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Cystatins, as reversible inhibitors of papain-like and legumain proteases, have been identified in several plant species. Although the cystatin family plays crucial roles in plant development and defense responses to various stresses, this family in wheat (Triticum aestivum L.) is still poorly understood. In this study, 55 wheat cystatins (TaCystatins) were identified. All TaCystatins were divided into three groups and both the conserved gene structures and peptide motifs were relatively conserved within each group. Homoeolog analysis suggested that both homoeolog retention percentage and gene duplications contributed to the abundance of the TaCystatin family. Analysis of duplication events confirmed that segmental duplications played an important role in the duplication patterns. The results of codon usage pattern analysis showed that TaCystatins had evident codon usage bias, which was mainly affected by mutation pressure. TaCystatins may be regulated by cis-acting elements, especially abscisic acid and methyl jasmonate responsive elements. In addition, the expression of all selected TaCystatins was significantly changed following viral infection and cold stress, suggesting potential roles in response to biotic and abiotic challenges. Overall, our work provides new insights into TaCystatins during wheat evolution and will help further research to decipher the roles of TaCystatins under diverse stress conditions.

Exposure to metals including lead (Pb), cadmium (Cd), and arsenic (As), may impair kidney function as individual toxicants or in mixtures. However, no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated indices combining information across biomarkers, are informative of adverse kidney function. Levels of Pb, Cd, and As were quantified in blood and urine in 4–6-year-old Mexican children (n = 300) in the PROGRESS longitudinal cohort study. We estimated the mixture effects of these metals, using weighted quantile sum regression (WQS) applied to urine biomarkers (Umix), blood biomarkers (Bmix), and MMBs, on the cystatin C-based estimated glomerular filtration rate (eGFR) and serum cystatin C assessed at 8–10 years of age, adjusted for covariates. Quartile increases in Umix and the MMB mixture were associated with 2.5% (95%CI: 0.1, 5.0) and 3.0% (95%CI: 0.2, 5.7) increased eGFR and −2.6% (95% CI: −5.1%, −0.1%) and −3.3% (95% CI: −6.5%, −0.1%) decreased cystatin C, respectively. Weights indicate that the strongest contributors to the associations with eGFR and serum cystatin C were Cd and Pb, respectively. MMBs detected mixture effects distinct from associations with individual metals or media-type, highlighting the benefits of incorporating information from multiple exposure media in mixtures analyses.

AIM The aim of this cross-sectional study is to compare creatinine-based estimated glomerular filtration rate (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) between patients with type 2 diabetes receiving and not receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS The plasma specimens from 90 patients with type 2 diabetes who had been receiving SGLT2 inhibitors for at least 24 weeks (SGLT2 inhibitors group) were selected. Meanwhile, the plasma specimens from age-, sex- and BMI-matched patients with type 2 diabetes not receiving SGLT2 inhibitors (non-SGLT2 inhibitors group) in 1:1 matching were also selected for comparison. eGFRcr and eGFRcys were calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS When compared with the non-SGLT2 inhibitors group, eGFRcr was significantly higher in the SGLT2 inhibitors group (70.54 ± 24.87 vs. 79.95 ± 19.57 mL/min/1.73 m2 , p = 0.014) while eGFRcys was not different (66.32 ± 24.98 vs 69.17 ± 20.10 ml/min/1.73 m2 , p = 0.401). Based on eGFRcr, the chronic kidney disease (CKD) stage in the SGLT2 inhibitors group was lower than that in the non-SGLT2 inhibitors group, but it was not different when CKD stage was classified by eGFRcys. The difference between eGFRcr and eGFRcys (eGFRcr-cys) was significantly higher in the SGLT2 inhibitors group (4.22 ± 11.20 vs. 10.78 ± 10.42 ml/min/1.73 m2 , p

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DKD is glomeru- lar basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease (MCD). According to fundamental transport physiological principles, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C. Twenty- nine patients with a kidney biopsy diagnosis of either DKD (n = 17) or MCD (n = 12) were retrospectively included in the study. GBM thickness was measured at 20 sepa- rate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport. The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/ eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (p < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine- ratio (Pearson's r = −0.61, p < 0.01). Two-pore modeling predicted a eGFRcystatin C/ eGFRcreatinine-ratio of 78% in DKD. We provide clinical and theoretical evidence sug- gesting that thickening of the glomerular filter, increasing the diffusion length of cys- tatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DKD. (Less)

The authors describe a patient with severe hypothyroidism due to Hashimoto’s thyroiditis and describe the pitfalls of estimated glomerular filtration rate interpretation in such cases. LEARNING POINTS Manifest hypothyroidism can lead to a functional reduction in glomerular filtration rates (GFRs). Restoration of a normal thyroid stimulating hormone (TSH) will also restore kidney function. Cystatin C-based GFR formulas will overestimate renal filtration rates in cases of hypothyroidism and underestimate GFRs in cases of hyperthyroidism. Keywords: Hashimoto, thyroiditis, AKIN, cystatin C, eGFR INTRODUCTION Thyroid dysfunction is associated with impaired renal function. The interpretation of cystatin C-based glomerular filtration rate (GFR) estimates should be evaluated differently depending on the hormonal situation. In cases of renal dysfunction of unknown origin, thyroid dysfunction should be considered in the differential diagnosis. We describe a case of difficult interpretation of laboratory results in autoimmunogenic thyroiditis with manifest severe hypothyroidism.

Background Serum cystatin C is a sensitive indicator for early renal impairment in patients with obstructive sleep apnea (OSA). In patients with OSA without known chronic kidney disease (CKD), serum cystatin C was found to be elevated, indicating latent renal disease, which may be caused by recurrent episodes of hypoxemia and reoxygenation that trigger inflammatory process. Objective To evaluate serum levels of cystatin C in otherwise healthy patients with OSA to predict the future risk of latent renal impairment in these patients. Patients and methods A total of 30 patients were classified into two groups: group I included 10 healthy controls, and group II included 20 patients with OSA. The following were done: full history taking, clinical examination, pulmonary function tests, subjective evaluation of daytime sleepiness using the Epworth Sleepiness Scale, and overnight polysomnography. Finally, serum cystatin C levels at the end of polysomnography and glomerular filtration rate was calculated using modification of diet in renal disease formula and CKD-Epidemiology Collaboration cystatin equation. Results In patients with OSA, the mean level of serum cystatin C was statistically significantly higher than that in controls. These higher levels were sex, age, and BMI independently. Moreover, serum levels of cystatin C in patients with OSA were significantly correlated with OSA severity (apnea-hypopnea index) and degree of nocturnal hypoxia through positive correlation with total sleep time less than 90%, total sleep time less than 80%, and respiratory disturbance index and negative correlation with average SPO2%, lowest SPO2%, and estimated glomerular filtration rate by CKD-Epidemiology Collaboration cystatin equation. Conclusions Higher serum levels of cystatin C were detected in patients with OSA without known comorbidities, which indicates that these patients are at a higher risk of developing CKD. Intermittent hypoxia seems to have the main role in the progression of this process.

Cystatin C, also known as γ-trace or post-γ-globulin, is a cysteine protease inhibitor from the cystatin superfamily. It is usually used as a marker of the glomerular filtration rate owing to its low molecular weight and constant secretion. The recently available methods for cystatin C preparation have low outputs. Hence, a productive preparation system is urgently required. In this study, a 6 × His-tag coupled with a thrombin cleavage site was fused to the C-terminus of cystatin C, and the protein was well expressed in Escherichia coli after optimization. Then, two different systems were used to obtain no-tag cystatin C: a traditional nickel (Ni)-column system and a subtly Ni magnetic bead system. The column system was more commonly used, and the magnetic bead system was more convenient. Cystatin C (purity > 97%) was successfully obtained, and the yields in both the systems were higher than those in previous studies. Further, the proper folding status and bioactivity of recombinant cystatin C were confirmed using the papain inhibition assay, dynamic light scattering, and circular dichroism spectroscopy.

Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T-cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex-II presentation owing to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T-helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.

Summary Vacuolar processing enzymes (VPEs) play an important role during regular growth and development and defence responses. Despite substantial attempts to understand the molecular basis of plant–cyst nematode interaction, the mechanism of VPEs functioning during this interaction remains unknown. The second‐stage Heterodera filipjevi juvenile penetrates host roots and induces the formation of a permanent feeding site called a syncytium. To investigate whether infection with H. filipjevi alters plant host VPEs, the studies were performed in Hordeum vulgare roots and leaves on the day of inoculation and at 7, 14 and 21 days post‐inoculation (dpi). Implementing molecular, biochemical and microscopic methods we identified reasons for modulation of barley VPE activity during interaction with H. filipjevi. Heterodera filipjevi parasitism caused a general decrease of VPE activity in infected roots, but live imaging of VPEs showed that their activity is up‐regulated in syncytia at 7 and 14 dpi and down‐regulated at 21 dpi. These findings were accompanied by tissue‐specific VPE gene expression patterns. Expression of the barley cystatin HvCPI‐4 gene was stimulated in leaves but diminished in roots upon infestation. External application of cyclotides that can be produced naturally by VPEs elicits in pre‐parasitic juveniles vesiculation of their body, enhanced formation of granules, induction of exploratory behaviour (stylet thrusts and head movements), production of reactive oxygen species (ROS) and final death by methuosis. Taken together, down‐regulation of VPE activity through nematode effectors promotes the nematode invasion rates and leads to avoidance of the induction of the plant proteolytic response and death of the invading juveniles.

Most of the current published population pharmacokinetic (PopPK) models are based on serum creatinine, but we often encounter an underestimation of its concentration in our clinical work. Therefore, we established a cystatin C-based model of vancomycin. The purpose of this study was to externally verify the PopPK model of vancomycin based on the glomerular filtration rate (GFR) estimated by serum cystatin C in our previous study and to compare the prediction performance of cystatin C (Cys C) and serum creatinine (SCR)-based models. The external data set consists of adults receiving vancomycin treatment at The First Affiliated Hospital of Guangxi Medical University. We summarized and restored published models based on serum creatinine values from the literature and used our external data set for initial screening. Visual and external verifications were used to further select candidate models for comparison. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were the primary outcomes for the overall comparison. Group comparisons of patients with different glomerular filtration rates (GFRs), ages and body mass index (BMI) levels were obtained by the Bayesian method. A total of 156 patients with 233 samples were collected as an external data set. Sixteen published models were summarized and restored. After screening, four candidate models suitable for the external data set were finally obtained for comparison. The cystatin C-based model has a smaller ME value in the overall comparison. In the group comparison, serum creatinine-based models were underestimated in the prediction for patient groups with age ≥ 60 years, abnormal BMI values and GFR

Obstructive sleep apnea syndrome (OSAS) was suggested to exert an effect on renal function. However, the specific mechanism was still unknown. We try to find the association among OSAS, adiponectin, and cystatin C and the effect of adiponectin on renal function in OSAS patients. Seventeen healthy men and seventy-three men which only had OSAS were included in the end. Apnea-hypopnea index (AHI), oxygen desaturation index (ODI), the percentage of total sleep time spent with SpO2

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is treated using oral/topical steroids and surgery. Despite maximal medical therapy, some patients remain recalcitrant. Mucus cystatin 2, pappalysin-A, and periostin can predict the presence of CRSwNP and correlate with disease severity. This study was designed to determine whether prospective sampling of these mucus proteins could predict medical failure and the need for revision surgery. Methods This investigation was an institutional review board‒approved, prospective study of 66 patients with CRSwNP. All patients underwent surgery, administration of topical/oral steroids, and outpatient mucus sampling at 10 time-points over 2 years. Five proteins, including cystatin 2 (CST2), pappalysin-A (PAPP-A), and periostin (PST), were analyzed and correlated with subjective parameters (including scores on the 22-item Sino-Nasal Outcomes Test [SNOT-22]). Variables were then analyzed and compared between those requiring revision surgery within 2 years (n = 5) and those with stable disease (n = 61). Results All patients demonstrated a significant decline in CST2, PAPP-A, and periostin after their initial surgery. The recalcitrant group demonstrated escalations in all proteins despite steroids, with levels higher than those of the stable group at 1 year (CST2: 258.1 ± 205.2 pg/mL vs 235.3 ± 275.7 pg/mL, p = 0.86; PAPP-A: 170.3 ± 150.4 pg/mL vs 74.6 ± 106.7 pg/mL, p < 0.05; periostin: 188.8 ± 192.4 ng/mL vs 54.5 ± 47.6 ng/mL, p < 0.001). Escalation in all proteins correlated significantly with worsening SNOT-22 score at each time-point (domain 1: 8.2 ± 1.3 vs 5.5 ± 1.1; p < 0.05). Conclusion Early recurrences and medical recalcitrance in CRSwNP may be predicted noninvasively through the serial, prospective sampling of mucus CST2, PAPP-A, and periostin levels. These biosignatures may help to predict disease course and guide individualized therapy.

Drug protein interactions have gained considerable attention over the past many years. In the current communication the association of muscle cystatin (MC) with anti-rheumatic drugs methotrexate and dexamethasone was studied by thiol proteinase inhibitor assay, ultra violet (UV) absorption, fluorescence spectroscopy, and fluorescence transform infra-red spectroscopy (FTIR). A static pattern of quenching was noticed between muscle cystatin and methotrexate (MTX). Binding constant (

Human cystatin C (hCC), a member of the superfamily of papain-like cysteine protease inhibitors, is the most widespread cystatin in human body fluids. This small protein, in addition to its physiological function, is involved in various diseases, including cerebral amyloid angiopathy, cerebral hemorrhage, stroke, and dementia. Physiologically active hCC is a monomer. However, all structural studies based on crystallization led to the dimeric structure formed as a result of a three-dimensional exchange of the protein domains (3D domain swapping). The monomeric structure was obtained only for hCC variant V57N and for the protein stabilized by an additional disulfide bridge. With this study, we extend the number of models of monomeric hCC by an additional hCC variant with a single amino acid substitution in the flexible loop L1. The V57G variant was chosen for the X-ray and NMR structural analysis due to its exceptional conformational stability in solution. In this work, we show for the first time the structural and dynamics studies of human cystatin C variant in solution. We were also able to compare these data with the crystal structure of the hCC V57G and with other cystatins. The overall cystatin fold is retained in the solute form. Additionally, structural information concerning the N terminus was obtained during our studies and presented for the first time. DATABASE: Crystallographic structure: structural data are available in PDB databases under the accession number 6ROA. NMR structure: structural data are available in PDB and BMRB databases under the accession numbers 6RPV and 34399, respectively.

BACKGROUND Cystatins are epithelial protease inhibitors that participate in sinonasal immunity and inflammation. Nasal mucus-derived exosomes (NMDEs) are small vesicles secreted by epithelial cells that carry protein cargo reflective of their host cell. NMDEs have been used as a noninvasive biomarker source to study chronic rhinosinusitis with nasal polyps (CRSwNP) proteomics with superior sensitivity to whole mucus. The purpose of this study was to noninvasively quantify exosomal cystatins in a heterogenous population to determine their utility in predicting phenotype and disease severity. METHODS This was an Institutional Review Board-approved study in which NMDEs were purified from 105 patients undergoing sinonasal surgery by ultracentrifugation. Demographic and clinical variables were collected and phenotypes were assigned a priori. Linear discriminant analysis was executed based on normalized Cystatin values as phenotype predictor variables. Unsupervised cluster analysis was performed using Ward's linkage followed by Duda/Hart Je(2)/Je(1) index cluster stopping rules. Analysis of variance (ANOVA), Welch's test, and Fisher's exact tests were used for continuous and categorical variables. RESULTS NMDE Cystatin-2 expression segregated by phenotype (mean ± standard error [SEM]): control (23.4 ± 4.2 pg/µg, n = 32); CRS without NP (CRSsNP) (56.6 ± 8.3 pg/µg, n = 33); and CRSwNP (130.5 ± 16.7 pg/µg, n = 40) (p < 0.0001). Seven clusters were identified among patients where the highest NMDE Cystatin-2 levels clustered with asthma, tissue eosinophilia, and aspirin-exacerbated respiratory disease (AERD). CONCLUSION Cystatin levels in NMDEs predict CRS phenotype and disease severity. As a "liquid biopsy," noninvasive NMDE collection offers a promising opportunity to study disease pathophysiology, discriminate disease states, and potentially reveal novel therapeutic targets.

Autophagy is a dynamic cellular process involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. It is particularly important in neurons, which do not have a proliferative option for cellular repair. Autophagy has been shown to be suppressed in the striatum of a transgenic mouse model of Parkinson’s disease. Cystatin C is one of the potent regulators of autophagy. Changes in the expression and secretion of cystatin C in the brain have been shown in amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases, and in some animal models of neurodegeneration, thus proving a protective function of cystatin C. It has been suggested that cystatin C plays the primary role in amyloidogenesis and shows promise as a therapeutic agent for neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases). Cystatin C colocalizes with the amyloid β-protein in the brain during Alzheimer’s disease. Controlled expression of a cystatin C peptide has been proposed as a new approach to therapy for Alzheimer’s disease. In Parkinson’s disease, serum cystatin C levels can predict disease severity and cognitive dysfunction, although the exact involvement of cystatin C remains unclear. The aim: to study the role of cystatin C in neurodegeneration and evaluate the results in relation to the mechanism of autophagy. In our study on humans, a higher concentration of cystatin C was noted in cerebrospinal fluid than in serum; much lower concentrations were observed in other biological fluids (intraocular fluid, bile, and sweat). In elderly persons (61–80 years old compared to practically healthy people at 40–60 years of age), we revealed increased cystatin C levels both in serum and intraocular fluid. In an experiment on C57Bl/6J mice, cystatin C concentration was significantly higher in brain tissue than in the liver and spleen: an indication of an important function of this cysteine protease inhibitor in the brain. Using a transgenic mouse model of Parkinson’s disease (5 months old), we demonstrated a significant increase in osmotic susceptibility of brain lysosomes, depending on autophagy, while in a murine model of Alzheimer’s disease, this parameter did not differ from that in the appropriate control.

Acute kidney injury (AKI), in contrast to acute renal failure, is a broader concept. Even minor changes in the excretory function of the kidneys have a significant impact on the work of the whole organism. The occurrence of AKI increases the risk of death, the length of hospitalization and the cost of treating any pathology. The purpose of this literature review is to analyze the possibilities of using a number of markers in the early diagnosis of various types of AKI in pediatrics. The review includes the most studied and applicable markers in pediatric practice - interleukin-18, Neutrophil Gelatinase-Associated Lipocalin (NGAL), kidney damage molecule-1 (KIM-1), cystatin C.

The aim : to identify the correlations between cognitive dysfunctions and biochemical factors of blood - S100B protein and neuron-specific enolase - in young and middle-aged patients with chronic kidney disease (CKD) Stages 1-3. Patients and methods . 108 young and middle-aged patients with chronic kidney disease Stages 1-3 were examined. 70 patients (64.8%) were diagnosed with chronic kidney disease Stage 1, 18 patients (16.6%) had CKD Stage 2, and 20 patients (18.5%) had CKD Stage 3 (A+B). Cognitive dysfunctions were assessed with MMSE survey and software package Status PF. Results. The patients with CKD Stages 2-3 showed a higher degree of cognitive dysfunctions than those with CKD Stage 1. Statistically significant differences in the average exposure in simple visual-motor response (p=0.008) and minimal and average exposures in complex visual-motor response ( р =0,004; р =0,0001) between these two groups of patients were discovered. A statistically significant negative correlation between the level of S100B protein and the glomerular filtration rate was found (Rs=-0,37; p=0,001). Positive correlations were discovered between the minimal exposure in complex visual-motor response and the level of cystatin C, and the average exposure in complex visual-motor response and the level of cystatin C (Rs=0,50, p=0,001; Rs=0,37, p=0,01), while negative correlations were found between the number of errors in complex visual-motor response and the level of cystatin C (Rs=-0,33, p=0,02). Positive correlation was discovered between the level of S100B protein and the minimal and average exposures in complex visual-motor response (Rs=0,29, p=0,001; Rs=0,39, p=0,001). A weak positive correlation was found between the level of S100B protein and the number of delays in reactions to the moving object (Rs=0,23; p=0,04). Statistically significant negative correlations were discovered between S100B protein and the total anticipation time and the number of accurate reactions in tests with moving objects (Rs=-0,39, p=0,001; Rs=-0,31, p=0,001). No correlations between neuron-specific enolase and neurodynamic indicators were discovered. Conclusion. Patients with chronic kidney disease (CKD) Stages 1-3 demonstrated minor cognitive dysfunctions associated with the glomerular filtration rate, cystatin C level, and S100B protein level.

Cystatins are the thiol Proteinase inhibitors, present ubiquitously in mammalian body. They prevent unwanted proteolysis and play important role in several diseases. Regulation of cysteine Proteinase and their inhibitors is of utmost importance in neurodegenerative diseases like Alzheimer, amyloid angiopathy and in many other diseases. The action of these cysteine proteases is biologically controlled by proteinase inhibitors namely cystatins(cys) they constitute a superfamily of homologous proteins. The major role of cystatins is to protect the organism against endogenous proteases released from lysosomes, invading microorganisms and parasites that use cysteine proteases to enter the body. An enormous progress has been made in understanding of protein degradation process under normal and pathological conditions; in fact proteases are now clearly viewed as important drug targets. Some studies have suggested that cystatin C is a target for intervention in neurological disorders because its expression increases in response to human neurological disorders and in animal models of neurodegenerative states. Although, these studies did not clarify whether CysC up-regulation is a pathogenic factor in neurodegenerative disorders or whether it represents a neuroprotective compensatory response of the organisms aimed to prevent progression of the disease. However, for other diseases in some cases cystatins other than cys C are up regulated and in some it is down regulated. Cystatins have been implicated in the processes of neuronal degeneration and repair of the nervous system. Both CysC and CysB are potent, reversible inhibitors of most of the currently known cathepsins. The extent of proteolytic activity at any given time and location is the result of a balance between active proteases and physiological inhibitors. Uncontrolled proteolysis as a result of imbalance between active proteases and their endogenous inhibitors has been associated with neuronal cell death in different neuronal diseases, including brain tumors, stroke, some forms of epilepsy, Alzheimer’s disease, and neurological autoimmune diseases. An antidepressant is a psychiatric medication used to alleviate mood disorders, major depression and other brain diseases. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly used antidepressant. They are also used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, and chronic pain. Although the mechanisms of the action of these antidepressants are not precisely understood, their principal target of action is at the monoamine transporter proteins located at nerve endings. Monoamine neurotransmitter transporters act to terminate synaptic neurotransmission. Selective serotonin reuptake inhibitors or SSRIs are also most widely used class of antidepressants. They work by increasing the level of serotonin in the brain. SSRIs have fewer and milder side effects, fewer drug interactions, and are much less likely to be associated with suicide than TCAs. These antidepressants shows binding when incubated with cystatin, presenting the involvement of these antidepressant in cascade of disease, as leaving no cystatin to inhibit the cathepsin showing the myriad side effect after the administration of antidepressant. This might be one of the reason in the mechanism of action of antidepressant. So this review expound about the role of cystatins in neurological diseases which is considered to be highly significant as it pave the way for commanding tool in the drug design. Communicated by Ramaswamy H. Sarma

Background Many studies have evaluated the usefulness of creatinine- (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) at specific time points in predicting renal outcome. This study compared the performance of both eGFR changing slopes in identifying patients at high risk of end-stage renal disease (ESRD). Methods From 2012 to 2017, patients with more than three simultaneous measurements of serum creatinine and cystatin C for 1 year were identified. Rapid progression was defined as eGFR slope

Cystatins are important regulators of papain-like cysteine proteases. In the protozoan parasite Giardia intestinalis, papain-like cysteine proteases play an essential role in the parasite's biology and pathogenicity. Here, we characterized a cysteine protease inhibitor of G. intestinalis that belongs to type-I-cystatins. The parasite cystatin is shown to be a strong inhibitor of papain (Ki ≈ 0.3 nm) and three parasite cysteine proteases (CP14019, CP16160 and CP16779, Ki ≈ 0.9-5.8 nm), but a weaker inhibitor of human cathepsin B (Ki ≈ 79.9 nm). The protein localizes mainly in the cytoplasm. Together, these data suggest that cystatin of G. intestinalis plays a role in the regulation of cysteine protease activities in the parasite and, possibly, in the interaction with the host.

Cystatin SN, belonging to the type 2 cystatin superfamily, is widely expressed and distributed in mammals. Cystatin SN is involved in inflammation, cell cycle, cellular senescence, tumorigenesis, and metastasis. Cystatin SN is also known to participate in signaling pathways like Wnt signaling pathway, GSK3 signaling pathway, AKT signaling pathway, and IL-6 signaling pathway. Cystatin SN was found to be highly expressed in peritumoral normal tissues in esophageal squamous cell carcinoma (ESCC); however, low cystatin SN expression was found in ESCC cancer tissues. Conversely, in other cancer types such as lung cancer, breast cancer, gastric cancer, pancreatic cancer, and colorectal cancer, high cystatin SN expression in cancer tissues but low cystatin SN expression in peritumoral normal tissues was found. Survival analyses showed that high cystatin SN expression benefited ESCC patients but did harm to other types of cancer patients. Univariate and multivariate analyses indicated that cystatin SN possibly acts as a marker for cancer prognosis. Here, we provide a brief introduction about the role of cystatin SN in cancer and discuss the different prognostic effects of cystatin SN on different tumors. Cystatin SN might be a potential marker for cancer prognosis and a target for cancer therapy.

The present study aimed to investigate the clinical significance and prospective molecular mechanism of cystatin (CST) genes in patients with hepatitis B virus (HBV)‑related hepatocellular carcinoma (HCC). The role of CST genes in the molecular mechanism of HCC was revealed through bioinformatics analysis. The clinical significance of CST genes was investigated using GSE14520‑derived data from patients with HBV‑related HCC. Gene set enrichment analysis (GSEA) was used to identify pathways in which the CST genes were enriched, as well as the association between these pathways and HCC. The expression levels of CST1, CST2, CST5, CSTA and CSTB genes were higher in HCC tissue compared with in normal tissue; conversely, CST3 and CST7 were reduced in HCC tissue. Subsequent receiver operating characteristic analysis of the CST genes demonstrated that CST7 and CSTB genes may function as potential diagnostic markers for HCC. Furthermore, the expression levels of CST6 and CST7 were strongly associated with recurrence‑free survival and overall survival of patients with HBV‑related HCC. GSEA of the CST genes revealed that CST7 was significantly enriched in tumor evasion and tolerogenicity, cancer progenitors, liver cancer late recurrence, liver cancer progression and several liver cancer subclasses. In addition, CST genes demonstrated homology in terms of protein structure and were revealed to be strongly co‑expressed. The present findings suggested that CST7 and CSTB genes may serve as potential prognostic and diagnostic biomarkers for HCC.

Cysteine proteinase inhibitor (cystatin) genes belong to one family of proteinase inhibitors and play an important role in the resistance to insect pests. Cystatin (CYS) genes have been studied in different plant–insect interactions, but there are few reports about the importance of potato cystatin genes. In this study, a cystatin gene named SpCYS was characterized from the wild diploid potato Solanum pinnatisectum Dun, which exhibits high resistance to insect pests. We also investigated the impact of SpCYS in the development of Spodoptera litura when feed from leaves of genetically modified potato. Bioinformatic analysis revealed that SpCYS encoded protein possessed conserved domains of the cystatin family. The SpCYS expression was observed in leaves, stems, roots and tubers with the expression level being almost the same in roots, stems and leaves but greater in tubers. After mechanical damage, SpCYS expression in leaves was induced reaching its peak at 9 h and then decreased to normal levels. Further, we constructed transgenic lines of cultivated potato (cultivar Desiree) expressing SpCYS and performed insect bioassays and feeding preference experiments. Both tests showed that the over-expression of SpCYS lowered the weight increase rate of both Spodoptera litura larvae and pupa. S. litura larvae preferred to feed on the leaves of non-transformed controls rather than the transgenic lines. Taken together, our data suggest that SpCYS is a significant asset for the defense mechanism of potato against S. litura.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and early diagnosis and assessment may enhance the quality of life and survival of patients. The prognostic value of key family 2 cystatins subunit in PDAC patients remains unknown. The potential molecular roles of family 2 cystatins and related pathways were investigated using bioinformatics analysis. The relationship of family 2 cystatin expression levels and clinical outcomes of 112 patients with early‑stage PDAC were evaluated via univariate and combined survival analysis. A prognostic nomogram model was also constructed and gene set enrichment analysis was performed to investigate potential pathways in PDAC. The pathways, interaction networks, and Gene Ontology term analysis of the cystatin gene family were analyzed in the present study. Cystatin F (CST7) was identified as the key subunit of family 2 cystatins in survival analysis. PDAC patients who harbored a higher expression level of CST7 had a lower risk in overall survival (adjusted HROS=0.44, 95% CI=0.25‑0.77, P=0.004) and a longer survival time in various subgroups. The prognostic nomogram indicated that the CST7 expression model effectively predicted the outcomes of patients with early‑stage PDAC (predictive ability >0.75). In the gene set enrichment analysis, it was revealed that CST7 expression may be involved in immune regulation and be associated with cell adhesion. CST7 could be a useful biomarker for the prognostic prediction of early‑stage PDAC after pancreaticoduodenectomy.

Background The present diagnostic methods for detecting graft damage after kidney transplantation are either invasive or not available early enough. The microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) have been suggested as promising biomarkers. Methods Using quantitative real-time polymerase chain reaction, we identified 9 miRNAs (miR-142-5p, miR-142-3p, miR-223, miR-211, miR-486, miR-155, miR-10b, miR-30a, and let-7c) related to the human renal allograft status in PBMCs from 104 kidney transplant recipients. Results The miR-142-5p, miR-142-3p, and miR-223 were significantly upregulated and miR-10b was significantly downregulated in recipients with abnormal levels of serum creatinine 3 to 4 weeks after initial sample collection. Moreover, the miR-142-5p and miR-142-3p were also found to be significantly upregulated in recipients with abnormal levels of cystatin C. Through a combination of the validated miRNAs, receiver operating characteristic analyses yielded the highest area under the curve value of 0.7913 and 0.7063 in predicting the levels of serum creatinine and cystatin C, respectively. In the testing stage, the developed models correctly predicted allograft function in 16 to 17 of 22 recipients (false rate, 22.7%-27.2%). Conclusions miRNAs in PBMCs of recipients hold great promise to be used as predictive and noninvasive biomarkers after transplantation.

Background Ticks, as blood-feeding arthropod vectors, have evolved their own unique mechanism to suppress host immune responses and evade immune defenses in order to complete blood-feeding. The immunoregulatory effect of tick bioactive molecules on hosts has been widely reported, and the cystatin family has been identified as one of the major immunomodulators. In previous studies, we obtained a novel tick salivary bioactive protein named RHcyst-1, which belongs to the type 1 cystatin family. Here, we demonstrated the effects of RHcyst-1 on the host immune response mainly on dendritic cell (DC) function. Understanding the function of tick-derived bioactive molecule may help to clarify the mechanisms of how ticks escape the host immune response and help to control ticks and tick-borne disease transmission. Methods Bone marrow-derived DCs (BMDCs) were generated and induced by GM-CSF and IL-4 with or without RHcyst-1 addition. Flow cytometry was used to analyze the differentiation and maturation of BMDCs and T cell cytokine production. Quantitative real-time PCR (qRT-PCR) and western blot were used to measure changes in expression within STAT and p38 MAPK signaling pathways. Results Flow cytometry analysis revealed that RHcyst-1 inhibited the differentiation of BMDCs, but had no effect on the maturation of BMDCs. T cells co-cultured with DCs treated with RHcyst-1 produced significantly less TNF-α, IFN-γ and IL-2 than the control group. Further analysis showed that the mRNA level and phosphorylation of p38, ERK and STAT were significantly changed after RHcyst-1 added to bone marrow monocytes during the differentiation stage. Conclusions Our results suggest that RHcyst-1 is one of the major immunosuppressive proteins of BMDC function from blood-feeding ticks. Electronic supplementary material The online version of this article (10.1186/s13071-019-3411-1) contains supplementary material, which is available to authorized users.