Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

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.

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets

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.

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

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.

MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury

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. Micro RNAs control a range of physiological and pathological functions such as development, 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 micro RNAs in serum/plasma(mi R-425-p,-21,-93,-191 and-499) and cerebro-spinal fluid(CSF)(mi R-328,-362-3 p,-451,-486 a) as possible indicators of the diagnosis, severity, and prognosis of TBI. Experimental animal studies have examined specific micro RNAs as biomarkers and therapeutic targets for moderate and mild TBI(e.g., mi R-21, mi R-23 b). Micro RNA profiling was altered by voluntary exercise. Differences in basal micro RNA expression in the brain of adult and aged animals and alterations in response to TBI(e.g., mi R-21) have also been reported. Further large-scale studies with TBI patients are needed to provide more information on the changes in micro RNA profiles in different age groups(children, adults, and elderly).

MicroRNAs in Parkinson's disease and emerging therapeutic targets

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.

Damage-associated molecular patterns in inflammatory bowel disease:From biomarkers to therapeutic targets

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.

MicroRNAs as biomarkers in glaucoma and potential therapeutic targets

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.

MicroRNAs in laser-induced choroidal neovascularization in mice and rats:their expression and potential therapeutic targets

Choroidal neovascularization characterizes wet age-related macular degeneration.Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis.A primary cause of choroidal neovascularization pathogenesis is alterations in pro-and anti-angiogenic factors derived from the retinal pigment epithelium,with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization.MicroRNAs(miRNAs)which are short,non-coding,endogenous RNA molecules have a major role in regulating various pathological processes,including inflammation and angiogenesis.A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration.Upregulation of miR-505(days 1 and 3 post-laser),miR-155(day 14)occurred in retina;miR-342-5p(days 3 and 7),miR-126-3p(day 14)in choroid;miR-23a,miR-24,miR-27a(day 7)in retina/choroid;miR-505(days 1 and 3)in retinal pigment epithelium/choroid;downregulation of miR-155(days 1 and 3),miR-29a,miR-29b,miR-29c(day 5),miR-93(day 14),miR-126(day 14)occurred in retinal pigment epithelium/choroid.Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions.Choroidal neovascularization development was reduced by overexpression of miR-155,miR-188-5p,miR-(5,B,7),miR-126-3p,miR-342-5p,miR-93,miR-126,miR-195a-3p,miR-24,miR-21,miR-31,miR-150,and miR-184,or suppression of miR-505,miR-126-3p,miR-155,and miR-23/27.Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings.Important experimental variables need to be standardized;these include the strain and age of animals,gender,number and position of laser burns to the eye,laser parameters to induce choroidal neovascularization lesions including wavelength,power,spot size,and duration.

Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.

Materials and extracellular matrix rigidity highlighted in tissue damages and diseases:Implication for biomaterials design and therapeutic targets

Rigidity(or stiffness)of materials and extracellular matrix has proven to be one of the most significant extracellular physicochemical cues that can control diverse cell behaviors,such as contractility,motility,and spreading,and the resultant pathophysiological phenomena.Many 2D materials engineered with tunable rigidity have enabled researchers to elucidate the roles of matrix biophysical cues in diverse cellular events,including migration,lineage specification,and mechanical memory.Moreover,the recent findings accumulated under 3D environments with viscoelastic and remodeling properties pointed to the importance of dynamically changing rigidity in cell fate control,tissue repair,and disease progression.Thus,here we aim to highlight the works related with material/matrix-rigidity-mediated cell and tissue behaviors,with a brief outlook into the studies on the effects of material/matrix rigidity on cell behaviors in 2D systems,further discussion of the events and considerations in tissue-mimicking 3D conditions,and then examination of the in vivo findings that concern material/matrix rigidity.The current discussion will help understand the material/matrix-rigidity-mediated biological phenomena and further leverage the concepts to find therapeutic targets and to design implantable materials for the treatment of damaged and diseased tissues.

Molecular alterations and therapeutic targets in pancreatic neuroendocrine tumors

Human pancreatic neuroendocrine tumors(PanNETs)are a rare,deadly tumor type that is sporadic or arises in the background of a hereditary syndrome.A critical genetic event in sporadic tumors is inactivation of the gene menin 1(MEN1)on chromosome 11,and indeed,PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1(MEN1)due to germline mutations in the gene.Here,we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs.The key genomic alterations,including MEN1,ATRX/DAXX,mammalian target of rapamycin(mTOR),DNA damage and repair associated genes,vascular endothelial growth factor receptor(VEGFR)and SSTRs,and epigenetic aberrations in PanNETs are discussed.In addition,the commonly used preclinical models for PanNETs are enumerated.

From gene identifications to therapeutic targets for asthma:Focus on great potentials of TSLP,ORMDL3,and GSDMB

Asthma is a chronic respiratory disease,and clinically,asthma exacerbations remain difficult to treat.The disease is caused by combinations of and interactions between genetic and environmental factors.Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease.The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells.Genetic factors also interact with environmental factors such as air pollutants,and bacterial and viral infections to trigger the disease.Thymic stromal lymphopoietin(TSLP),orosomucoid-like 3(ORMDL3),and gasdermin B(GSDMB)are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma.TSLP is an important driver of type 2 inflammation.ORMDL3 mediates cell stress,sphingolipid synthesis,and viral and bacterial infections.GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response.Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.

Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

Leukocyte immunoglobulin-like receptor B2 overexpression as a promising therapeutic target and noninvasive screening biomarker for colorectal cancer

BACKGROUND Colorectal cancer(CRC)has become the second most deadly malignancy in the world,and the exploration of screening markers and precise therapeutic targets is urgent.Our previous research identified leukocyte immunoglobulin-like receptor B2(LILRB2)protein as a characteristic protein of CRC,but the association between LILRB2 expression and clinicopathological features,the internal mechanism related to CRC progression,and screening diagnostic efficacy are not clear.Therefore,we hypothesized that LILRB2 is significantly highly expressed in CRC tissues,correlated with advanced stage and a poor prognosis,and could be used as a therapeutic target and potential screening biomarker for CRC.AIM To explore whether LILRB2 can be used as a potential therapeutic target and noninvasive screening biomarker for CRC.METHODS Patients who underwent radical surgery for CRC at China-Japan Friendship Hospital between February 2021 and October 2022 were included.Cancer and paracancerous tissues were collected to verify LILRB2 expression,and the association between LILRB2 expression and clinicopathological features was analysed.Serum was collected from CRC patients,adenoma patients and healthy controls during the same period to assess the diagnostic value of LILRB2 as a noninvasive screening biomarker,and its diagnostic value was further compared with that of the traditional markers carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9).RESULTS A total of 58 CRC patients were included,and LILRB2 protein was significantly overexpressed in cancer tissues compared with paracancerous tissues(P<0.001).Angiopoietin-like protein 2(ANGPTL2)protein,as the ligand of LILRB2,was synergistically overexpressed in CRC tissues(P<0.001),and overexpression of LILRB2 and ANGPTL2 protein was significantly correlated with poor to moderate differentiation,vascular involvement,lymph node metastasis,distant metastasis,advanced tumor-node-metastasis stage and a poor prognosis(P<0.05),which suggested that LILRB2 and ANGPTL2 are closely associated with CRC progression.In addition,serum LILRB2 concentrations increased stepwise in healthy individuals,adenoma patients and CRC patients with statistically significant differences.The sensitivity of serum LILRB2 for the diagnosis of CRC was 89.74%,the specificity was 88.89%,the area under the curve was 0.95,and the diagnostic efficacy was better than that of conventional CEA and CA19-9.CONCLUSION LILRB2 protein can be used as a potential novel therapeutic target and noninvasive screening biomarker for CRC,which is beneficial for early screening and precise treatment.

Molecular profiling reveals potential targets in cholangiocarcinoma

BACKGROUND Cholangiocarcinoma(CCA)is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver.Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease.AIM To determine the molecular pathogenesis in CCA progression.METHODS In silico analysis,in vitro cell culture,CCA transgenic animals,histological,and molecular assays were adopted to determine the molecular pathogenesis.RESULTS The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas(TGCA,CHOL),European Bioinformatics Institute(EBI,GAD-00001001076),and Gene Expression Omnibus(GEO,GSE107943)databases.Using Gene set enrichment analysis,the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets.We,through differentially expressed genes,found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples.The associated genes,via quantitative real-time PCR and western blotting assays,were further examined in normal human cholangiocytes,CCA cell lines,mouse normal bile ducts,and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver.Consistently,we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors.Interestingly,targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy.More importantly,we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test.CONCLUSION In summary,our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

New insight into the role of exosomes in idiopathic membrane nephropathy

Exosomes,nanoscale extracellular vesicles(EVs)derived from the invagination of the endosomal membrane,are secreted by a majority of cell types.As carriers of DNA,mRNA,proteins,and microRNAs,exosomes are implicated in regulating biological activities under physiological and pathological conditions.Kidney-derived exosomes,which vary in origin and function,may either contribute to the pathogenesis of disease or represent a potential therapeutic resource.Membranous nephropathy(MN),an autoimmune kidney disease characterized by glomerular damage,is a predominant cause of nephrotic syndrome.Notably,MN,especially idiopathic membranous nephropathy(IMN),often results in end-stage renal disease(ESRD),affecting approximately 30%of patients and posing a considerable economic challenge to healthcare systems.Despite substantial research,therapeutic options remain ineffective at halting IMN progression,underscoring the urgent need for innovative strategies.Emerging evidence has implicated exosomes in IMN’s pathophysiology;Providing a fresh perspective for the discovery of novel biomarkers and therapeutic strategies.This review aims to scrutinize recent developments in exosome-related mechanisms in IMN and evaluate their potential as promising therapeutic targets and diagnostic biomarkers,with the hope of catalyzing further investigations into the utility of exosomes in MN,particularly IMN,ultimately contributing to improved patient outcomes in these challenging disease settings.