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Heliyon Jun 2024To explore the potential targets for melatonin in the treatment of periodontitis through network pharmacologic analysis and experimental validation via animal models...
OBJECTIVE
To explore the potential targets for melatonin in the treatment of periodontitis through network pharmacologic analysis and experimental validation via animal models and cellular experiments.
MATERIALS AND METHODS
In this study, we first screened melatonin targets from Pharm Mapper for putative targets, Drug Bank, and TCMSP databases for known targets. Then, disease database was searched and screened for differential expressed genes associated with periodontitis. The intersection of disease and melatonin-related genes yielded potential target genes of melatonin treatment for periodontitis. These target genes were further investigated by protein-protein interaction network and GO/KEGG enrichment analysis. In addition, the interactions between melatonin and key target genes were interrogated by molecular docking simulations. Then, we performed animal studies to validate the therapeutic effect of melatonin by injecting melatonin into the peritoneal cavity of ligation-induced periodontitis (LIP) mice. The effects of melatonin on the predicted target proteins were also analyzed using Western blot and immunofluorescence techniques. Finally, we constructed an cellular model and validated the direct effect of melatonin on the predicted targets by using qPCR.
RESULTS
We identified 8 potential target genes by network pharmacology analysis. Enrichment analysis suggests that melatonin may treat periodontitis by inhibiting the expression of three potential targets (MPO, MMP8, and MMP9). Molecular docking results showed that melatonin could effectively bind to MMP8 and MMP9. Subsequently, melatonin was further validated in a mouse LIP model to inhibit the expression of MPO, MMP8, and MMP9 in the periodontal tissue. Finally, we verified the direct effect of melatonin on the mRNA expression of MPO, MMP8, and MMP9 in an cellular model.
CONCLUSIONS
Through a combination of network pharmacology and experimental validation, this study provides a more comprehensive understanding of the mechanism of melatonin to treat periodontitis. Our study suggests that MPO, MMP8, and MMP9 as key target genes of melatonin to treat periodontitis. These findings present a more comprehensive basis for further investigation into the mechanisms of pharmacological treatment of periodontitis by melatonin.
PubMed: 38948030
DOI: 10.1016/j.heliyon.2024.e32494 -
Tremor and Other Hyperkinetic Movements... 2024Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers.
METHODS
We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment.
FINDINGS
19 men and 2 women with musicians' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found.
INTERPRETATION
Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer's cramp, and spasmodic dysphonia.
Topics: Humans; Double-Blind Method; Male; Female; Botulinum Toxins, Type A; Dystonic Disorders; Cross-Over Studies; Adult; Music; Neuromuscular Agents; Middle Aged; Treatment Outcome; Occupational Diseases
PubMed: 38948014
DOI: 10.5334/tohm.903 -
Bioinformatics Advances 2024In recent years, applying computational modeling to systems biology has caused a substantial surge in both discovery and practical applications and a significant shift...
MOTIVATION
In recent years, applying computational modeling to systems biology has caused a substantial surge in both discovery and practical applications and a significant shift in our understanding of the complexity inherent in biological systems.
RESULTS
In this perspective article, we briefly overview computational modeling in biology, highlighting recent advancements such as multi-scale modeling due to the omics revolution, single-cell technology, and integration of artificial intelligence and machine learning approaches. We also discuss the primary challenges faced: integration, standardization, model complexity, scalability, and interdisciplinary collaboration. Lastly, we highlight the contribution made by the Computational Modeling of Biological Systems (SysMod) Community of Special Interest (COSI) associated with the International Society of Computational Biology (ISCB) in driving progress within this rapidly evolving field through community engagement (via both in person and virtual meetings, social media interactions), webinars, and conferences.
AVAILABILITY AND IMPLEMENTATION
Additional information about SysMod is available at https://sysmod.info.
PubMed: 38948011
DOI: 10.1093/bioadv/vbae090 -
Canadian Journal of Gastroenterology &... 2024To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI)...
Lobe-Based Hepatic Uptake Index of Gd-EOB-DTPA on Contrast-Enhanced MRI to Quantitatively Discriminate between Compensated and Decompensated Hepatitis B-Related Cirrhosis.
PURPOSE
To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) to discriminate between patients with hepatitis B-related cirrhosis in compensated and decompensated statuses.
METHODS
Forty-four consecutive patients with hepatitis B-related cirrhosis who underwent Gd-EOB-DTPA-enhanced MRI were divided into compensated and decompensated statuses based on clinical evaluation. Volume and signal intensity of individual lobes were retrospectively measured to calculate HUI of the right liver lobe (RHUI), medial (MHUI) and lateral (LHUI) left liver lobes, and caudate lobe (CHUI). Spearman's rank correlation analyses were performed to evaluate relationships of lobe-based HUI with Child-Pugh and model for end-stage liver disease (MELD) scoring system scores in compensated and decompensated statuses. The Mann-Whitney U-test was used to compare the lobe-based HUI between compensated and decompensated statuses. The performance of lobe-based HUI in distinguishing cirrhosis was evaluated using receiver operating characteristic (ROC) analysis, and the area under the ROC curve (AUC) was calculated as a measure of accuracy. Delong's method was used for statistical analysis to elucidate which HUI is optimal.
RESULTS
Compensated and decompensated liver cirrhosis were confirmed in 25 (56.82%) and 19 (43.18%) patients, respectively. According to Spearman's rank correlation analysis, RHUI, MHUI, LHUI, and CHUI were all significantly associated with Child-Pugh and MELD scores (all values <0.05). Receiver operating characteristic analysis demonstrated that among all lobe-based HUI parameters, RHUI could best perform the previous discrimination with a cut-off of 485.73 and obtain an AUC of 0.867. The AUC of RHUI improved and was significantly different from that of MHUI, LHUI, and CHUI ( = 0.03, = 0.007, and < 0.001, respectively, Delong's test).
CONCLUSIONS
The RHUI could help quantitatively discriminate hepatitis B-related cirrhosis between compensated and decompensated statuses.
Topics: Humans; Gadolinium DTPA; Liver Cirrhosis; Female; Male; Contrast Media; Middle Aged; Magnetic Resonance Imaging; Retrospective Studies; Liver; Adult; ROC Curve; Aged; Severity of Illness Index; Hepatitis B
PubMed: 38947874
DOI: 10.1155/2024/6623848 -
Kidney Medicine Jul 2024The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist...
RATIONALE & OBJECTIVE
The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist candidates. Despite excellent reported outcomes, center uptake has remained low across the United States. Here, we examined the effect of implementing an A2/A2B protocol using a cutoff titer of ≤1:8 for IgG and ≤1:16 for IgM on blood group B kidney transplant recipients at a single center.
STUDY DESIGN
Retrospective observational study.
SETTING & PARTICIPANTS
Blood group B recipients of deceased donor kidney transplants at a single center from January 1, 2019, to December 2022.
EXPOSURE
Recipients of deceased donor kidney transplants were analyzed based on donor blood type with comparisons of A2/A2B versus blood group compatible.
OUTCOMES
One-year patient survival, death-censored allograft function, primary nonfunction, delayed graft function, allograft function as measured using serum creatinine levels and estimated glomerular filtration rate at 1 year, biopsy-proven rejection, and need for plasmapheresis.
ANALYTICAL APPROACH
Comparison between the A2/A2B and compatible groups were performed using the Fisher test or the χ test for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables.
RESULTS
A total of 104 blood type B patients received a deceased donor kidney transplant at our center during the study period, 49 (47.1%) of whom received an A2/A2B transplant. Waiting time was lower in A2/A2B recipients compared with blood group compatible recipients (57.9 months vs 74.7 months, = 0.01). A2/A2B recipients were more likely to receive a donor after cardiac death (24.5% vs 1.8%, < 0.05) and experience delayed graft function (65.3% vs 41.8%). There were no observed differences in the average serum creatinine level or estimated glomerular filtration rate at 1 month, 3 months, and 1 year post kidney transplantation, acute rejection, or primary nonfunction.
LIMITATIONS
Single-center study. Small cohort size limiting outcome analysis.
CONCLUSIONS
Implementation of an A2/A2B protocol increased transplant volumes of blood group B waitlisted patients by 83.6% and decreased the waiting time for transplantation by 22.5% with similar transplant outcomes.
PubMed: 38947773
DOI: 10.1016/j.xkme.2024.100843 -
IScience Jun 2024The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited...
The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor . We initially isolated bioactive from cockroach () extracts and then developed the synthesis of this compound Further investigation revealed that impaired SIRT7 enzymatic activities through occupation of the NAD binding pocket. attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
PubMed: 38947512
DOI: 10.1016/j.isci.2024.110014 -
IScience Jun 2024High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS...
High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.
PubMed: 38947509
DOI: 10.1016/j.isci.2024.109798 -
IScience Jun 2024Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the...
Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium increases drug absorption in mice. Experiments in cell culture revealed that produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.
PubMed: 38947502
DOI: 10.1016/j.isci.2024.110122 -
Heliyon Jun 2024L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various...
L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various ailments. This study aims to comprehensively evaluate the antioxidant, anti-inflammatory, and dermatoprotective properties of essential oil derived from , and thyme honey as well as their combined effects. To unravel the chemical composition, a rigorous GC-MS analysis was conducted. Subsequently, we examined their antioxidant potential through three distinct assays: DPPH●, hydrogen peroxide assay, and xanthine oxidase assay. The anti-inflammatory properties were scrutinized through both in vitro and experiments. Simultaneously, the dermatoprotective efficacy was investigated in vitro by evaluating tyrosinase inhibition. Our findings revealed that pulegone constitutes the predominant compound in essential oil (MPEO), constituting a remarkable 74.82 % of the composition. Significantly, when the essential oil was combined with thym honey, it exhibited superior anti-inflammatory and dermatoprotective effects across all and in vitro tests. Moreover, our in silico molecular docking analysis hinted at the potential role of cyclohexanone, 3-methyl, an element found in the MPEO, in contributing to the observed outcomes. While this study has unveiled promising results regarding the combined in vitro, and in silico biological activities of the essential oil and honey, it is imperative to delve further into the underlying mechanisms through additional experimentation and alternative experimental methods. Understanding these mechanisms in greater detail will not only enhance our comprehension of the therapeutic potential but also pave the way for the development of innovative treatments and applications rooted in the synergy of these natural compounds. Furthermore, it would be advantageous to test different possible combinations using experimental design model. Moreover, it would be better to test the effect of single compounds of MPEO to clearly elucidate their efficiency. MPEO alone or combined with thyme honey may be a useful for the development of novel biopharmaceuticals.
PubMed: 38947443
DOI: 10.1016/j.heliyon.2024.e31922 -
Global Health & Medicine Jun 2024Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective...
Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-β peptide (Aβ). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs.
PubMed: 38947412
DOI: 10.35772/ghm.2024.01033