A novel saliva-based miRNA profile to diagnose and predict oral cancer

Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD).The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n=50), OPMD (n=52), and controls(n=60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p,miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was:area under curve (AUC):0.954, sensitivity:86%, specificity:90%,positive predictive value (PPV):87.8%and negative predictive value (NPV):88.5%whereas between OC and OPMD was:AUC:0.911,sensitivity:90%, specificity:82.7%, PPV:74.2%and NPV:89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC,revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.

Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

Elucidating the role of gut microbiota dysbiosis in hyperuricemia and gout:Insights and therapeutic strategies

Hyperuricemia(HUA)is a condition associated with a high concentration of uric acid(UA)in the bloodstream and can cause gout and chronic kidney disease.The gut microbiota of patients with gout and HUA is significantly altered compared to that of healthy people.This article focused on the complex interconnection between alterations in the gut microbiota and the development of this disorder.Some studies have suggested that changes in the composition,diversity,and activity of microbes play a key role in establishing and progressing HUA and gout pathogenesis.Therefore,we discussed how the gut microbiota contributes to HUA through purine metabolism,UA excretion,and intestinal inflammatory responses.We examined specific changes in the composition of the gut microbiota associated with gout and HUA,highlighting key bacterial taxa and the metabolic pathways involved.Additionally,we discussed the effect of conventional gout treatments on the gut microbiota composition,along with emerging therapeutic approaches that target the gut microbiome,such as the use of probiotics and prebiotics.We also provided insights into a study regarding the gut microbiota as a possible novel therapeutic intervention for gout treatment and dysbiosis-related diagnosis.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance

Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing

Skeletal stem/progenitor cell(SSPC)senescence is a major cause of decreased bone regenerative potential with aging,but the causes of SSPC senescence remain unclear.In this study,we revealed that macrophages in calluses secrete prosenescent factors,including grancalcin(GCA),during aging,which triggers SSPC senescence and impairs fracture healing.Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair.Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence.Mechanistically,GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction,resulting in cellular senescence.Depletion of Plxnb2 in SSPCs impaired fracture healing.Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice.Thus,our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence,and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

Efficacy and safety of acupuncture in treating low back and pelvic girdle pain during pregnancy:a systematic review and meta-analysis of randomized controlled trials

Objectives:Low back and pelvic girdle pain(LBPGP)is common during pregnancy.Acupuncture is an effective and safe therapy for pain relief.However,further evidence is required to confirm the efficacy and safety of acupuncture in treating LBPGP during pregnancy.This study aimed to systematically review and investigate the clinical efficacy and safety of acupuncture for the treatment of pregnancy-related LBPGP.Methods:The PubMed,EMBASE,Cochrane Library,CNKI,VIP,and WanFang databases were searched from January 2000 to August 2023.Only the randomized controlled trials(RCTs)involving pregnant women between 16 and 34 weeks of gestation diagnosed with LBPGP were included in the study.A meta-analysis was conducted and pooled risk ratios(RRs)or mean differences(MDs)with 95%confidence intervals(CIs)were compared.Results:Meta-analysis included 12 RCTs involving 1,641 participants.Eleven trials compared acupuncture alone or acupuncture combined with standard care(SC),of which three trials also used non-penetrating or placebo acupuncture as the control group.One trial compared acupuncture alone with non-penetrating acupuncture.Compared with SC,acupuncture combined with SC group significantly decreased visual analog scale score(mean difference(MD)=−2.83,95%CI=−3.41 to−2.26,P<0.00001),cesarean section rate(RR=0.69,95%CI=0.49–0.97,P=0.03),preterm birth rate(RR=0.42,95%CI=0.27–0.65,P<0.0001),labor duration(MD=−1.97,95%CI=−2.73 to−1.20,P<0.0001),and Oswestry disability index score(MD=−9.14,95%CI=−15.68 to−2.42,P=0.008).In addition,acupuncture combined with SC significantly improved 12-Items Short Form Health Survey of physical component summaries(SF12-PCS).No significant differences were observed in the spontaneous delivery rate,newborn weight,drowsiness,and 12-Items Short Form Health Survey of mental component summaries(SF12-MCS)between the two groups.Adverse events such as needle pain and needle bleeding were aggravated in both the SC and acupuncture treatment groups but none were associated with acupuncture during or after the treatment period.Conclusions:Meta-analysis showed that acupuncture combined with SC had better efficacy than SC alone and could be a potential therapy for LBPGP during pregnancy.The safety results imply that acupuncture caused few adverse reactions;however,more evidence is required for further confirmation.

The Impact of Opioid Drugs on Memory and Other Cognitive Functions: A Review

Background and Purpose: Opioids, used for centuries to alleviate pain, have become a double-edged sword. While effective, they come with a host of adverse effects, including memory and cognition impairment. This review delves into the impact of opioid drugs on cognitive functions, explores underlying mechanisms, and investigates their prevalence in both medical care and illicit drug use. The ultimate goal is to find ways to mitigate their potential harm and address the ongoing opioid crisis. Methods: We sourced data from PubMed and Google Scholar, employing search combinations like “opioids,” “memory,” “cognition,” “amnesia,” “cognitive function,” “executive function,” and “inhibition.” Our focus was on English-language articles spanning from the inception of these databases up to the present. Results: The literature consistently reveals that opioid use, particularly at high doses, adversely affects memory and other cognitive functions. Longer deliberation times, impaired decision-making, impulsivity, and behavioral disorders are common consequences. Chronic high-dose opioid use is associated with conditions such as amnesiac syndrome (OAS), post-operative cognitive dysfunction (POCD), neonatal abstinence syndrome (NAS), depression, anxiety, sedation, and addiction. Alarming trends show increased opioid use over recent decades, amplifying the risk of these outcomes. Conclusion: Opioids cast a shadow over memory and cognitive function. These effects range from amnesiac effects, lessened cognitive function, depression, and more. Contributing factors include over-prescription, misuse, misinformation, and prohibition policies. Focusing on correct informational campaigns, removing punitive policies, and focusing on harm reduction strategies have been shown to lessen the abuse and use of opioids and thus helping to mitigate the adverse effects of these drugs. Further research into the impacts of opioids on cognitive abilities is also needed as they are well demonstrated in the literature, but the mechanism is not often completely understood.

Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease,with insights into Pink1 knockout models

Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.

Skeletal muscle atrophy,regeneration,and dysfunction in heart failure:Impact of exercise training

This review highlights some established and some more contemporary mechanisms responsible for heart failure(HF)-induced skeletal muscle wasting and weakness.We first describe the effects of HF on the relationship between protein synthesis and degradation rates,which determine muscle mass,the involvement of the satellite cells for continual muscle regeneration,and changes in myofiber calcium homeostasis linked to contractile dysfunction.We then highlight key mechanistic effects of both aerobic and resistance exercise training on skeletal muscle in HF and outline its application as a beneficial treatment.Overall,HF causes multiple impairments related to autophagy,anabolic-catabolic signaling,satellite cell proliferation,and calcium homeostasis,which together promote fiber atrophy,contractile dysfunction,and impaired regeneration.Although both wasting and weakness are partly rescued by aerobic and resistance exercise training in HF,the effects of satellite cell dynamics remain poorly explored.

Large animal models of cardiac ischemia-reperfusion injury:Where are we now?

Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models,which are not transferable or reproducible in large animal models due to different factors such as:(i)complex and varied features of human ischemic cardiac disease(ICD),which are challenging to mimic in animal models,(ii)significant differences in surgical techniques applied,and(iii)differences in cardiovascular anatomy and physiology between small versus large animals.This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury(IRI),as well as the different methods used to induce and assess IRI,and the obstacles faced in using large animals for translational research in the settings of cardiac IR.

Promising applications of D-amino acids in periprosthetic joint infection

Due to the rise in our aging population,a disproportionate demand for total joint arthroplasty(TJA)in the elderly is forecast.Periprosthetic joint infection(PJI)represents one of the most challenging complications that can occur following TJA,and as the number of primary and revision TJAs continues to rise,an increasing PJI burden is projected.Despite advances in operating room sterility,antiseptic protocols,and surgical techniques,approaches to prevent and treat PJI remain difficult,primarily due to the formation of microbial biofilms.This difficulty motivates researchers to continue searching for an effective antimicrobial strategy.The dextrorotatory-isoforms of amino acids(D-AAs)are essential components of peptidoglycan within the bacterial cell wall,providing strength and structural integrity in a diverse range of species.Among many tasks,D-AAs regulate cell morphology,spore germination,and bacterial survival,evasion,subversion,and adhesion in the host immune system.When administered exogenously,accumulating data have demonstrated that D-AAs play a pivotal role against bacterial adhesion to abiotic surfaces and subsequent biofilm formation;furthermore,D-AAs have substantial efficacy in promoting biofilm disassembly.This presents D-AAs as promising and novel targets for future therapeutic approaches.Despite their emerging antibacterial efficacy,their role in disrupting PJI biofilm formation,the disassembly of established TJA biofilm,and the host bone tissue response remains largely unexplored.This review aims to examine the role of D-AAs in the context of TJAs.Data to date suggest that D-AA bioengineering may serve as a promising future strategy in the prevention and treatment of PJI.

Development status of novel spectral imaging techniques and application to traditional Chinese medicine

Traditional Chinese medicine(TCM)is a treasure of the Chinese nation,providing effective solutions to current medical requisites.Various spectral techniques are undergoing continuous development and provide new and reliable means for evaluating the efficacy and quality of TCM.Because spectral techniques are noninvasive,convenient,and sensitive,they have been widely applied to in vitro and in vivo TCM evaluation systems.In this paper,previous achievements and current progress in the research on spectral technologies(including fluorescence spectroscopy,photoacoustic imaging,infrared thermal imaging,laser-induced breakdown spectroscopy,hyperspectral imaging,and surface enhanced Raman spectroscopy)are discussed.The advantages and disadvantages of each technology are also presented.Moreover,the future applications of spectral imaging to identify the origins,components,and pesticide residues of TCM in vitro are elucidated.Subsequently,the evaluation of the efficacy of TCM in vivo is presented.Identifying future applications of spectral imaging is anticipated to promote medical research as well as scientific and technological explorations.

Comparison of Obesity Prevalence among Middle and High School Graduates before and after the COVID-19 Lockdown

The world has been engulfed in a COVID-19 pandemic that has significantly affected the health and economics of the population.The Chinese authorities imposed lockdown measures to limit the spread of COVID-19 and stopped school programs for children and adolescents.Such measures have been associated with increased sedentary time and reduced physical activity[1-3].An online questionnaire study of youth in China compared activity patterns before and after the COVID-19 lockdown.

Gradient descent decomposition of force-field motor primitives optogenetically elicited for motor mapping of the murine lumbosacral spinal cord

Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system(CNS)of all animals.During movement execution,the CNS performs complex calculations to control a large number of neuromusculoskeletal elements.The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns.These modules have been previously represented as stimulus-evoked force fields(FFs)comprising isometric limb-endpoint forces across workspace locations.Here,we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules.To probe for potentially more elementary modules,we optogenetically stimulated the lumbosacral spinal cord of intact and spinalized Thy1-ChR2 transgenic mice(n=21),eliciting FFs from as many single stimulation loci as possible(20-70 loci per mouse)at minimally necessary power.We found that the resulting varieties of FFs defied simple categorization with just a few clusters.We used gradient descent to further decompose the FFs into their underlying basic force fields(BFFs),whose linear combination explained FF variability.Across mice,we identified 4-5 BFFs with partially localizable but overlapping representations along the spinal cord.The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral spinal cord may generate a swing-to-stance gait cycle.These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.

Bioactive Components of Chinese Herbal Medicines in the Treatment of Glucose and Lipid Metabolism Disorders:Evidence and Potential Mechanisms

Disturbed cholesterol and glucose homeostasis play crucial roles in the development of various diseases such as cardiovascular diseases,cerebrovascular diseases,central nervous system diseases,and cancer.An increasing number of studies have shown that excessive body fat accumulation is associated with type 2 diabetes or insulin resistance in a vicious cycle.This vicious cycle promotes the occurrence and development of the aforementioned diseases.Therefore,stabilizing the blood lipids and blood glucose of patients is the predominant strategy for improving the symptoms of patients with cardiovascular,cerebrovascular,and central nervous system diseases.Traditional Chinese medicine,mainly Chinese herbal medicine(CHM),has a history of more than 2000 years in China,which has established a unique theory and accumulated a great wealth of clinical experience.Moreover,CHM has been widely used in China and other countries for the treatment of cardiovascular and cerebrovascular diseases,with the advantages of preventing and curing hyperlipidemia,diabetes,hypertension,and other diseases.However,the use of CHM in Western countries remains rather limited,partly because of the incomplete understanding of multiple complex components and uncertain pharmacological mechanisms.Herein,we review and discuss the benefits,molecular mechanisms,and clinical research progress of bioactive components of CHM and their preparations as therapeutics for hyperlipidemia and hyperglycemia.

Mechanosensitive Piezo1 channel regulation of microglial cell function and implications to neurodegenerative diseases and neuroinflammation

Microglial cells are the key immunocompetent cells in the central nervous system (CNS) and play a crucial role in CNS health and disease (Paolicelli et al.,2022).Under the homeostatic conditions,microglial cells assume diverse and dynamic states,depending upon interactions with neighboring cells and structures in local contextual settings,continuously patrol brain parenchyma utilizing their highly mobile fine processes,phagocytize protein aggregates,unwanted synapses and cells to maintain CNS health,and secrete neurotrophic factors to support neuronal function (Colonna and Butovsky,2017;Paolicelli et al.,2022).

Role of circulating tumor cell clusters in patients with metastatic hormone-sensitive prostate cancer receiving a gonadotropin-releasing hormone antagonist: A pilot study

Dear Editor,Prostate cancer is the most common cancer among men[1].Androgen deprivation therapy(ADT)has remained the primary treatment of metastatic-hormone-sensitive prostate cancer(mHSPC),providing a temporary disease control in the majority of patients.Despite initial ADT response,castration-resistance prostate cancer(CRPC)still develops.Previous study have attempted to determine possible biomarkers for poor prognosis in patients with CRPC[2].

Comparison of sublingual microcirculatory parameters measured by sidestream darkfield videomicroscopy in anesthetized pigs and adult humans

Background:This study aimed to compare sublingual microcirculatory parameters between anesthetized pigs and conscious adult humans using sidestream darkfield videomicroscopy.The overarching aim of the work was to validate the pig as an experimental model of changes in microcirculatory function following traumatic haemorrhagic shock and resuscitation.Methods:Fourteen large white pigs and 14 humans were recruited for the study.Sublingual sidestream darkfield videomicroscopy clips were captured in anesthetized pigs and conscious humans.Clips underwent manual analysis in Automated Vascular Analysis 3.2 software.The total vessel density(TVD),perfused vessel density(PVD),proportion of perfused vessels(PPVs)and microvascular flow index(MFI)were quantified.An independent samples t test was used for between species comparison of microcirculatory parameters.Results and Conclusions:Conscious humans had a significantly lower TVD,PVD and MFI than anesthetized pigs.No significant difference in PPVs was observed between the species.Perfusion of the microcirculation is a critical determinant of tissue metabolic function and viability.Whilst it may not be surprising that some inter species differences in the sublingual microcirculatory anatomy were identified between pig and human subjects,it is interesting to report the insignificant difference in PPVs.This direct microcirculatory measure represents a relative change which should hold translatable value across species.We therefore conclude the pig is a suitable model for microcirculatory research and may be a suitable species to investigate changes in microcirculatory perfusion following perturbations in cardiovascular homeostasis,for example during traumatic haemorrhagic shock and resuscitation.

Structure and function of the membrane microdomains in osteoclasts

The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the development of therapeutic strategies for these diseases.Strong experimental evidence supports the existence of membrane microdomains in osteoclasts(OCs).However,the potential membrane microdomains and the crucial mechanisms underlying their roles in OCs have not been fully characterized.Membrane microdomain components,such as scaffolding proteins and the actin cytoskeleton,as well as the roles of individual membrane proteins,need to be elucidated.In this review,we discuss the compositions and critical functions of membrane microdomains that determine the biological behavior of OCs through the three main stages of the OC life cycle.