Hypothalamic circuits and aging:keeping the circadian clock updated

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

Topical ocular administration of DPP-Ⅳ inhibitors:a new approach for treating diabetes-induced retinal neurodegeneration

Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy(DR),the leading cause of preventable blindness.In fact,the American Diabetes Association has defined DR as a highly specific neurovascular complication(Solomon et al.,2017).Therefore,it is no longer acceptable to consider DR as merely a microvascular complication.In this regard,the term diabetic retinal disease(DRD)has been proposed as a broader term comprising microangiopathy and neurodegeneration.However,there are currently no treatments available that directly target the neurodegenerative changes of DR.This paper will give new insights into the translational research in this field with particular emphasis on glucagon-like peptide 1/dipeptidyl peptidase IV(GLP-1/DPP-IV)inhibitors.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

The dorsal root ganglion as a target for neurorestoration in neuropathic pain

Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.

Omics-based biomarkers as useful tools in metabolic dysfunctionassociated steatotic liver disease clinical practice:How far are we?

Unmet needs exist in metabolic dysfunction-associated steatotic liver disease(MASLD)risk stratification.Our ability to identify patients with MASLD with advanced fibrosis and at higher risk for adverse outcomes is still limited.Incorporating novel biomarkers could represent a meaningful improvement to current risk predictors.With this aim,omics technologies have revolutionized the process of MASLD biomarker discovery over the past decades.While the research in this field is thriving,much of the publication has been haphazard,often using single-omics data and specimen sets of convenience,with many identified candidate biomarkers but lacking clinical validation and utility.If we incorporate these biomarkers to direct patients’management,it should be considered that the roadmap for translating a newly discovered omics-based signature to an actual,analytically valid test useful in MASLD clinical practice is rigorous and,therefore,not easily accomplished.This article presents an overview of this area’s current state,the conceivable opportunities and challenges of omics-based laboratory diagnostics,and a roadmap for improving MASLD biomarker research.

Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.

Detection and clearance in Alzheimer’s disease: leading with illusive chemical, structural and morphological features of the targets

Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex organisms.The same principles may be tentatively used in molecular medicine for diagnosis and therapeutics.A molecule can be designed to selectively bind a protease and thereby inhibit the production of a peptide that forms toxic aggregates in the brain or an antibody may be produced to bind specifically to that peptide for detection or clearance purposes.Unfortunately,interference in biological systems is not that simple.For a start there is the inhibition of the physiological role of the protease;moreover,several cleavage fragments may be produced,which may continue to diverge due to putative post-translational modification and self-assembly processes,hiding the toxic target in a“soup”of peptide species varying in size,structure and chemical composition.A perspective of the current status and challenges in targeting peptide species for diagnosis and treatment in the context of Alzheimer’s disease is given.

Biomaterial engineering strategies for modeling the Bruch's membrane in age-related macular degeneration

Age-related macular degeneration,a multifactorial inflammatory degenerative retinal disease,ranks as the leading cause of blindness in the elderly.Strikingly,there is a scarcity of curative therapies,especially for the atrophic advanced form of age-related macular degeneration,likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier,the prime to rget tissue of age-related macular degeneration.Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier,integrated by the dynamic interaction of the retinal pigment epithelium,the Bruch's membrane,and the underlying choriocapillaris.The Bruch's membrane provides structu ral and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier,and therefo re adequate Bruch's membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrie r.In the last years,advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch's membrane from a variety of materials.This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healt hy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch's membrane biomimetic systems.Then,we discuss novel materials and techniques to fabricate Bruch's membrane-like scaffolds for age-related macular degeneration in vitro modeling,discussing their advantages and challenges with a special focus on the potential of Bruch's membrane-like mimics based on decellularized tissue.

小胶质细胞在卒中中的作用

小胶质细胞在缺血后的炎症反应和受损组织的清除中扮演关键角色,它们对缺血引起的干扰反应迅速,致力于恢复失去的稳态。然而,被修改的环境,包括离子失衡、关键的神经元-小胶质细胞相互作用的中断、去极化传播以及来自坏死神经元的危险信号的产生,诱导了小胶质细胞的形态和表型转变。这导致它们表现为促炎表型并增加吞噬活动。从缺血后的第3天开始,巨噬细胞渗透到坏死组织核心,而小胶质细胞则在病灶周边聚集。此外,炎症促使代谢转向有利于糖酵解、戊糖磷酸途径和脂质合成。这些转变与吞噬脂质的摄入相结合,促进了脂滴生成、合成代谢,并使小胶质细胞增殖。增殖的小胶质细胞释放营养因子,有助于神经保护和修复。然而,一些小胶质细胞持续积累脂质,并转变为功能失调且可能有害的泡沫细胞。研究还表明,有些小胶质细胞要么清除凋亡细胞能力的受损,要么消除突触、活神经元或内皮细胞。然而,阐明被吞噬细胞的生存能力、局部环境特征、组织损伤程度和时间序列将是至关重要的。缺血为小胶质细胞提供了丰富多样的、依赖于区域和损伤的刺激,随着时间演变导致出现不同的小胶质细胞表型,包括表现为促炎性或功能失调特征的细胞,以及显示出促进修复功能的细胞。准确分析小胶质细胞表型,以及更精确地了解相关的缺血后组织条件,是对卒中进行针对性干预的必要步骤。

Metabolic reprogramming of the inflammatory response in the nervous system:the crossover between inflammation and metabolism

Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.

Sustaining forest biodiversity:Exploring the effect of long-term natural disturbance dynamics on contemporary lichen communities in primary forest ecosystems

In this era of biodiversity loss and climate change,quantifying the impacts of natural disturbance on forest communities is imperative to improve biodiversity conservation efforts.Epiphytic and epixylic lichens are effective forest quality bioindicators,as they are generally long-lived organisms supported by continuity of specific forest structures and their associated microclimatic features.However,how lichen communities respond to the effects of fluctuating historical disturbances remains unclear.Using a dendrochronological approach,this study investigates how natural disturbance dynamics indirectly influence various lichen community metrics in some of Europe's best-preserved primary mixed-beech forests.Mixed modelling revealed that natural historical disturbance processes have decades-long effects on forest structural attributes,which had both congruent and divergent impacts on lichen community richness and composition.Total species richness indirectly benefited from both historical and recent higher-severity disturbances via increased standing dead tree basal area and canopy openness respectively-likely through the presence of both pioneer and late-successional species associated with these conditions.Red-listed species richness showed a dependence on habitat continuity(old trees),and increased with disturbance-related structures(standing dead trees)whilst simultaneously benefiting from periods without severe disturbance events(old trees and reduced deadwood volume).However,if the disturbance occurred over a century in the past,no substantial effect on forest structure was detected.Therefore,while disturbance-mediated forest structures can promote overall richness,threatened species appear vulnerable to more severe disturbance events-a concern,as disturbances are predicted to intensify with climate change.Additionally,the high number of threatened species found reinforce the critical role of primary forest structural attributes for biodiversity maintenance.Hence,we recommend a landscape-scale conservation approach encompassing forest patches in different successional stages to support diverse lichen communities,and the consideration of long-term disturbance dynamics in forest conservation efforts,as they provide critical insights for safeguarding biodiversity in our changing world.

Molecular mechanisms underlying SARS-CoV-2 hepatotropism and liver damage

In coronavirus disease 2019(COVID-19),severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)primarily targets the respiratory system,but evidence suggests extrapulmonary organ involvement,notably in the liver.Viral RNA has been detected in hepatic tissues,and in situ hybridization revealed virions in blood vessels and endothelial cells.Electron microscopy confirmed viral particles in hepatocytes,emphasizing the need for understanding hepatotropism and direct cytopathic effects in COVID-19-related liver injury.Various factors contribute to liver injury,including direct cytotoxicity,vascular changes,inflammatory responses,immune reactions from COVID-19 and vaccinations,and druginduced liver injury.Although a typical hepatitis presentation is not widely documented,elevated liver biochemical markers are common in hospitalized COVID-19 patients,primarily showing a hepatocellular pattern of elevation.Long-term studies suggest progressive cholestasis may affect 20%of patients with chronic liver disease post-SARS-CoV-2 infection.The molecular mechanisms underlying SARS-CoV-2 infection in the liver and the resulting liver damage are complex.This“Editorial”highlights the expression of the Angiotensin-converting enzyme-2 receptor in liver cells,the role of inflammatory responses,the impact of hypoxia,the involvement of the liver's vascular system,the infection of bile duct epithelial cells,the activation of hepatic stellate cells,and the contribution of monocyte-derived macrophages.It also mentions that pre-existing liver conditions can worsen the outcomes of COVID-19.Understanding the interaction of SARS-CoV-2 with the liver is still evolving,and further research is required.

MicroRNA-630:A promising avenue for alleviating inflammation in diabetic kidney disease

Diabetic kidney disease(DKD)is one of the complications of diabetes,affecting millions of people worldwide.The relentless progression of this condition can lead to kidney failure,requiring life-altering interventions such as dialysis or transplants.Accumulating evidence suggests that immunologic and inflammatory elements play an important role in initiating and perpetuating the damage inflicted on renal tissues,exacerbating the decline in organ function.Toll-like receptors(TLRs)are a family of receptors that play a role in the activation of the innate immune system by the recognition of pathogen-associated molecular patterns.Recent data from in vitro and in vivo studies have highlighted the critical role of TLRs,mainly TLR2 and TLR4,in the pathogenesis of DKD.In the diabetic milieu,these TLRs recognize diabetic-associated molecular signals,triggering a proinflammatory cascade that initiates and perpetuates inflammation and fibrogenesis in the diabetic kidney.Emerging non-traditional strategies targeting TLR signaling with potential therapeutic implications in DKD have been proposed.One of these approaches is the use of microRNAs,small non-coding RNAs that can regulate gene expression.This editorial comments on the results of this approach carried out in a rat model of diabetes by Wu et al,published in this issue of the World Journal of Diabetes.The results of the experimental study by Wu et al shows that microRNA-630 decreased levels compared to non-diabetic rats.Additionally,microRNA-630 exerted anti-inflammatory effects in the kidneys of diabetic rats through the modulation of TLR4.These findings indicate that the microRNA-630/TLR4 axis might represent a pathological mechanism of DKD and a potential therapeutic target capable of curbing the destructive inflammation characteristic of DKD.

The impact of maternal immune activation on the morphology and electrophysiological properties of postnatally-born neurons in the offspring

Pregnancy comes with a combination of physical changes and physiological immunosuppression that increases the susceptibility of women to pathogens and in turn,rises the prevalence of infectious diseases.

Oligodendroctyes:the forgotten players of diabetes pathophysiology

Oligodendrocytes(OLs),glial cells that provide myelin sheaths to axons in the central nervous system(CNS),have a dual role.First,this myelin fatty cover around the axons protects the nerves and is crucial for the saltatory propagation of action potentials.Second and not less important,OLs provide trophic support to neurons and axons.Thus,OL metabolism is important for OL well-being and the proper accomplishment of their functions,and OL metabolism energetics directly affect the energy metabolism of neighboring neurons.

Perilipin 2 inhibits replication of hepatitis B virus deoxyribonucleic acid by regulating autophagy under high-fat conditions

Hepatitis B virus(HBV)infection poses a global health concern without a definitive cure;however,antiviral medications can effectively suppress viral replication.This study delves into the intricate interplay between lipid metabo-lism and HBV replication,implicating molecular mechanisms such as the stearoyl coenzyme A desaturase 1 autophagy pathway,SAC1-like phosphatidylinositol phosphatase,and galectin-9 mediated selective autophagy of viral core proteins in regulating HBV replication.Within lipid droplets,perilipin 2(PLIN2)emerges as a pivotal guardian,with its overexpression protecting against autophagy and downregulation stimulating triglyceride catabolism through the autophagy pathway.This editorial discusses the correlation between hepatic steatosis and HBV replication,emphasizing the role of PLIN2 in this process.The study underscores the multifaceted roles of lipid metabolism,autophagy,and perilipins in HBV replication,shedding light on potential therapeutic avenues.

Preventing brain aging by the artificial enforcement of the unfolded protein response:future directions

As the life expectancy of the world’s population increases,age-related diseases are emerging as one of the greatest problems facing modern society.The onset of dementia and neurodegenerative diseases is strictly dependent on aging as a major risk factor and has a profound impact on various aspects of the lives of individuals and their families.

Insights from an academic endeavor into central nervous system drug discovery

Historically,"big pharma"did most central nervous system drug discovery R&D in-house.Yet,in modern times their"management reductionism"resulted in disappointing pipelines and pharma resided to(late)development,regulatory approval,and marketing(Thong,2015).This had significant consequences for financing and executing research,resulting in a larger role for funding by governments and patient-organizations and a shift of research to academia(Mazzucato,2013).

Microbial phenolic metabolites are associated with better frontal lobe cognition

With increasing life expectancy,neurodegenerative diseases have become one of the leading causes of illhealth in the elderly.Preventive strategies include following healthy diets,such as the Mediterranean diet,which is particularly rich in polyphenols,bioactive compounds with neuroprotective properties.The aim of this study was to assess the association of microbial phenolic metabolites(MPM)with cognition.This cross-sectional analysis was performed with 200 participants of the PREDIMED trial(Barcelona-Clinic recruitment center).A novel method based on liquid chromatography coupled to mass spectrometry was used to identify urinary MPM(protocatechuic acid,enterodiol glucuronide,enterolactone glucuronide,urolithin B glucuronide,and vanillic acid glucuronide),and cognitive function was evaluated with neuropsychological tests.Multivariable-adjusted ordinary least squares regression was used to assess the associations between cognitive function and MPM,and a score was calculated as the weighted sum of MPM.A higher MPM score was associated with better frontal lobe function.Among individual metabolites,vanillic acid glucuronide was correlated with frontal cognitive performance.Participants with higher concentrations of vanillic acid glucuronide and urolithin B glucuronide obtained better scores in the Color Trail Test part 2.A higher score for urinary multiMPM was associated with better frontal cognitive performance in an older Mediterranean population.

Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents

Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDNF).A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.