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International Journal of Molecular... May 2024Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine...
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
Topics: Deoxyadenosines; Humans; Neoplasms; Cyclic AMP; Molecular Dynamics Simulation; Adenosine Triphosphate; Signal Transduction; Computer Simulation; Adenylyl Cyclases
PubMed: 38891880
DOI: 10.3390/ijms25115692 -
SAGE Open Nursing 2024Contraceptive switching from a more effective to a less effective method is a concern, especially in developing countries with high unmet needs for family planning....
INTRODUCTION
Contraceptive switching from a more effective to a less effective method is a concern, especially in developing countries with high unmet needs for family planning. Indeed, the lack of understanding regarding the reasons behind contraceptive switching behavior in the study area poses a significant challenge in effectively addressing this issue.
OBJECTIVE
This study aimed to assess the magnitude and factors associated with long-acting contraceptive switching in Mizan-Aman town, southwest Ethiopia.
METHODS
A community-based cross-sectional study was conducted, involving 345 women randomly selected from the population of married women in their reproductive age group. Data collection was conducted through interviewer-administered questionnaires. Bivariate and multivariable logistic regression analyses were employed to ascertain factors linked with contraceptive method switching status. Statistical significance was determined at a -value of less than .05.
RESULTS
Out of the 345 participants interviewed, the prevalence of switching from long-acting to short-acting contraceptives was 28.4%, 95% CI (13.6%, 33.2%). Upon adjusting for confounding variables, factors significantly associated with contraceptive switching included women aged 31-35 [adjusted odds ratio (AOR) = 0.58; 95% CI (0.36, 0.74)] and aged 41-49 [AOR = 0.54; 95% CI (0.48, 0.82)], those with formal education [AOR = 0.79; 95% CI (0.52, 0.87)], those desiring future pregnancy [AOR = 2.12; 95% CI (1.98, 3.38)], experiencing complications from previous method use [AOR = 3.67; 95% CI (2.57, 7.40)], and encountering stockouts of their preferred contraceptive choice [AOR = 2.01; 95% CI (1.39, 3.24)].
CONCLUSION AND RECOMMENDATION
The study area exhibited a notable prevalence of switching from long-acting contraceptives. Complications arising from prior method use and the unavailability of preferred contraceptive options emerged as significant factors influencing this switching behavior. Thus, it underscores the importance of providing counseling and ongoing support to women, ensuring access to safer and more effective modern contraceptive methods.
PubMed: 38887366
DOI: 10.1177/23779608241262908 -
Retrovirology Jun 2024An essential regulatory hub for retroviral replication events, the 5' untranslated region (UTR) encodes an ensemble of cis-acting replication elements that overlap in a... (Review)
Review
An essential regulatory hub for retroviral replication events, the 5' untranslated region (UTR) encodes an ensemble of cis-acting replication elements that overlap in a logical manner to carry out divergent RNA activities in cells and in virions. The primer binding site (PBS) and primer activation sequence initiate the reverse transcription process in virions, yet overlap with structural elements that regulate expression of the complex viral proteome. PBS-segment also encompasses the attachment site for Integrase to cut and paste the 3' long terminal repeat into the host chromosome to form the provirus and purine residues necessary to execute the precise stoichiometry of genome-length transcripts and spliced viral RNAs. Recent genetic mapping, cofactor affinity experiments, NMR and SAXS have elucidated that the HIV-1 PBS-segment folds into a three-way junction structure. The three-way junction structure is recognized by the host's nuclear RNA helicase A/DHX9 (RHA). RHA tethers host trimethyl guanosine synthase 1 to the Rev/Rev responsive element (RRE)-containing RNAs for m7-guanosine Cap hyper methylation that bolsters virion infectivity significantly. The HIV-1 trimethylated (TMG) Cap licenses specialized translation of virion proteins under conditions that repress translation of the regulatory proteins. Clearly host-adaption and RNA shapeshifting comprise the fundamental basis for PBS-segment orchestrating both reverse transcription of virion RNA and the nuclear modification of m7G-Cap for biphasic translation of the complex viral proteome. These recent observations, which have exposed even greater complexity of retroviral RNA biology than previously established, are the impetus for this article. Basic research to fully comprehend the marriage of PBS-segment structures and host RNA binding proteins that carry out retroviral early and late replication events is likely to expose an immutable virus-specific therapeutic target to attenuate retrovirus proliferation.
Topics: Virus Replication; RNA, Viral; Humans; HIV-1; 5' Untranslated Regions; Binding Sites; Gene Expression Regulation, Viral; Reverse Transcription; Retroviridae
PubMed: 38886829
DOI: 10.1186/s12977-024-00646-x -
Journal of Ethnopharmacology Jun 2024Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease....
ETHNOPHARMACOLOGICAL RELEVANCE
Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease. The decoction has demonstrated its capability to protect arteries and resist atherosclerosis. Its mechanisms for anti-atherosclerosis effect, nevertheless, remain unknown.
AIMS OF THE STUDY
The goal of the present study is to explore the effectiveness of ZSXBGZD acting on atherosclerosis and its key components based on experimental verification and network pharmacology analysis.
MATERIALS AND METHODS
The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and databases were used to identify chemical components in ZSXBGZD. Network pharmacological analysis and molecular docking were implemented in order to reveal the possible therapeutic targets of ZSXBGZD. To form the model of atherosclerosis, we gave Apolipoprotein E knocked out mice a high-fat diet. H&E staining was performed to observe the effects of ZSXBGZD on atherosclerosis. Immunofluorescence and Western blot were used to investigate whether ZSXBGZD could affect autophagy, apoptosis, AGE-RAGE signaling pathway and other related mechanisms.
RESULTS
In total, 30 core compounds were screened through intersecting UPLC-Q-TOF-MS and the databases. The anti-atherosclerotic effect of ZSXBGZD might relate to the AGE-RAGE signaling pathway via network pharmacology analysis. ZSXBGZD could inhibit apoptosis, activate autophagy and ease inflammation by modifying AGE-RAGE signaling pathway to reduce the area of atherosclerotic plaque.
CONCLUSION
ZSXBGZD could treat atherosclerosis by regulating autophagy and apoptosis via adjusting the AGE-RAGE signaling pathway.
PubMed: 38885915
DOI: 10.1016/j.jep.2024.118466 -
Frontiers in Public Health 2024In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human...
BACKGROUND
In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany.
METHODS
Based on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation.
RESULTS
The bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was €11,940 (maintenance therapy with initiation) and €10,950 (maintenance therapy without initiation).
CONCLUSION
To our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.
Topics: Humans; Germany; HIV Infections; Anti-HIV Agents; HIV-1; Rilpivirine; Drug Prescriptions; Male; Adult; Female; Pyridones; Diketopiperazines
PubMed: 38873299
DOI: 10.3389/fpubh.2024.1404255 -
Hepatic Medicine : Evidence and Research 2024The hepatitis C virus (HCV) poses a significant risk to global public health and is linked to life-threatening clinical outcomes. According to the WHO, there are an... (Review)
Review
The hepatitis C virus (HCV) poses a significant risk to global public health and is linked to life-threatening clinical outcomes. According to the WHO, there are an estimated 58 million people worldwide who have a chronic hepatitis C virus (HCV) infection; there are 1.5 million new cases and more than 350,000 fatalities from HCV-related illnesses each year. Even though there are numerous diagnostic techniques, the lack of funding, inadequate healthcare infrastructure, and low public awareness of the Hepatitis C virus can make diagnosis and treatment difficult to obtain throughout the continent. The frequency of hepatitis C virus infection is highest in African nations (1-26%), raising serious concerns about the virus's impact on public health. The world's highest rate of Hepatitis C virus infection was found in Egypt, an African nation. Its nationwide hepatitis C elimination program stands out as a prime example of achievement, having screened, and treated over 60 million people, significantly reducing the disease's incidence and prevalence. Other African nations facing similar difficulties might benefit greatly from Egypt's methods, which provide valuable insights and flexible frameworks. This review aims to shed light on Egypt's successes and challenges while offering strategic recommendations to African nations to quicken their progress in eliminating hepatitis C.
PubMed: 38854483
DOI: 10.2147/HMER.S470344 -
Open Forum Infectious Diseases Jun 2024Long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) offers a novel drug delivery option for persons with human immunodeficiency virus (PWH) but requires...
Patient Attitudes Toward Self- or Partner-, Friend-, or Family-Administered Long-acting Injectable Antiretroviral Therapy: A Mixed-Methods Study Across 3 Urban Human Immunodeficiency Virus Clinics.
BACKGROUND
Long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) offers a novel drug delivery option for persons with human immunodeficiency virus (PWH) but requires administration every 4 or 8 weeks by a medical professional.
METHODS
To facilitate LAI antiretroviral therapy (ART) scale-up, we evaluated patient interest in alternative administration approaches via a mixed-methods, serial cross-sectional study across 3 US HIV clinics. We surveyed PWH (December 2021 to May 2022) on appeal of self- or partner/friend/family-administered LAI-CAB/RPV; multivariable ordinal logistic regression explored associated characteristics. To contextualize survey results, we thematically analyzed semi-structured interview data collected from PWH (August 2020 to July 2021) on attitudes toward out-of-clinic LAI-ART administration.
RESULTS
Among 370 surveyed PWH (median age, 46 years; 26% cisgender female, 59% Black, 56% sexual minority, 34% housing instability), self-administering LAI-CAB/RPV appealed to 67%. PWH who were White (adjusted odds ratio [aOR], 3.30 [95% confidence interval {CI}, 1.42-7.64]), stably housed (aOR, 2.16 [95% CI, 1.30-3.59]), or gay/bisexual (aOR, 1.81 [1.14-2.89]) were more likely to endorse self-administration. Fewer PWH (60%) reported partner/friend/family administration as appealing; adjusted models revealed similar sociodemographic preferences for this outcome. In 72 interviews, PWH noted that acceptability of out-of-clinic LAI-ART administration was qualified by convenience, prior injection experience, and potential fear of self-inflicted pain, dependence on others, and/or HIV disclosure.
CONCLUSIONS
In a multisite sample of PWH, self- and, to a lesser extent, partner/friend/family-administration of LAI-CAB/RPV appealed to most; however, was less appealing among populations more impacted by health disparities. Innovative LAI-ART delivery options could free up in-clinic resources to focus scale-up among marginalized populations.
PubMed: 38854389
DOI: 10.1093/ofid/ofae265 -
BMC Sports Science, Medicine &... Jun 2024Multi-ingredient pre-workout dietary supplements (MIPS), which are combinations of different ingredients acting on different physiological mechanisms, can have a...
BACKGROUND
Multi-ingredient pre-workout dietary supplements (MIPS), which are combinations of different ingredients acting on different physiological mechanisms, can have a synergistic effect and improve performance. The aim of the study was to determine the acute effects of a multi-ingredient pre-workout supplement containing: beta-alanine, taurine, caffeine, L-tyrosine, and cayenne pepper (capsaicin) on anaerobic performance.
METHODS
A randomized, crossover, single-blind study was designed. Twelve young, healthy, untrained men aged 22.4 ± 1.44 years participated in the study. The participants performed a supramaximal all-out test (20 s Wingate test) twice, day by day, in random order: test after placebo or MIPS consumption. In both trials, the following variables were measured in the exercise test: total work performed, peak power, mean power, time to reach peak power, and power decrease.
RESULTS
MIPS was found to be effective in improving peak power (p = 0.009, ES = 0.77) and mean power (p = 0.04, ES = 0.62) in the Wingate test. However, the supplement consumption did not affect the amount of total work done (p = 0.10, ES = 0.48) in the test or power decrease (p = 0.07, ES = 0.53). The data indicate, that the improvement in anaerobic power was due to a significant improvement in pedaling speed, which was manifested in a significant improvement (i.e. shortening) in time to peak power (p = 0.003, ES = 0.88).
CONCLUSION
A multi-ingredient pre-workout dietary supplement was found to be effective in improving Wingate (anaerobic) performance.
TRIAL REGISTRATION
NCT06363669, retrospectively registered on 11.04.2024 (ClinicalTrials.gov).
PubMed: 38853269
DOI: 10.1186/s13102-024-00918-1 -
Journal of Advanced Research Jun 2024Salmonella Enteritidis has brought great harm to public health, animal production and food safety worldwide. The biofilm formed by Salmonella Enteritidis plays a...
INTRODUCTION
Salmonella Enteritidis has brought great harm to public health, animal production and food safety worldwide. The biofilm formed by Salmonella Enteritidis plays a critical role in microbial cross-contamination. Small non-coding RNAs (sRNAs) have been demonstrated to be responsible for regulating the formation of biofilm. The sRNA SaaS has been identified previously, that promotes pathogenicity by regulating invasion and virulence factors. However, whether the SaaS is implicated in regulating biofilm formation in abiotic surfaces remains unclear.
OBJECTIVES
This study aimed to clarify the effect of SaaS in Salmonella Enteritidis and explore the modulatory mechanism on the biofilm formation.
METHODS
Motility characteristics and total biomass of biofilm of test strains were investigated by the phenotypes in three soft agar plates and crystal violet staining in polystyrene microplates. Studies of microscopic structure and extracellular polymeric substances (EPS) of biofilm on solid surfaces were carried out using confocal laser scanning microscope (CLSM) and Raman spectra. Transcriptomics and proteomics were applied to analyze the changes of gene expression and EPS component. The RNA-protein pull-down and promoter-reporter β-galactosidase activity assays were employed to analyze RNA binding proteins and identify target mRNAs, respectively.
RESULTS
SaaS inhibits biofilm formation by repressing the adhesion potential and the secretion of EPS components. Integration of transcriptomics and proteomics analysis revealed that SaaS strengthened the expression of the flagellar synthesis system and downregulated the expression of curli amyloid fibers. Furthermore, RNA-protein pull-down interactome datasets indicated that SaaS binds to Hfq (an RNA molecular chaperone protein, known as a host factor for phage Qbeta RNA replication) uniquely among 193 candidate proteins, and promoter-reporter β-galactosidase activity assay confirmed target mRNAs including hilD, cheA, and csgA.
CONCLUSION
SaaS inhibits the properties of bacterial mobility, perturbs the secretion of EPS, and contributes to the inhibition of biofilm formation by interacting with target mRNA (hilD, cheA, and csgA) through the Hfq-mediated pathway.
PubMed: 38852803
DOI: 10.1016/j.jare.2024.06.008 -
Medicina Clinica Jun 2024The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic...
INTRODUCTION
The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022.
MATERIALS AND METHODS
A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry).
RESULTS
The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction.
CONCLUSIONS
It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.
PubMed: 38851948
DOI: 10.1016/j.medcli.2024.03.027