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Mast cells (MCs) are abundantly distributed in the human intestinal mucosa and submucosa. However, their roles and mechanisms in the development of colorectal cancer (CRC) are still unclear. In the present research, we found that the infiltration density of MCs in CRC tissues was positively correlated with improved patients’ prognoses. Moreover, MCs suppressed the growth and induced the apoptosis of CRC cells in vitro and in vivo but had no effect on normal colonic epithelial cells. The present study revealed that MCs specifically induced endoplasmic reticulum stress (ERS) and activated the unfolded protein response (UPR) in CRC cells but not in normal cells, which led to the suppression of CRC development in vivo. Furthermore, we found that the secreted Cystatin C protein was the key factor for the MC-induced ERS in CRC cells. This work is of significance for uncovering the antitumor function of MCs in CRC progression and identifying the potential of CRC to respond to MC-targeted immunotherapy.

Cystatin C (CYS C, Cst3 ) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson’s disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α -synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro , we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro , we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal–vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

Periodontal disease is considered one of the most prevalent chronic infectious diseases, often leading to the disruption of tooth-supporting tissues, including alveolar bone, causing tooth mobility and loss. is considered the major etiological agent of this disease, having a plethora of virulence factors, including, lipopolysaccharides (LPS), hemolysins, and proteinases. Antimicrobial peptides are one of the main components of the innate immune response that inhibit the growth of . The aim of this study was to analyze the antimicrobial activity of cystatin C and to assess the effect on the inflammatory and anti-inflammatory cytokines, the production of reactive oxygen species, and in the release of nitric oxide by human gingival fibroblasts incubated with in the presence and absence of cystatin C. ATCC 33277 was exposed to cystatin C for 24h and co-cultured with human gingival fibroblasts (HGFs) ATCC CRL-2014. The effect of cystatin on growth of and HGFs was evaluated. Pro-inflammatory (TNF , IL-1 ) and anti-inflammatory (IL-10) cytokines were determined by ELISA in the supernatants of HGFs incubated with exposed to cystatin C. Additionally, nitrites and reactive oxygen species (ROS) production were evaluated. Cystatin Cinhibited the growth of without affecting HGFs. Incubation of HGFs with led to a significant increase of TNF- and IL-1 . In contrast, HGFs incubated with exposed to cystatin C showed a decreased production of both cytokines, whereas IL-10 was enhanced. Incubation of HGFs with led to an increase of nitric oxide (NO) and ROS production, which was reduced in the presence of the peptide. Cystatin C inhibits the growth of P. gingivalis and decreases the inflammatory cytokines, ROS, and NO production during infection of HGFs with . Knowledge on the antimicrobial and immunomodulatory properties of cystatin C could aid in the design of new therapeutic approaches to facilitate the elimination of this bacterium to improve the treatment of periodontal disease.

Lung transplantation (LTx) offers life-saving therapy for end-stage lung disease, yet primary graft dysfunction (PGD) and bronchiolitis obliterans syndrome remain major complications, which limit long-term outcomes. The risk of PGD increases with prolonged storage and reperfusion injury. This study investigated the protective effects of cystatin C (CysC), a cysteine protease inhibitor, against PGD, through neutralization of cathepsin B activity. LTx recipients exhibited reduced levels of CysC and greater lung damage reflected by increased γ-H2AX and ACSL4 expression, correlating with poorer outcome. Using an orthotopic LTx model, we engineered CysC-Alb, an albumin-fused, cell-permeable CysC derivative for enhanced lung preservation. Adding CysC-Alb to preservation solutions during cold storage and ex vivo lung perfusion improved oxygenation, reduced DNA damage, and minimized cell death, particularly in alveolar type 2 cells. In murine grafts, CysC-Alb decreased γ-H2AX and ACSL4 expression, markers of DNA damage and ferroptosis, respectively. These findings highlight CysC-Alb as an effective additive to mitigate early pulmonary dysfunction after LTx and improve lung graft viability and transplantation outcomes.

Amyloid-β (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from sequential proteolytic cleavage of amyloid protein precursor (APP) by secretases. In this study, we found that cystatin C (CysC), a natural cysteine protease inhibitor, is able to reduce Aβ40 secretion in human brain microvascular endothelial cells (HBMEC). The CysC-induced Aβ40 reduction was caused by degradation of β-secretase BACE1 through the ubiquitin/proteasome pathway. In contrast, we found that CysC promoted secretion of soluble APPα indicating the activated non-amyloidogenic processing of APP in HBMEC. Further results revealed that α-secretase ADAM10, which was transcriptionally upregulated in response to CysC, was required for the CysC-induced sAPPα secretion. Knockdown of SIRT1 abolished CysC-triggered ADAM10 upregulation and sAPPα production. Taken together, our results demonstrated that exogenously applied CysC can direct amyloidogenic APP processing to non-amyloidgenic pathway in brain endothelial cells, mediated by proteasomal degradation of BACE1 and SIRT1-mediated ADAM10 upregulation. Our study unveils previously unrecognized protective role of CysC in APP processing.

Cystatin C (CysC) is a cysteine protease inhibitor and previous studies have demonstrated that increasing endogenous CysC expression has therapeutic implications on brain ischemia, Alzheimer’s disease, and other neurodegenerative disorders. Our previous reports have demonstrated that the autophagy pathway was activated in the brain after experimental subarachnoid hemorrhage (SAH), and it may play a beneficial role in early brain injury (EBI). This study investigated the effects of exogenous CysC on EBI, cognitive dysfunction, and the autophagy pathway following experimental SAH. All SAH animals were subjected to injections of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. As a result, treatment with CysC with low and medial concentrations significantly ameliorated the degree of EBI when compared with vehicle-treated SAH rats. Microtubule-associated protein light chain-3 (LC3), a biomarker of autophagosomes, and beclin-1, a Bcl-2-interacting protein required for autophagy, were significantly increased in the cortex 48 h after SAH and were further up-regulated after CysC therapy. By ultrastructural observation, there was a marked increase in autophagosomes and autolysosomes in neurons of CysC-treated rats. Learning deficits induced by SAH were markedly alleviated after CysC treatment with medial doses. In conclusion, pre-SAH CysC administration may attenuate EBI and neurobehavioral dysfunction in this SAH model, possibly through activating autophagy pathway.

Cathepsin B is one of the major lysosomal cysteine proteases involved in neuronal protein catabolism. This cathepsin is released after traumatic injury and increases neuronal death; however, release of cystatin C, a cathepsin inhibitor, appears to be a self-protective brain response. Here we describe the effect of cystatin C intracerebroventricular administration in rats prior to inducing a traumatic brain injury. We observed that cystatin C injection caused a dual response in post-traumatic brain injury recovery: higher doses (350 fmoles) increased bleeding and mortality, whereas lower doses (3.5 to 35 fmoles) decreased bleeding, neuronal damage and mortality. We also analyzed the expression of cathepsin B and cystatin C in the brains of control rats and of rats after a traumatic brain injury. Cathepsin B was detected in the brain stem, cerebellum, hippocampus and cerebral cortex of control rats. Cystatin C was localized to the choroid plexus, brain stem and cerebellum of control rats. Twenty-four hours after traumatic brain injury, we observed changes in both the expression and localization of both proteins in the cerebral cortex, hippocampus and brain stem. An early increase and intralysosomal expression of cystatin C after brain injury was associated with reduced neuronal damage.

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents. HCCAA is a dominantly inherited disease which causes brain hemorrhages as a result of mutant cystatin C aggregation in carriers. Here, the authors show that n- acetyl cysteine can prevent aggregation of mutant protein in a cell model system and reverse protein deposition in the skin of mutation-carrying subjects.

In most patients with hypertensive nephropathy and low glomerular filtration rate (GFR), the kidney function progressively declines despite the adequate control of the hypertension with angiotensin-converting enzyme inhibition. Previously we found that 2 years of oral sodium citrate slowed GFR decline in patients whose estimated GFR (eGFR) was very low (mean 33ml/min). This treatment also slowed GFR decline in an animal model of surgically reduced nephron mass. Here, we tested if daily oral sodium bicarbonate slowed GFR decline in patients with hypertensive nephropathy with reduced but relatively preserved eGFR (mean 75ml/min) in a 5-year, prospective, randomized, placebo-controlled, and blinded interventional study. Patients matched for age, ethnicity, albuminuria, and eGFR received daily placebo or equimolar sodium chloride or bicarbonate while maintaining antihypertensive regimens (including angiotensin-converting enzyme inhibition) aiming for their recommended blood pressure targets. After 5 years, the rate of eGFR decline, estimated using plasma cystatin C, was slower and eGFR was higher in patients given sodium bicarbonate than in those given placebo or sodium chloride. Thus, our study shows that in hypertensive nephropathy, daily sodium bicarbonate is an effective kidney protective adjunct to blood pressure control along with angiotensin-converting enzyme inhibition.

Cathepsins are involved in a variety of physiological processes including antigen processing and presentation and extracellular matrix degradation. In the present study, we evaluated whether expression levels of cathepsins S and B and their inhibitors cystatins B and C are affected by multiple sclerosis (MS) disease state (relapse and remission) and therapies (interferon‐β[IFN‐β] and the glucocorticoid [GC] methylprednisolone), and whether they are associated with the IFN‐β response phenotype. Real‐time PCR was employed to compare RNA expression levels in peripheral blood leucocytes (PBLs) and ELISA to determine serum protein levels of MS patients and matched healthy individuals. Cathepsin S RNA was higher in MS patients in the relapse state compared to controls (by 74%, P= 3 × 10−5, n= 30 versus n= 18) with a similar increase observed in serum (66%, P= 0.002, n= 18 versus n= 20). GC treatment reduced cathepsin S levels in PBL RNA (by 44%, P= 6 × 10−6, n= 27) and serum proteins (by 27%, P= 1 × 10−5, n= 26), reduced the serum protein levels of pro‐cathepsin B (by 8%, P= 0.0007, n= 23), and in parallel increased the serum levels of their inhibitor cystatin C (by 82%, P= 8 × 10−6, n= 26). IFN‐β therapy significantly elevated the RNA levels (n= 16) of cathepsin B (by 16%, P= 0.03), cystatin B (44%, P= 0.004) and cystatin C (48%, P= 0.011). In the serum, only cathepsin S levels were reduced by IFN‐β (16%, P= 0.006, n= 25). Interestingly, pre‐treatment serum cathepsin S/cystatin C ratio was higher in ‘good responders’ to IFN‐β therapy compared to patients without a good response (by 94%, P= 0.003). These results suggest that cathepsin S and cystatin C may contribute to disease activity in MS, specifically in a subgroup of patients that are responsive to IFN‐β therapy, and that these proteins should be further evaluated as biomarkers in MS.