMed: 38890020
DOI: 10.1016/j.jsams.2024.05.011