Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neuro...Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical...This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.展开更多
BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS...BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.展开更多
Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the gl...Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the global population continues to age,there is an urgent and unmet need to effectively prevent,assess,and manage chronic pain in older adults.Although age-related changes in pain perception,processing,and coping mechanisms have been increasingly recognized over recent decades,many aspects of the relationship between aging and pain remain poorly understood.In addition,aging is associated with increased susceptibility to chronic pain conditions,particularly following peripheral nerve injury[2,3].However,the incomplete understanding of the mechanisms underlying pain in the aged population represents a major barrier to the development of effective medical treatment is often insufficient to provide complete pain relief[4,5].Targeted interventions for geriatric pain management are needed.Therefore,elucidating the impact of aging on the pathogenesis of chronic pain is urgently needed.展开更多
Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer's disease.H oweve r,the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels r...Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer's disease.H oweve r,the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclea r.In this study,we conducted meta-analyses and a systematic review using studies from the PubMed,Embase,Web of Science,and Cochrane Library databases,including journal articles published from inception to J une 30,2023.The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood,cere b rospinal fluid,and brain of healthy controls,patients with mild cognitive impairment,and patients with Alzheimer's disease.Additionally,we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer's disease.The methodological quality of the studies was assessed via the Newcastle-Ottawa Scale.Owing to heterogeneity,we utilized either a fixed-effect or random-effect model to assess the 95%confidence interval(CI)of the standard mean difference(SMD)among healthy controls,patients with mild cognitive impairment,and patients with Alzheimer's disease.The findings revealed significant alterations in the levels of insulin-degrading enzymes,neprilysin,matrix metalloproteinase-9,cathepsin D,receptor for advanced glycation end products,and P-glycoprotein in the brains of patients with Alzheimer's disease,patients with mild cognitive impairment,and healthy controls.In cerebrospinal fluid,the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered,whereas the levels of TREM2,CD40,CD40L,CD14,CD22,cathepsin D,cystatin C,andα2 M in peripheral blood differ.Notably,TREM2 and cathepsin D showed changes in both brain(SMD=0.31,95%CI:0.16-0.47,P<0.001,I^(2)=78.4%;SMD=1.24,95%CI:0.01-2.48,P=0.048,I^(2)=90.1%)and peripheral blood(SMD=1.01,95%CI:0.35-1.66,P=0.003,I^(2)=96.5%;SMD=7.55,95%CI:3.92-11.18,P<0.001,I^(2)=98.2%)samples.Furthermore,correlations were observed between amyloid-beta levels and the levels of TREM2(r=0.16,95%CI:0.04-0.28,P=0.009,I^(2)=74.7%),neprilysin(r=-0.47,95%CI:-0.80-0.14,P=0.005,I^(2)=76.1%),and P-glycoprotein(r=-0.31,95%CI:-0.51-0.11,P=0.002,I^(2)=0.0%)in patients with Alzheimer's disease.These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer's disease,whereas triggering receptor expressed on myeloid cells 2,neprilysin,and P-glycoprotein may represent potential therapeutic targets.展开更多
One of the main causes of cancer-related morbidity and mortality globally is hepatocellular carcinoma(HCC).At every stage of the disease,HCC may now be treated using a variety of therapy techniques.Nevertheless,despit...One of the main causes of cancer-related morbidity and mortality globally is hepatocellular carcinoma(HCC).At every stage of the disease,HCC may now be treated using a variety of therapy techniques.Nevertheless,despite the abundance of effective therapeutic choices,the prognosis for patients with HCC is still typically dismal.Prognostic indicators are crucial when assessing prognosis and tracking tumor metastases or recurrence.There are many prognostic markers in HCC.We mainly focused on newly reported prognostic markers such as MEX3A,apolipoprotein B,alpha-fetoprotein,circulating tumor cells,SAMD13,Agrin,and Glypican-3 in the pathogenesis of HCC.Further,we highlighted how these prognostic markers correlated to clinical parameters such as tumor node metastasis,tumor diameter,differentiation,hepatocirrhosis,vascular invasion,and others in HCC.Therefore,identifying specific prognostic biomarkers of HCC helps to provide a great opportunity to improve the prognosis in patients with HCC and provide therapeutic targets.展开更多
The cytochrome P4503A(CYP3A)gene family’s role in early progression of gastric cancer was comprehensively investigated.Its potential as a therapeutic target was evaluated.Upon literature review,aberrant expression of...The cytochrome P4503A(CYP3A)gene family’s role in early progression of gastric cancer was comprehensively investigated.Its potential as a therapeutic target was evaluated.Upon literature review,aberrant expression of the CYP3A gene family has a strong correlation with gastric cancer onset,although the precise underlying mechanisms remain unclear.To assess its potential as a biomarker for early diagnosis and a therapeutic target,we have provided a comprehensive review of the regulatory mechanisms governing CYP3A gene family expression in gastric cancer,as well as its relation with early tumor progression and the tumor microenvironment.The CYP3A gene family is crucial in the proliferation,migration,and invasion of gastric cancer cells and promotes cancer progression by modulating inflammatory responses and oxidative stress within the tumor microenvironment.Furthermore,genetic polymorphisms in CYP3A enzymes highlight its potential value in personalized medicine.Based on these findings,this paper explores the feasibility of developing inhibitors and activators targeting CYP3A enzymes and discusses potential applications in gene therapy.This research provides crucial theoretical support for the CYP3A gene family as an early diagnostic marker and therapeutic target for gastric cancer.In the future,multi-omics studies and large-scale clinical trials will be essential to advance clinical translation of these findings.展开更多
Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),h...Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.展开更多
Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gas...Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.展开更多
Pancreatic cancer is one of the most aggressive and difficult cancers to treat.Despite numerous research efforts,limited success has been achieved in the therapeutic management of patients with this disease.In the cur...Pancreatic cancer is one of the most aggressive and difficult cancers to treat.Despite numerous research efforts,limited success has been achieved in the therapeutic management of patients with this disease.In the current review,we focus on one component of morphogenesis signaling,Hedgehog(Hh),with the aim of developing novel,effective therapies for the treatment of pancreatic cancer.Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells.In addition,we propose a novel concept linking Hh signaling and tumor hypoxic conditions,and discuss the effects of Hh inhibitors in clinical trials.The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.展开更多
Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination....Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.展开更多
Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and relea...Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer＇s disease. An important role of exosomes in Alzheimer＇s disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer＇s disease.展开更多
Parkinson＇s disease（PD） is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain ...Parkinson＇s disease（PD） is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species（ROS） and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.展开更多
Traumatic brain injury （TBI） is characterized by primary damage to the brain from the external mechanical force and by subsequent secondary injury due to various molecular and pathophysiological responses that event...Traumatic brain injury （TBI） is characterized by primary damage to the brain from the external mechanical force and by subsequent secondary injury due to various molecular and pathophysiological responses that eventually lead to neuronal cell death. Secondary brain injury events may occur minutes, hours, or even days after the trauma, and provide valuable therapeutic targets to prevent further neuronal degeneration. At the present time, there is no effective treatment for TBI due, in part, to the widespread impact of numerous complex secondary biochemical and pathophysiological events occurring at different time points following the initial injury. MicroRNAs control a range of physiological and pathological functions such as develop- ment, differentiation, apoptosis and metabolism, and may serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain. This has implications regarding improving the diagnostic accuracy of brain impairment and long-term outcomes as well as potential novel treatments. Recent human studies have identified specific microRNAs in serum/plasma （miR-425-p, -21, -93, -191 and -499） and cerebro-spinal fluid （CSF） （miR-328, -362-3p, -451, -486a） as possible indicators of the diagnosis, severity, and prognosis of TBI. Experimental animal studies have examined specific microRNAs as biomarkers and therapeutic targets for moderate and mild TBI （e.g., miR-21, miR-23b）. MicroRNA profil- ing was altered by voluntary exercise. Differences in basal microRNA expression in the brain of adult and aged animals and alterations in response to TBI （e.g., miR-21） have also been reported. Further large-scale studies with TBI patients are needed to provide more information on the changes in microRNA profiles in different age groups （children, adults, and elderly）.展开更多
To determine the molecular mechanism of cerebral ischemia/reperfusion injury, we examined the micro RNA（mi RNA） expression profile in rat cortex after focal cerebral ischemia/reperfusion injury using mi RNA microarr...To determine the molecular mechanism of cerebral ischemia/reperfusion injury, we examined the micro RNA（mi RNA） expression profile in rat cortex after focal cerebral ischemia/reperfusion injury using mi RNA microarrays and bioinformatic tools to systematically analyze Gene Ontology（GO） function classifications, as well as the signaling pathways of genes targeted by these differentially expressed mi RNAs. Our results show significantly changed mi RNA expression profiles in the reperfusion period after focal cerebral ischemia, with a total of 15 mi RNAs up-regulated and 44 mi RNAs down-regulated. Target genes of these differentially expressed mi RNAs were mainly involved in metabolic and cellular processes, which were identified as hub nodes of a mi RNA-GO-network. The most correlated pathways included D-glutamine and D-glutamate metabolism, the renin-angiotensin system, peroxisomes, the PPAR signaling pathway, SNARE interactions in vesicular transport, and the calcium signaling pathway. Our study suggests that mi RNAs play an important role in the pathological process of cerebral ischemia/reperfusion injury. Understanding mi RNA expression and function may shed light on the molecular mechanism of cerebral ischemia/reperfusion injury.展开更多
Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chron...Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.展开更多
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. ...The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of nonimmune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct proinflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD.The effects determine pathologic changes,which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes.In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers,research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.展开更多
Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur.It is a leading cause of irreversible blindness.Its pathogenesis is largely unknown although several risk factors have...Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur.It is a leading cause of irreversible blindness.Its pathogenesis is largely unknown although several risk factors have been identified,with an increase in intraocular pressure being the main one.Lowering of intraocular pressure is the only treatment available.Open-angle glaucoma is the most common form of the condition,accounting for~90%of all cases of glaucoma,with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types.There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma.Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients.A very large number of microRNAs were dysregulated but with limited overlap between individual studies.MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p,miR-125b-5p,and miR-1260b.No ove rlap of findings occurred within the dysregulated miRNAs for blood plasma,blood serum,peripheral blood mononuclear cells,and tears of primary open-angle glaucoma patients.Seve ral impo rtant limitations were identified in these studies.Further studies are warranted of mic roRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated.In addition,whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.展开更多
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
文摘Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.
基金Supported by the Key Project of the Affiliated Hospital of North Sichuan Medical College,No.2023ZD008the Project of the Doctoral Initiation Fund,No.2023GC002+3 种基金Scientific Research and Development Program Project,No.2024PTZK008Sichuan Province Clinical Key Specialty Construction Project,No.2023GZZKP002Science and Technology Project of Nanchong,No.22SXQT0364Research Development Plan Project of Affiliated Hospital of North Sichuan Medical College,No.2024MPZK003.
文摘BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.
基金supported by the National Natural Science Foundation of China(82171229 and 82471232).
文摘Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the global population continues to age,there is an urgent and unmet need to effectively prevent,assess,and manage chronic pain in older adults.Although age-related changes in pain perception,processing,and coping mechanisms have been increasingly recognized over recent decades,many aspects of the relationship between aging and pain remain poorly understood.In addition,aging is associated with increased susceptibility to chronic pain conditions,particularly following peripheral nerve injury[2,3].However,the incomplete understanding of the mechanisms underlying pain in the aged population represents a major barrier to the development of effective medical treatment is often insufficient to provide complete pain relief[4,5].Targeted interventions for geriatric pain management are needed.Therefore,elucidating the impact of aging on the pathogenesis of chronic pain is urgently needed.
基金supported by the National Natural Science Foundation of China,No.81571046(to KZ)Key Project of Educational Department of Liaoning Province,No.LJKZ0755(to KZ)+2 种基金Project of Department of Science&Technology of Liaoning Province,No.2023JH2/20200116(to KZ)Shenyang Young and Middleaged Innovative Talents Support Program,No.RC210240(to KZ)the 345 Talent Project of Shengjing Hospital of China Medical University(to LH)。
文摘Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer's disease.H oweve r,the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclea r.In this study,we conducted meta-analyses and a systematic review using studies from the PubMed,Embase,Web of Science,and Cochrane Library databases,including journal articles published from inception to J une 30,2023.The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood,cere b rospinal fluid,and brain of healthy controls,patients with mild cognitive impairment,and patients with Alzheimer's disease.Additionally,we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer's disease.The methodological quality of the studies was assessed via the Newcastle-Ottawa Scale.Owing to heterogeneity,we utilized either a fixed-effect or random-effect model to assess the 95%confidence interval(CI)of the standard mean difference(SMD)among healthy controls,patients with mild cognitive impairment,and patients with Alzheimer's disease.The findings revealed significant alterations in the levels of insulin-degrading enzymes,neprilysin,matrix metalloproteinase-9,cathepsin D,receptor for advanced glycation end products,and P-glycoprotein in the brains of patients with Alzheimer's disease,patients with mild cognitive impairment,and healthy controls.In cerebrospinal fluid,the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered,whereas the levels of TREM2,CD40,CD40L,CD14,CD22,cathepsin D,cystatin C,andα2 M in peripheral blood differ.Notably,TREM2 and cathepsin D showed changes in both brain(SMD=0.31,95%CI:0.16-0.47,P<0.001,I^(2)=78.4%;SMD=1.24,95%CI:0.01-2.48,P=0.048,I^(2)=90.1%)and peripheral blood(SMD=1.01,95%CI:0.35-1.66,P=0.003,I^(2)=96.5%;SMD=7.55,95%CI:3.92-11.18,P<0.001,I^(2)=98.2%)samples.Furthermore,correlations were observed between amyloid-beta levels and the levels of TREM2(r=0.16,95%CI:0.04-0.28,P=0.009,I^(2)=74.7%),neprilysin(r=-0.47,95%CI:-0.80-0.14,P=0.005,I^(2)=76.1%),and P-glycoprotein(r=-0.31,95%CI:-0.51-0.11,P=0.002,I^(2)=0.0%)in patients with Alzheimer's disease.These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer's disease,whereas triggering receptor expressed on myeloid cells 2,neprilysin,and P-glycoprotein may represent potential therapeutic targets.
文摘One of the main causes of cancer-related morbidity and mortality globally is hepatocellular carcinoma(HCC).At every stage of the disease,HCC may now be treated using a variety of therapy techniques.Nevertheless,despite the abundance of effective therapeutic choices,the prognosis for patients with HCC is still typically dismal.Prognostic indicators are crucial when assessing prognosis and tracking tumor metastases or recurrence.There are many prognostic markers in HCC.We mainly focused on newly reported prognostic markers such as MEX3A,apolipoprotein B,alpha-fetoprotein,circulating tumor cells,SAMD13,Agrin,and Glypican-3 in the pathogenesis of HCC.Further,we highlighted how these prognostic markers correlated to clinical parameters such as tumor node metastasis,tumor diameter,differentiation,hepatocirrhosis,vascular invasion,and others in HCC.Therefore,identifying specific prognostic biomarkers of HCC helps to provide a great opportunity to improve the prognosis in patients with HCC and provide therapeutic targets.
文摘The cytochrome P4503A(CYP3A)gene family’s role in early progression of gastric cancer was comprehensively investigated.Its potential as a therapeutic target was evaluated.Upon literature review,aberrant expression of the CYP3A gene family has a strong correlation with gastric cancer onset,although the precise underlying mechanisms remain unclear.To assess its potential as a biomarker for early diagnosis and a therapeutic target,we have provided a comprehensive review of the regulatory mechanisms governing CYP3A gene family expression in gastric cancer,as well as its relation with early tumor progression and the tumor microenvironment.The CYP3A gene family is crucial in the proliferation,migration,and invasion of gastric cancer cells and promotes cancer progression by modulating inflammatory responses and oxidative stress within the tumor microenvironment.Furthermore,genetic polymorphisms in CYP3A enzymes highlight its potential value in personalized medicine.Based on these findings,this paper explores the feasibility of developing inhibitors and activators targeting CYP3A enzymes and discusses potential applications in gene therapy.This research provides crucial theoretical support for the CYP3A gene family as an early diagnostic marker and therapeutic target for gastric cancer.In the future,multi-omics studies and large-scale clinical trials will be essential to advance clinical translation of these findings.
基金supported by the Health and Medical Research Fund,Food and Health Bureau,Hong Kong SAR Government(HMRF 07180186).
文摘Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.
基金Supported by Basic Science Research Program through the National Research of Korea(NRF)funded by the Ministry of Education,Science and Technology,NRF-2009-0076540,NRF-2009-0067256
文摘Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.
基金Supported by The Japan Society for the Promotion of Science,Kakenhi Grant,No.24390303
文摘Pancreatic cancer is one of the most aggressive and difficult cancers to treat.Despite numerous research efforts,limited success has been achieved in the therapeutic management of patients with this disease.In the current review,we focus on one component of morphogenesis signaling,Hedgehog(Hh),with the aim of developing novel,effective therapies for the treatment of pancreatic cancer.Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells.In addition,we propose a novel concept linking Hh signaling and tumor hypoxic conditions,and discuss the effects of Hh inhibitors in clinical trials.The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.
文摘Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.
基金financially supported by the Health and Family Planning Scientific Research Project of Hubei Province of China,No.WJ2015MB219
文摘Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer＇s disease. An important role of exosomes in Alzheimer＇s disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer＇s disease.
文摘Parkinson＇s disease（PD） is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons. Oxidative stress is also recognized as one of the main causes of PD, and excessive reactive oxygen species（ROS） and reactive nitrogen species can lead to dopaminergic neuron vulnerability and eventual death. Micro RNAs control a range of physiological and pathological functions, and may serve as potential targets for intervention against PD to mitigate damage to the brain. Several studies have demonstrated that micro RNAs can regulate oxidative stress and prevent ROS-mediated damage to dopaminergic neurons, suggesting that specific micro RNAs may be putative targets for novel therapeutic strategies in PD. Recent human and animal studies have identified a large number of dysregulated micro RNAs in PD brain tissue samples, many of which were downregulated. The dysregulated micro RNAs affect downstream targets such as SNCA, PARK2, LRRK2, TNFSF13 B, LTA, SLC5 A3, PSMB2, GSR, GBA, LAMP-2 A, HSC. Apart from one study, none of the studies reviewed had used agomirs or antagomirs to reverse the levels of downregulated or upregulated micro RNAs, respectively, in mouse models of PD or with isolated human or mouse dopaminergic cells. Further large-scale studies of brain tissue samples collected with short postmortem interval from human PD patients are warranted to provide more information on the micro RNA profiles in different brain regions and to test for gender differences.
文摘Traumatic brain injury （TBI） is characterized by primary damage to the brain from the external mechanical force and by subsequent secondary injury due to various molecular and pathophysiological responses that eventually lead to neuronal cell death. Secondary brain injury events may occur minutes, hours, or even days after the trauma, and provide valuable therapeutic targets to prevent further neuronal degeneration. At the present time, there is no effective treatment for TBI due, in part, to the widespread impact of numerous complex secondary biochemical and pathophysiological events occurring at different time points following the initial injury. MicroRNAs control a range of physiological and pathological functions such as develop- ment, differentiation, apoptosis and metabolism, and may serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain. This has implications regarding improving the diagnostic accuracy of brain impairment and long-term outcomes as well as potential novel treatments. Recent human studies have identified specific microRNAs in serum/plasma （miR-425-p, -21, -93, -191 and -499） and cerebro-spinal fluid （CSF） （miR-328, -362-3p, -451, -486a） as possible indicators of the diagnosis, severity, and prognosis of TBI. Experimental animal studies have examined specific microRNAs as biomarkers and therapeutic targets for moderate and mild TBI （e.g., miR-21, miR-23b）. MicroRNA profil- ing was altered by voluntary exercise. Differences in basal microRNA expression in the brain of adult and aged animals and alterations in response to TBI （e.g., miR-21） have also been reported. Further large-scale studies with TBI patients are needed to provide more information on the changes in microRNA profiles in different age groups （children, adults, and elderly）.
基金supported by grants from the National Natural Science Foundation of ChinaNo.81271358+1 种基金Yunnan Science Foundation of ChinaNo.2013FZ199
文摘To determine the molecular mechanism of cerebral ischemia/reperfusion injury, we examined the micro RNA（mi RNA） expression profile in rat cortex after focal cerebral ischemia/reperfusion injury using mi RNA microarrays and bioinformatic tools to systematically analyze Gene Ontology（GO） function classifications, as well as the signaling pathways of genes targeted by these differentially expressed mi RNAs. Our results show significantly changed mi RNA expression profiles in the reperfusion period after focal cerebral ischemia, with a total of 15 mi RNAs up-regulated and 44 mi RNAs down-regulated. Target genes of these differentially expressed mi RNAs were mainly involved in metabolic and cellular processes, which were identified as hub nodes of a mi RNA-GO-network. The most correlated pathways included D-glutamine and D-glutamate metabolism, the renin-angiotensin system, peroxisomes, the PPAR signaling pathway, SNARE interactions in vesicular transport, and the calcium signaling pathway. Our study suggests that mi RNAs play an important role in the pathological process of cerebral ischemia/reperfusion injury. Understanding mi RNA expression and function may shed light on the molecular mechanism of cerebral ischemia/reperfusion injury.
文摘Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.
基金Supported by the Brazilian research foundations Fundacao de Amparo à Pesquisa do Estado do Rio de Janeiro--FAPERJ,No.E26/202.781/2017Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq,No.302401/2016-4
文摘The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of nonimmune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct proinflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD.The effects determine pathologic changes,which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes.In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers,research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
文摘Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur.It is a leading cause of irreversible blindness.Its pathogenesis is largely unknown although several risk factors have been identified,with an increase in intraocular pressure being the main one.Lowering of intraocular pressure is the only treatment available.Open-angle glaucoma is the most common form of the condition,accounting for~90%of all cases of glaucoma,with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types.There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma.Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients.A very large number of microRNAs were dysregulated but with limited overlap between individual studies.MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p,miR-125b-5p,and miR-1260b.No ove rlap of findings occurred within the dysregulated miRNAs for blood plasma,blood serum,peripheral blood mononuclear cells,and tears of primary open-angle glaucoma patients.Seve ral impo rtant limitations were identified in these studies.Further studies are warranted of mic roRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated.In addition,whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma.
