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.

Disease Biomarkers for Precision Medicine:Challenges and Future Opportunities

Most of the human diseases are complex diseases,which could be caused by many genetic pathways.This means that for a given phenotype(i.e.,a complex disease),there are multiple potential genes which could be genomically or epigenetically changed(i.e.,mutations,copy number variations,epigenetic modifications,and so on).Therefore,it is understandable that different individuals who share the same phenotype/diseases may have different causal genes and thus,may have different drug targets.For example,mutated genes are rarely common between the cancer patients of the same cancer type[1];furthermore,for a given drug,only 10%-30% of the patients

Biomarkers in inflammatory bowel diseases:Current status and proteomics identification strategies

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases (IBD): Ulcerative colitis (UC) and Crohn’s disease (CD), represents a challenge in the early stages of the diseases. The diagnosis may be established several years after the debut of symptoms. Hence, protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients. Moreover, the biomarkers could aid physicians to predict disease courses and in this way, identify patients in need of intensive treatment. Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine or stool later can be screened for. When considering the protein complexity encountered in intestinal biopsy-samples and the recent development within the field of mass spectrometry driven quantitative proteomics, a more thorough and accurate biomarker discovery endeavor could today be performed than ever before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis.

Developing biomarkers for neurodegenerative diseases using genetically-modified common marmoset models

Mouse and non-human primate models of neurodegenerative disease：The prevalence of age-related neurodegenerative diseases continues to increase with ever increasing aging population over the age of 60.Although the difficulties associated with neurodegenerative diseases present an urgent global issue,there is no effective treatment for these conditions.

A deeper understanding of the gut microbiota of different human races in search of disease specific microbial and metabolic biomarkers

Objective:Resident microorganisms live in dynamic harmony with their hosts to influence various physical and psychological health aspects.The majority of the resident microbes are found in the digestive tract,aka the gut of mammals.If and when perturbed,the composition of gut microbiota could jeopardize the physiological balance or homeostasis.In this article,we aim to establish how different diseases could be accompanied by notable changes in gut microbial composition and lend insight into microbial regulation of health.Methods:Literature search was done in PubMed using relevant keywords and summarized in tabular form as well as in narration.Results:We try to focus on the concept of microbial and metabolite biomarkers for diseases.We also try to capture the renewed perspective of good and harmful microorganisms in the context of host health.We have presented a comparative network analysis of microbial roles in select diseases.Recent findings also suggested that the growth of some traditionally disease-causing pathogenic microorganisms promotes health in other human communities.We have listed major taxa of gut microbes in communities worldwide,which signifies that gut microbiota can be healthy or harmful depending on the urbanization and ethnicity of the hosts.The traditional and current schools of thoughts are both limited by the technology of metagenomic studies;we have elucidated some of their shortcomings.Conclusion:Research in the field of gut microbiota must take into account the different populations and the changing narrative of healthy and harmful microbes.

Lipocalin-2 as a biomarker for diabetic nephropathy

Diabetes is a major global public health issue.The prevalence of type 1 diabetes is comparatively static,as hereditary and genetic causes are involved,while type 2 diabetes(T2D)prevalence is increasing day by day.T2D is associated with chronic complications,including diabetic neuropathy(DN),nephropathy,retinopathy,and other complications like diabetic foot.DN is the main complication of both types of diabetes.DN can be diagnosed by routine laboratory tests,microalbuminuria>300 mg/24 h,and a gradual decrease in glomerular filtration rate.As the appearance of microalbuminuria is a late manifestation,an early marker for renal damage is needed.Lipocalin-2,also known as neutrophil gelatinaseassociated lipocalin(NGAL),is a small protein purified from neutrophil granules and a good marker for kidney disease.NGAL is a transporter protein responsible for many physiological processes,such as inflammation,generation of the immune response,and metabolic homeostasis.NGAL has been reported to depict the early changes in renal damage when urine microalbumin is still undetecable.Therefore,elucidating the role of NGAL in detecting DN and understanding its mechanism can help establish it as a potential early marker for DN.

Downregulation of serum mi R-17 and mi R-106b levels in gastric cancer and benign gastric diseases

Altered micro RNA（mi RNA） associated with gastric cancer（GC） development and mi R-17 and mi R-106 b were differentially expressed in GC tissues. This study detected serum levels of mi R-17 and mi R-106 b expression in GC, benign gastric disease（BGD） and healthy controls to assess them as tumor markers for GC. Serum samples from 40 GC, 32 BGD（10 gastric ulcer, 14 gastric polyps, and 8 gastric ulcer with polyps） and 36 healthy individuals were subjected to quantitative reverse transcription polymerase chain reaction（q RT-PCR） analysis of mi R-17 and mi R-106 b expression. The data showed that the serum levels of mi R-17 and mi R-106 b were significantly reduced in healthy individuals and BGD patients compared to GC patients. There was a significant association of mi R-17 and mi R-106 b expression with age, but not with other clinicopathological features, such as gender, tumor differentiation, stage and lymphatic metastasis. Further analysis showed that, in discriminating GC patients from healthy controls, mi R-17 could yield a receiver-operating characteristic（ROC） area under the curve（AUC） of 0.879 with 80.6% sensitivity and 87.5% specificity and mi R-106 b could yield an AUC of 0.856 with 75.0% sensitivity and 92.5% specificity. The combined AUC of mi R-17 and mi R-106 b was 0.913 with 83.3% sensitivity and 87.5% specificity. Collectively, these data suggest that detection of serum mi R-17 and mi R-106 b levels should be further evaluated as novel non-invasive biomarkers in early GC detection and surveillance of disease progression.

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.

Establishing the presence or absence of chronic kidney disease:Uses and limitations of formulas estimating the glomerular filtration rate

The development of formulas estimating glomerular filtration rate(eG FR) from serum creatinine and cystatin C and accounting for certain variables affecting the production rate of these biomarkers, including ethnicity, gender and age, has led to the current scheme of diagnosing and staging chronic kidney disease(CKD),which is based on e GFR values and albuminuria.This scheme has been applied extensively in various populations and has led to the current estimates of prevalence of CKD. In addition, this scheme is applied in clinical studies evaluating the risks of CKD and the efficacy of various interventions directed towards improving its course. Disagreements between creatinine-based and cystatin-based e GFR values and between e GFR values and measured GFR have been reported in various cohorts. These disagreements are the consequence of variations in the rate of production and in factors, other than GFR, affecting the rate of removal of creatinine and cystatin C. The disagreements create limitations for all e GFR formulas developed so far. The main limitations are low sensitivity in detecting early CKD in several subjects, e.g., those with hyperfiltration, and poor prediction of the course of CKD. Research efforts in CKD are currently directed towards identification of biomarkers that are better indices of GFR than the current biomarkers and,particularly, biomarkers of early renal tissue injury.

Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease

High prevalence of non-alcoholic fatty liver disease (NAFLD) and very diverse outcomes that are related to disease form and severity at presentation have made the search for noninvasive diagnostic tools in NAFLD one of the areas with most intense development in hepatology today.Various methods have been investigated in the recent years,including imaging methods like ultrasound and magnetic resonance imaging,different forms of liver stiffness measurement,various biomarkers of necroinflammatory processes (acute phase reactants,cytokines,markers of apoptosis),hyaluronic acid and other biomarkers of liver fibrosis.Multicomponent tests,scoring systems and diagnostic panels were also developed with the purposes of differentiating non-alcoholic steatohepatitis from simple steatosis or discriminating between various fibrosis stages.In all of the cases,performance of noninvasive methods was compared with liver biopsy,which is still considered to be a gold standard in diagnosis,but is by itself far from a perfect comparative measure.We present here the overview of the published data on various noninvasive diagnostic tools,some of which appear to be very promising,and we address as well some of still unresolved issues in this interesting field.

Novel biomarkers for progression of chronic kidney disease

Although there are different initiators of CKD, it is generally recognized that the secondary pathological pathway is quite common to all CKD. CKD may inevitably progress to end stage renal disease （ESRD） due to a vicious cycle of nephron destruction by progressive glomemlosclerosis and tubulointerstitial fibrosis. The chronic processes include kidney resident cell activation,

Biomarkers for Parkinson's Disease:Recent Advancement

As a multi-factorial degenerative disease, Parkinson＇s disease （PD） leads to tremor, gait rigidity, and hypokinesia, thus hampering normal living. As this disease is usually detected in the later stages when neurons have degenerated completely, cure is on hold, ultimately leading to death due to the lack of early diagnostic techniques. Thus, biomarkers are required to detect the disease in the early stages when prevention is possible. Various biomarkers providing early diagnosis of the disease include those of imaging, cerebrospinal fluid, oxidative stress, neuroprotection, and inflammation. Also, biomarkers, alone or in combination, are used in the diagnosis and evolution of PD. This review encompasses various biomarkers available for PD and discusses recent advances in their development.

Olfactory Dysfunction as an Early Biomarker in Parkinson's Disease

Olfactory dysfunction is common in Parkinson＇s disease （PD） and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histo- logic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of ＂pre-motor＂ PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.

Can Biomarkers Help the Early Diagnosis of Parkinson's Disease?

Parkinson＇s disease （PD） is a complex neurode- generative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non-motor symptoms. In order to provide better early diagnosis and subsequent disease-modifying therapies for PD patients, there is an urgent need to identify sensitive and specific biomarkers. Biomarkers can be divided into four categories： clinical, imaging, biochemical, and genetic. Ideal biomarkers not only improve our under- standing of PD pathogenesis and progression, but also provide benefits for early risk evaluation and clinical diagnosis of PD. Although many efforts have been made and several biomarkers have been extensively investigated, few if any have been found useful for early diagnosis. Here, we summarize recent developments in the discovered biomarkers of PD and discuss their merits and limitations for the early diagnosis of PD.

Biomarker Discovery in Parkinson's Disease:Present Challenges and Future Opportunities

Parkinson＇s disease （PD） is the second most common neurodegenerative disorder affecting more than 1% of the older population. Histopathologically, PD is characterized by a severe loss of dopaminergic neurons in the substantia nigra and cytoplasmic inclusions composed of insoluble protein aggregates （Lewy bodies）, which lead to a pro- gressive movement disorder including the classic triad of tremor, bradykinesia, and rigidity.

Region-Specific Iron Measured by MRI as a Biomarker for Parkinson's Disease

The identification of sensitive and specific biomarkers for Parkinson＇s disease （PD） poses an impor- tant clinical challenge. A potential biomarker for early diagnosis and disease monitoring of PD is region-specific iron. Iron accumulation in the substantia nigra pars compacta is considered a main characteristic of PD. However, questions remain, such as the relationship between nigral iron and clinical indices of PD （motor impairment or disease duration）. Further, previous studies have suggested the influence of iron on other nuclei. Iron quantification using magnetic resonance imaging （MRI） allows for studies of the relationship between regional iron and clinical symptoms in vivo. Thus, in this review we discuss the following topics： the technological develop- ment of MRI in measuring brain iron, nigral iron as a potential marker for PD in both clinical and prodromal stages, other influences of regional iron on PD, and clinical translation and future perspectives.

Urinary Biomarkers for Chronic Kidney Disease with a Focus on Gene Transcript

Objective：In the upcoming era of precision medicine,searching for the early,noninvasive biomarkers has been the cornerstone and major challenge in the management of chronic kidney disease （CKD）.Urine contains rich biological information which could be the ideal source for noninvasive biomarkers of CKD.This review will discuss the recent advance in urinary biomarker.Data Sources：This review was based on data in articles published in the PubMed databases up to June 20,2017,with the following keywords：＂Chronic kidney disease＂,＂Biomarker＂,and ＂Urine＂.Study Selection：Original articles and important reviews on urinary biomarker were selected for this review.Results：Urinary biomarker studies of CKD mainly focused on urine sediment,supernatant,and urinary extracellular vesicles.The gene transcript （microRNA [miRNA],messenger RNA [mRNA]） biomarkers have been recently shown with diagnostic potential for CKD reflecting kidney function and histological change.However,challenges regarding technique and data analysis need to be resolved before translation to clinic.Conclusions：Different fractions of urine contain rich information for biomarker discovery,among which urine （extracellular vesicles） mRNA,miRNA,might represent promising biomarker for CKD.

Special Issue on“Biomarkers for Diseases”

The journal Genomics Proteomics ＆ Bioinformatics （GPB） is now inviting submissions for a special issue （to be published in the winter of 2015） on the topic of ＂Biomarkers for Diseases＂.

Special Issue on ＂Biomarkers for Diseases＂

The journal Genomics Proteomics ＆ Bioinformatics （GPB） is now inviting submissions for a special issue （to be published in June of 2015） on the topic of ＂Biomarkers for Diseases＂. As an emerging index, disease biomarkers have demonstrated the potential application in diagnosis and prognosis. The detection of the disease indicators at molecular level, DNA, RNA, protein or metabolites, could gain highly sensitive and specific signals that truly reflect the pathological changes and fully facilitate diagnostic analysis at early phase with invasive mode. Revolution of high-throughput techniques, such as genome-sequencing and mass spectrometers, greatly promotes the discovery and application of the disease biomarkers. The existing disease biomarkers have covered nearly all the macromolecular categories as well as their variants and modifications, including predisposing genetic variations （such as SNPs）, mutations, epigenetic modifications, miRNAs, splice isoforms, abnormal proteins and autoantibodies. Although some biomarkers have been adopted in clinical practice, there are still great needs for studies on identifying new ones, understanding the existing ones and applying the well-studied ones in practice.

Special Issue on “Biomarkers for Human Diseases and Translational Medicine”

The journal Genomics, Proteomics ＆ Bioinformatics （GPB） is now inviting submissions for a special issue （to be published in the fall of 2016） on the topic of ＂Biomarkers for Human Diseases and Translational Medicine＂. In the personalized medicine era, disease biomarkers have potential application in diagnosis, prognosis, and guidance for treatment, and are important tools in translational medicine. Diagnosis upon biomarkers would aid in early and more efficient intervention, while prognostic biomarkers could lead to right decision of medical treatment.