Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury

Traumatic spinal cord injury is a devastating disorder chara cterized by sensory,motor,and autonomic dysfunction that seve rely compromises an individual's ability to perform activities of daily living.These adve rse outcomes are closely related to the complex mechanism of spinal cord injury,the limited regenerative capacity of central neurons,and the inhibitory environment fo rmed by traumatic injury.Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury.A number of therapeutic agents have been shown to improve the injury environment,mitigate secondary damage,and/or promote regeneration and repair.Among them,the spinal cord microcirculation has become an important target for the treatment of spinal cord injury.Drug inte rventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury.These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neuro ns,axons,and glial cells.This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury,including its structure and histopathological changes.Further,it summarizes the progress of drug therapies targeting the spinal cord mic rocirc ulation after spinal cord injury.

Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma

BACKGROUND Cellular senescence,a state of stable growth arrest,is intertwined with human cancers.However,characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma(HCC)remains unexplored.AIM To address this issue,we delineated cellular senescence landscape across HCC.METHODS We enrolled two HCC datasets,TCGA-LIHC and International Cancer Genome Consortium(ICGC).Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes.Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system.TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry,immunoblotting and quantitative real-time polymerase chain reaction.The influence of TMF-regulated nuclear protein(TRNP)1 on HCC senescence and growth was proven via a series of experiments.RESULTS TCGA-LIHC patients were classified as three cellular senescence subtypes,named C1–3.The robustness and reproducibility of these subtypes were proven in the ICGC cohort.C2 had the worst overall survival,C1 the next,and C3 the best.C2 presented the highest levels of immune checkpoints,abundance of immune cells,and immunogenetic indicators.Thus,C2 might possibly respond to immunotherapy.C2 had the lowest somatic mutation rate,while C1 presented the highest copy number variations.A cellular senescence-relevant gene signature was generated,which can predict patient survival,and chemo-or immunotherapeutic response.Experimentally,it was proven that TRNP1 presented the remarkable upregulation in HCCs.TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth.CONCLUSION These findings provide a systematic framework for assessing cellular senescence in HCC,which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.

Comparative effectiveness and safety of 32 pharmacological interventions recommended by guidelines for coronavirus disease 2019:a systematic review and network meta-analysis combining 66 trials

Background:The global pandemic coronavirus disease 2019(COVID-19)has become a major public health problem and presents an unprecedented challenge.However,no specific drugs were currently proven.This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19.Methods:Medline,Embase,the Cochrane Library,and clinicaltrials.gov were searched for randomized controlled trials(RCTs)in patients infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)/SARS-CoV.Random-effects network metaanalysis within the Bayesian framework was performed,followed by the Grading of Recommendations Assessment,Development,and Evaluation system assessing the quality of evidence.The primary outcome of interest includes mortality,cure,viral negative conversion,and overall adverse events(OAEs).Odds ratio(OR)with 95%confidence interval(CI)was calculated as the measure of effect size.Results:Sixty-six RCTs with 19,095 patients were included,involving standard of care(SOC),eight different antiviral agents,six different antibiotics,high and low dose chloroquine(CQ_HD,CQ_LD),traditional Chinese medicine(TCM),corticosteroids(COR),and other treatments.Compared with SOC,a significant reduction of mortality was observed for TCM(OR=0.34,95%CI:0.20–0.56,moderate quality)and COR(OR=0.84,95%CI:0.75–0.96,low quality)with improved cure rate(OR=2.16,95%CI:1.60–2.91,low quality for TCM;OR=1.17,95%CI:1.05–1.30,low quality for COR).However,an increased risk of mortality was found for CQ_HD vs.SOC(OR=3.20,95%CI:1.18–8.73,low quality).TCM was associated with decreased risk of OAE(OR=0.52,95%CI:0.38–0.70,very low quality)but CQ_HD(OR=2.51,95%CI:1.20–5.24)and interferons(IFN)(OR=2.69,95%CI:1.02–7.08)vs.SOC with very low quality were associated with an increased risk.Conclusions:COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care.CQ_HD might increase the risk of mortality.CQ,IFN,and other antiviral agents could increase the risk of OAEs.The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

COVID-19 pharmacological research trends:a bibliometric analysis

Background:The coronavirus disease 2019(COVID-19)pandemic is ravaging the world.Many therapies have been explored to treat COVID-19.This report aimed to assess the global research trends for the development of COVID-19 therapies.Methods:We searched the relevant articles on COVID-19 therapies published from January 1,2020,to May 25,2022,in the Web of Science Core Collection Database(WOSCC).VOSviewer 1.6.18 software was used to assess data on the countries,institutions,authors,collaborations,keywords,and journals that were most implicated in COVID-19 pharmacological research.The latest research and changing trends in COVID-19-relevant pharmacological research were analyzed.Results:After manually eliminating articles that do not meet the requirements,a total of 5,289 studies authored by 32,932 researchers were eventually included in the analyses,which comprised 95 randomized controlled trials.3,044(57.6%)studies were published in 2021.The USA conducted the greatest number of studies,followed by China and India.The primary USA collaborators were China and England.The topics covered in the publications included:the general characteristics,the impact on pharmacists’work,the pharmacological research,broad-spectrum antiviral drug therapy and research,and promising targets or preventive measures,such as vaccine.The temporal diagram revealed that the current research hotspots focused on the vaccine,molecular docking,Mpro,and drug delivery keywords.Conclusion:Comprehensive bibliometric analysis could aid the rapid identification of the principal research topics,potential collaborators,and the direction of future research.Pharmacological research is critical for the development of therapeutic and preventive COVID-19-associated measures.This study may therefore provide valuable information for eradicating COVID-19.

Glymphatic imaging and modulation of the optic nerve

Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.

Unique Pharmacology,Brain Dysfunction,and Therapeutic Advancements for Fentanyl Misuse and Abuse

Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties.It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere,consequently imposing devastating social,economic,and health burdens worldwide.However,the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown,and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce.This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action,including neural circuit dysfunction and neuroinflammation.We discuss recent progress in the development of pharmacological interventions,anti-fentanyl vaccines,anti-fentanyl/heroin conjugate vaccines,and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression.However,translational studies and clinical trials are still lacking.Considering the present opioid crisis,the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.