Functional dyspepsia (FD) is associated with both chronic gastrointestinal distress and anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression- and anxiety-like behavior, we found that vagal activity in response to gastric distention was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (CRF) and decreased brain-derived neurotrophic factor in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in CRF signaling in the amygdala that may be responsible for enhanced pain and anxiety- and depression-like behaviors. Together, these results support a “bottom-up” pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric co-morbidity in FD.
Zachary A. Cordner, Qian Li, Liansheng Liu, Kellie L. Tamashiro, Aditi Bhargava, Timothy H. Moran, Pankaj J. Pasricha
Recent advances in proteomic technologies have made high throughput profiling of low abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across two large longitudinal cohorts (n=2,839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic and clinical data from humans to nominate one specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Further, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 (WFIKKN2) was in turn associated with fasting glucose, hemoglobin A1c and HOMA-IR measurements in humans. In addition to identifying novel disease markers and potential pathways in T2DM, we provide publicly available data to be leveraged for new insights about gene function and disease pathogenesis in the context of human metabolism.
Debby Ngo, Mark D. Benson, Jonathan Z. Long, Zsu-Zsu Chen, Ruiqi Wang, Anjali K. Nath, Michelle J. Keyes, Dongxiao Shen, Sumita Sinha, Eric Kuhn, Jordan E. Morningstar, Xu Shi, Bennet D. Peterson, Christopher Chan, Daniel H. Katz, Usman A. Tahir, Laurie A. Farrell, Olle Melander, Jonathan D. Mosley, Steven A. Carr, Ramachandran S. Vasan, Martin G. Larson, J. Gustav Smith, Thomas J. Wang, Qiong Yang, Robert E. Gerszten
One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma which commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven success in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared to the primary tumors from which they were derived using copy number analysis, whole-exome and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft tissue sarcomas. Taken together, these data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis, and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
Carina A. Dehner, Chang In Moon, Xiyuan Zhang, Zhaohe Zhou, Christopher A. Miller, Hua Xu, Xiaodan Wan, Kuangying Yang, R. Jay Mashl, Sara J.C. Gosline, Yuxi Wang, Xiaochun Zhang, Abigail Godec, Paul A. Jones, Sonika Dahiya, Himanshi Bhatia, Tina Primeau, Shunqiang Li, Kai Pollard, Fausto J. Rodriguez, Li Ding, Christine A. Pratilas, Jack F. Shern, Angela C. Hirbe
Excess macrophages and smooth muscle cells (SMCs) characterize many cardiovascular diseases, but crosstalk between these cell types is poorly defined. Pulmonary hypertension (PH) is a lethal disease in which lung arteriole SMCs proliferate and migrate, coating the normally unmuscularized distal arteriole. We hypothesized that increased macrophage platelet-derived growth factor (PDGF)-B induces pathological SMC burden in PH. Our results indicate that clodronate attenuates hypoxia-induced macrophage accumulation, distal muscularization, PH and right ventricle hypertrophy (RVH). With hypoxia exposure, macrophage Pdgfb mRNA is upregulated in mice, and LysM Cre mice carrying floxed alleles for hypoxia-inducible factor 1a, 2a, or Pdgfb have reduced macrophage Pdgfb and are protected against distal muscularization and PH. Conversely, LysM Cre, von-Hippel Lindau(flox/flox) mice have increased macrophage Hifa and Pdgfb and develop distal muscularization, PH and RVH in normoxia. Similarly, Pdgfb is upregulated in macrophages from human idiopathic or systemic sclerosis-induced pulmonary arterial hypertension patients, and macrophage-conditioned medium from these patients increases SMC proliferation and migration via PDGF-B. Finally, in mice, orotracheal administration of nanoparticles loaded with Pdgfb siRNA specifically reduces lung macrophage Pdgfb and prevents hypoxia-induced distal muscularization, PH and RVH. Thus, macrophage-derived PDGF-B is critical for pathological SMC expansion in PH, and nanoparticle-mediated inhibition of lung macrophage PDGF-B has profound implications as an interventional strategy for PH.
Aglaia Ntokou, Jui M. Dave, Amy C. Kauffman, Maor Sauler, Changwan Ryu, John Hwa, Erica L. Herzog, Inderjit Singh, W. Mark Saltzman, Daniel M. Greif
Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil pro-inflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-Prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced pro-inflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within two independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provides a novel link between neutrophilic inflammation and cardiovascular injury, represents a potentially new target to reduce allogenic immune responses, and uncovers a previously unrecognized mechanism of cardiovascular disease.
Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Melanie Bosley, Dongqi Xing, Xin Xu, J. Michael Wells, James F. George, Jose A. Tallaj, Massoud Leesar, J. Edwin Blalock, Amit Gaggar
DNA methylation (DNAm) has been shown to play a role in mediating food allergy, however, the mechanism by which it does so is poorly understood. In this study, we used targeted NextGen bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) vs non-allergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity) as well as DNAm signature combinations with superior diagnostic potential compared to serum peanut specific-IgE for PA vs. NA. Further, we found that following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared to NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than that in randomly paired genetically unrelated individuals, suggesting that PA related DNAm signatures may be associated with genetic factors.
Xiaoying Zhou, Xiaorui Han, Shu-Chen Lyu, Bryan J. Bunning, Laurie Kost, Iris Chang, Shu Cao, Vanitha Sampath, Kari C. Nadeau
We are reporting on a phase IIa study which aimed to determine the intubation rate, survival, viral clearance, and the development of endogenous antibodies in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 antibodies. All 51 treated patients had COVID-19 pneumonia by radiographic and laboratory evaluation. Fresh or frozen CCP from donors with high titers of neutralizing antibodies was administered. The non-mechanically ventilated patients (n=36) had an intubation rate of 13.9% and a day-30 survival of 88.9%. The overall survival for a comparative group based on network data was 72.5% (1625/2241). Patients had rates of negative nasopharyngeal swab on day +10 and +30 of 43.8% and 73% respectively. Patients mechanically ventilated had a day-30 mortality of 46.7%; the mortality for a comparative group based on network data was 71% (369/520). All evaluable patients were found to have neutralizing antibodies on day +3 (n=47), and all but 1 had antibodies on day +30 and +60. The only adverse event was a mild rash. We are concluding that in this study of patients with COVID-19 pneumonia, CCP was safe and conferred transfer of antibodies while preserving endogenous immune response.
Michele L. Donato, Steven Park, Melissa Baker, Robert Korngold, Alison Morawski, Xue Geng, Ming Tan, Andrew Ip, Stuart Goldberg, Scott D. Rowley, Kar F. Chow, Emily Brown, Joshua Zenreich, Phyllis McKiernan, Kathryn Buttner, Anna Ullrich, Laura Long, Rena Feinman, Andrea Ricourt, Marlo Kemp, Mariefel Vendivil, Hyung C. Suh, Bindu Balani, Cristina Cicogna, Rani Sebti, Abdulla Al-Khan, Steven J. Sperber, Samit Desai, Stacey L. Fanning, Danit Arad, Ronaldo C. Go, Elizabeth Tam, Keith Rose, Sean Sadikot, David S. Siegel, Martin Gutierrez, Tatyana Feldman, Andre Goy, Andrew Pecora, Noa Biran, Lori A. Leslie, Alfred Gillio, Sarah Timmapuri, Michele S. Boonstra, Sam Singer, Sukhdeep Kaur, Ernest Richards, David S. Perlin
Myofibroblasts are the major cellular source of collagen, and their accumulation – via differentiation from fibroblasts and resistance to apoptosis – is a hallmark of tissue fibrosis. Clearance of myofibroblasts by de-differentiation and restoration of apoptosis sensitivity has the potential to reverse fibrosis. Prostaglandin E2 (PGE2) and mitogens such as FGF2 have each been shown to de-differentiate myofibroblasts, but the resultant cellular phenotypes have neither been comprehensively characterized nor compared. Here we show that PGE2 elicited de-differentiation of human lung myofibroblasts via cAMP/PKA while FGF2 utilized MEK/ERK. The two mediators yielded transitional cells with distinct transcriptomes, with FGF2 promoting but PGE2 inhibiting proliferation and survival. The gene expression pattern in fibroblasts isolated from the lungs of mice undergoing resolution of experimental fibrosis resembled that of myofibroblasts treated with PGE2 in vitro. We conclude that myofibroblast de-differentiation can proceed via distinct programs exemplified by treatment with PGE2 and FGF2, with that occurring in vivo most closely resembling the former.
Sean M. Fortier, Loka R. Penke, Dana M. King, Tho X. Pham, Giovanni Ligresti, Marc Peters-Golden
The impact of respiratory virus infections on global health is felt not just during a pandemic but for many, endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen independent innate immunity in the upper airways can prevent spread of respiratory virus infection to the vulnerable lower airways. Activation of Toll-like receptor-2 (TLR2), when restricted to the nasal turbinates results in prompt induction of innate immune-driven anti-viral responses through action of cytokines, chemokines and cellular activity in the upper but not the lower airways. We define how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to seven days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and also support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.
Georgia Deliyannis, Chinn Yi Wong, Hayley A. McQuilten, Annabell Bachem, Michele V. Clarke, Xiaoxiao Jia, Kylie Horrocks, Weiguang Zeng, Jason Girkin, Nichollas E. Scott, Sarah L. Londrigan, Patrick C. Reading, Nathan W. Bartlett, Katherine Kedzierska, Lorena E. Brown, Francesca A. Mercuri, Christophe Demaison, David C. Jackson, Brendon Y. Chua
One of the most fundamental and challenging questions in the cancer field is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identify the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is down-regulated by reactive oxygen species (ROS)-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 down-regulation leads to constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3), driving AM pro-tumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes (CTLs) and promote lung cancer. PDLIM2 down-regulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.
Liwen Li, Fan Sun, Lei Han, Xujie Liu, Yadong Xiao, Alyssa D. Gregory, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu
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