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Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood–brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.

Available studies demonstrate that receptor-type tyrosine-protein phosphatase zeta (PTPRZ1) is expressed in different tumor tissues, and functions in cell proliferation, cell adhesion and migration, epithelial-to-mesenchymal transition, cancer stem cells and treatment resistance by interacting with or binding to several molecules. These included pleiotrophin (PTN), midkine, interleukin-34, β-catenin, VEGF, NF-κB, HIF-2, PSD-95, MAGI-3, contactin and ErbB4. PTPRZ1 was involved in survival signaling and could predict the prognosis of several tumors. This review discusses: the current knowledge about PTPRZ1, its expression, co-receptors, ligands, functions, signaling pathway, prognostic values and therapeutic agents that target PTPRZ1.

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65–95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; β[SE] = 0.0262 [0.0012]; p = 3.21 × 10−86), WNT1‐inducible‐signaling pathway protein 2 (WISP‐2; β[SE] = 0.0189 [0.0009]; p = 4.60 × 10−82), chordin‐like protein 1 (CRDL1; β[SE] = 0.0203[0.0010]; p = 1.45 × 10−77), transgelin (TAGL; β[SE] = 0.0215 [0.0011]; p = 9.70 × 10−71), and R‐spondin‐1(RSPO1; β[SE] = 0.0208 [0.0011]; p = 1.09 × 10−70), were the proteins most significantly associated with age. Weighted gene co‐expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age‐associated diseases and other age‐related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E−16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity. Age‐associated proteomic changes studied using SomaScan assay showed a plethora of novel proteins and pathways to be associated with aging in older adults. Predicted age using elastic net regression captured mortality better than actual chronological age. Clusters of highly correlated proteins associated with chronological age were also associated with diverse phenotypes and traits giving clues for shared biology.

There is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients. Ancestry-related differences in immunobiology may explain the health disparities observed in prostate cancer patients, with men of African origin bearing the highest prostate cancer burden. By measuring immune-related proteins in serum samples, here the authors report that systemic cytokines linked to suppression of tumor immunity are upregulated in men of African ancestry and associated with reduced survival.

Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding \"invagination\" and \"metaplasia\" theories. The endometrial-myometrial junction (EMJ) connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis, but its in-depth study is just beginning. Using single-cell RNA sequencing and spatial profiling, we mapped transcriptional alterations across eutopic endometrium, lesions, and EMJ. Within lesions, we identified unique epithelial ( LGR5 +) and invasive stromal ( PKIB +) subpopulations, along with WFDC1 + progenitor cells, supporting a complex interplay between \"invagination\" and \"metaplasia\" theories of pathogenesis. Further, we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways. Cell-cell communication differed markedly between ectopic and eutopic endometrium, with aberrant signaling in lesions involving pleiotrophin, TWEAK, and WNT cascades. This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified, dysfunctional signaling, and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.

Vinculin (VCL), a linker between cells and their environment, has rarely been linked to disease. This study examines the role of VCL in the development of the enteric nervous system (ENS) and its relationship to Hirschsprung disease (HSCR). Using whole-genome sequencing and in vitro assays, we identified 4 VCL mutations associated with HSCR, most causing loss of function. Neural crest-specific Vcl knock-out mice (Vcl cKO) displayed ENS defects resembling short-segment HSCR, including partial colonic aganglionosis and abnormal gut musculature. Single-cell transcriptomics revealed dysregulation of genes involved in neuronal differentiation and MAPK signaling. Spatial RNA-seq revealed reduced ENS-mesenchyme interactions in Vcl cKO mice, accompanied by significant disruption of the Pleiotrophin (PTN) pathway; Ptn knock-out mice exhibited phenotypes similar to those of Vcl cKO mice, underscoring the importance of ENS-mesenchyme crosstalk. VCL works as a hub gene crucial for cell connection and signaling pathways essential for ENS formation. VCL deficiency subtly impacts various developmental stages and neighboring cells, cumulatively leading to a phenotype similar to short-segment HSCR. This research highlights the role of VCL in maintaining cellular interactions and signaling pathways, such as MAPK and PTN, which are crucial for ENS development and may inform therapeutic targets for ENS disorders.

Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort ( n  = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognosis local disease with the potential to metastasise warranting further investigation.

Background Subarachnoid hemorrhage (SAH) causes significant long-term neurocognitive dysfunction, which is associated with hippocampal neuroinflammation. Growing evidences have shown that astrocytes played a significant role in mediating neuroinflammation. Recently, in vivo reprogramming of astrocytes to neurons by NeuroD1 or PTBP1 administration has generated a lot of interests and controversies. While the debates centered on the source of neurogenesis, no attention has been paid to the changes of the astrocytes-mediated neuroinflammation and its impact on endogenous neurogenesis after NeuroD1 administration. Methods 80 adult male C57BL/6 mice were used in this study. SAH was established by pre-chiasmatic injection of 100 μl blood. AAV–NeuroD1–GFP virus was injected to the hippocampus 3 day post-SAH. Neurocognitive function, brain water content, in vivo electrophysiology, Golgi staining, western blot and immunofluorescent staining were assessed at day 14 post-virus injection. Results NeuroD1 administration markedly attenuated reactive astrocytes-mediated neuroinflammation by reversing neurotoxic A1 astrocytes transformation, decreasing the secretion of neuroinflammatory cytokines, and reducing the activation of harmful microglia. NeuroD1 treatment significantly reversed the brain–blood barrier impairment and promoted the release of neurotrophic factors pleiotrophin (PTN), all of which contributed to the improvement of cellular microenvironment and made it more suitable for neurogenesis. Interestingly, besides neurogenesis in the hippocampus from cells transfected with NeuroD1 at the early phase of SAH, NeuroD1 administration significantly boosted the endogenous neurogenesis at the late phase of SAH, which likely benefited from the improvement of the neuroinflammatory microenvironment. Functionally, NeuroD1 treatment significantly alleviated neurocognitive dysfunction impaired by SAH. Conclusions NeuroD1 significantly promoted neurofunctional recovery by attenuating reactive astrocytes-mediated neuroinflammation and boosting neurogenesis decimated by SAH. Specifically, NeuroD1 efficiently converted transfected cells, most likely astrocytes, to neurons at the early phase of SAH, suppressed astrocytes-mediated neuroinflammation and boosted endogenous neurogenesis at the late phase of SAH.

The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community‐dwelling adults. We applied an aptamer‐based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992–1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991–1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998–2001) and 8 (2005–2008) in FOS. The associations of individual protein levels (log‐transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed‐effects models. Meta‐analyses were implemented using random‐effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF‐15 (Meta‐analytic p = 1.58 × 10−15), pleiotrophin (1.23 × 10−9), and TIMP‐1 (5.97 × 10−8). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10−7), CDON (2.38 × 10−7), and SMOC1 (7.47 × 10−7). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age‐related functional decline. Several plasma proteins were associated with physical function decline in adults from middle to older age, including GDF‐15, pleiotrophin, and TIMP‐1 for gait speed decline, and CA III, CDON, and SMOC1 for grip strength decline. These novel proteomic biomarkers may by explored as future mechanisms and targets for age‐related functional decline.

Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.