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Linkers in chemical biology provide more than just connectivity between molecules; their intrinsic properties can be harnessed to enhance the stability and functionality of chemical probes. In this study, we explored the incorporation of a peptide nucleic acid (PNA)-based linker into RNA-targeting probes to improve their affinity and specificity. By integrating a PNA linker into a small molecule probe of the Riboglow platform, we enabled dual binding events: cobalamin (Cbl)-RNA structure-based recognition and sequence-specific PNA-RNA interaction. We show that incorporating a six-nucleotide PNA sequence complementary to a region of wild type RNA aptamer ( env 8) results in a 30-fold improvement in binding affinity compared to the probe with a nonfunctional PEG linker. Even greater improvements are observed when the PNA probe was tested against truncated versions of the RNA aptamer, with affinity increasing by up to 280-fold. Additionally, the PNA linker is able to rescue the Cbl-RNA interaction even when the cobalamin binding pocket is compromised. We demonstrate that PNA probes effectively bind RNA both in vitro and in live cells, enhancing visualization of RNA in stress granules and U-bodies at low concentrations. The modular nature of the Riboglow platform allows for flexible modifications of the PNA linker, fluorophore, and RNA tag, while maintaining high specificity and affinity. This work establishes a new approach for enhancing RNA imaging platforms through the use of PNA linkers, highlighting the potential of combining short oligonucleotides with small molecules to improve the affinity and specificity of RNA-targeting probes. Furthermore, this dual-binding approach presents a promising strategy for driving advancements in RNA-targeted drug development., Competing Interests: The authors declare the following competing financial interest(s): R. T. B. serves on the Scientific Advisory Boards of Expansion Therapeutics, SomaLogic, and MeiraGTx., (This journal is © The Royal Society of Chemistry.)

Background: Our team previously identified a stem cell-derived cardioprotective additive that can be added to standard cardioplegia to extend myocardial viability during prolonged myocardial cold ischemic time (CIT) in rodent models. The purpose of this study was to utilize a porcine model to compare in-vivo versus ex-vivo porcine simulation of CIT that accompanies cardiac transplantation in humans, in order to determine an optimal method for translation of our studies to larger animals., Methods: Eight 39-55 kg Yorkshire X pigs were randomly assigned to either in-vivo or ex-vivo simulation. After administration of general anesthesia and endotracheal intubation, baseline measurement of left ventricular performance was obtained via transesophageal echocardiography (TEE). After midline sternotomy and heparin administration, the aorta was cross-clamped and two liters of HTK-Custodiol were introduced via the aortic root. The in-vivo method utilized cold ischemic heart storage in the chest cavity while supporting the experimental animal with cardiopulmonary bypass (CPB). The ex-vivo method involved standard cardiac procurement, cold ischemic storage outside of the body, and subsequent cardiac reperfusion utilizing cardiac reanimation in a Langendorff heart perfusion mode. After CIT, measurements of post-ischemic left ventricular performance were obtained via echocardiography. Results are presented as: Mean ± Standard Deviation (Median, Minimum-Maximum)., Results: Weight (kilograms) was similar in the in-vivo group and the ex-vivo group: 44 ± 1.8 (44, 42-46) versus 44 ± 5.1 (43.5, 39-51), respectively. Cold ischemic time (minutes) was longer in the ex-vivo group: 360 ± 0 (360, 360-360) versus 141 ± 26.7 (149, 102-163). Temperature (degrees Celsius) was colder in the ex-vivo group: 8 ± 0 (8, 8-8) versus 16.5 ± 4.2 (16, 12-16).In the in-vivo group, baseline ejection fraction and ejection fraction after CIT were: 48.25% ± 14.95% (48.5%, 33%-63%) and 41.25% ± 22.32% (41.5%, 20%-62%), respectively. In the ex-vivo group, baseline ejection fraction and ejection fraction after CIT were: 56.4% ± 5.9% (57%, 50%-67%) and 60.4% ± 7.7% (61.5%, 51.9%-67%), respectively., Conclusion: The ex-vivo technique is suitable to evaluate cardioplegia additives that may substantially extend myocardial tolerance to cold ischemia.

Minocycline, an anti-inflammatory antibiotic drug, rebalances impaired gut microbiota, attenuates neuroinflammation and lowers high blood pressure in animal models of hypertension and in hypertensive patients. Our objective in this study was to investigate if antihypertensive effects of minocycline involve the expression of gut epithelial genes relevant to blood pressure homeostasis using human colonic 3-dimensional organoid culture and high-throughput RNA sequencing. The data demonstrates that minocycline could restore impaired expression of functional genes linked to viral and bacterial immunity, inflammation, protein trafficking and autophagy in human hypertensive organoids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Pulmonary hypertension (PH), characterized by elevated pulmonary pressure and right heart failure, is a systemic disease involving inappropriate sympathetic activation and an impaired gut-brain-lung axis. Global overexpression of angiotensin converting enzyme 2 (ACE2), a cardiopulmonary protective enzyme of the renin-angiotensin system, attenuates PH induced by chronic hypoxia. Neurons within the paraventricular nucleus of the hypothalamus (PVN) that synthesize corticotropin-releasing hormone (CRH) are activated by stressors, like hypoxia, and this activation augments sympathetic outflow to cardiovascular tissues. These data coupled with our observations that ACE2 overexpression in CRH cells (CRH-ACE2KI mice) decreases anxiety-like behavior via suppression of hypothalamic-pituitary-adrenal (HPA) axis activity by decreasing CRH synthesis, led us to hypothesize that selective ACE2 overexpression in CRH neurons would protect against hypoxia-induced PH., Methods: CRH-ACE2KI and WT male and female mice were exposed to chronic hypoxia (10%O2) or normoxia (21%O2) for 4 weeks in a ventilated chamber with continuous monitoring of oxygen and carbon dioxide concentrations ( n = 7-10/group). Pulmonary hemodynamics were measured with Millar pressure catheters then tissues were collected for histological analyses., Results: Chronic hypoxia induced a significant increase (36.4%) in right ventricular (RV) systolic pressure (RVSP) in WT mice, which was not observed in CRH-ACE2KI mice. No significant differences in RVSP were observed between male and female mice in any of the groups., Conclusion: Overexpression of ACE2 in CRH cells was protective against hypoxia-induced PH. Since the majority of expression of CRH is in brain nuclei such as paraventricular nucleus of the hypothalamus (PVN) and/or central nucleus of the amygdala (CeA) these data indicate that the protective effects of ACE2 are, at least in part, centrally mediated. This contributes to the systemic nature of PH disease and that CRH neurons may play an important role in PH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oliveira, Karas, Alves, He, de Kloet, Krause, Richards, Bryant and Raizada.)

Scholars have argued that social evaluation, the capacity to evaluate different potential social partners, is an important capacity not just for humans but for all cooperative species. Recent work has explored whether domesticated dogs share a human-like ability to evaluate others based on prosocial and antisocial actions toward third parties. To date, this work has shown mixed results, suggesting that individual differences may play a role in dogs' capacity to evaluate others. In the present study, we test whether attachment-an individual difference that affects human social evaluation performance-can explain the mixed pattern of social evaluation results observed in dogs. We first tested dogs on a social evaluation task in which an experimenter either helped or refused to help the dog's owner open a container. We then assessed dogs' attachment strength using a subset of the C-BARQ. We found that attachment was a statistically significant predictor of dogs' preference toward the prosocial actor but was not a predictor in antisocial or control conditions. This finding provides early evidence that attachment may drive positivity biases in dogs and that attachment might explain mixed results within canine social evaluation literature.

Background Hypertension is associated with gut dysbiosis, altered intestinal immunity, and gut pathology in animal models and humans. Although these findings have implicated impaired interactions between gut and gut microbiota in hypertension, little is known about the specific functional gut microbes that interact with intestinal mucosa. Methods and Results To identify these microbes, we sorted Immunoglobin A (IgA)-coated (IgA + ) and IgA-noncoated (IgA - ) bacteria using a combination of magnetic-activated cell sorting and fluorescence-activated cell sorting, and subsequently performed 16 S rRNA gene sequencing (IgA-SEQ) to determine the microbial composition of IgA + and IgA - fractions in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats. We observed a significant decrease in IgA + bacteria in SHR compared with Wistar Kyoto and a distinct composition of IgA + and IgA - bacteria between Wistar Kyoto and SHR, showing more IgA-bound Proteobacteria, Bacteroidetes and Actinobacteria but less of Firmicutes in SHR at the phylum level. We further identified enriched IgA-coated Romboutsia , Turicibacter , Ileibacterium , and Dubosiella in SHR that were negatively correlated with the various pathways including antigen presentation, immune response, cell junction organization, epithelium development, and defense response to virus. Conclusions We demonstrate new IgA-coated bacteria that participate in host-microbiota communication in hypertension, suggesting promising therapeutic interventions targeting these bacteria for hypertension management.

Hypertension (HTN) is associated with gut dysbiosis and the depletion of butyrate-producing bacteria in animal models and people. Furthermore, fecal material transfer from donor hypertensive patients increases blood pressure in normotensive recipient animals and ameliorates HTN-associated pathophysiology. These observations have implications in the impaired interactions between the gut and gut microbiota in HTN. Although this concept is supported in animal models, little is known about human HTN. Therefore, our objective for this study was to compare gene expression with transcriptomics and its potential to influence microbiota in subjects with normal and high blood pressure (HBP). Colon samples from reference subjects with normal blood pressure (REF) and HBP were used for RNA-seq to analyze their transcriptomes. We observed the significant downregulation of gene sets governing immune responses (e.g., SGK1 and OASL ), gut epithelial function (e.g., KRT20 and SLC9A3R1 ), gut microbiota (e.g., PPARG and CIDEC ) and genes associated with cardiovascular and gut diseases (e.g., PLAUR and NLN ) in HBP subjects; the expression of genes within these pathways correlated with blood pressure. Potential drug targets in the gut epithelium were identified using the Drug Gene International Database for possible use in HTN. They include peroxisome proliferator-activated receptor gamma ( PPRG), active serum/glucocorticoid regulated kinase 1 (SGK1) and 3 beta-hydroxysteroid isomerase type II inhibitor (HSD3B). Finally, butyrate, a microbiota-derived short-chain fatty acid, restored the disrupted expression of certain functional genes in colonic organoids from HBP subjects. Patients with HBP exhibit a unique transcriptome that could underlie impaired gut-microbiota interactions. Targeting these interactions could provide a promising new therapeutic intervention for hypertension management.

Background: Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects., Methods and Results: To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus . C. comes , an anaerobic species of Coprococcus , harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril., Conclusions: Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I  2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I  2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results., (Published by Oxford University Press 2022.)

Hypertension is a worldwide problem with major impacts on health including morbidity and mortality, as well as consumption of health care resources. Nearly 50% of American adults have high blood pressure, and this rate is rising. Even with multiple antihypertensive drugs and aggressive lifestyle modifications, blood pressure is inadequately controlled in about 1 of 5 hypertensive individuals. This review highlights a hypothesis for hypertension that suggests alternative mechanisms for blood pressure elevation and maintenance. A better understanding of these mechanisms could open avenues for more successful treatments. The hypothesis accounts for recent understandings of the involvement of gut physiology, gut microbiota, and neuroinflammation in hypertension. It includes bidirectional communication between gut microbiota and gut epithelium in the gut-brain axis that is involved in regulation of autonomic nervous system activity and blood pressure control. Dysfunction of this gut-brain axis, including dysbiosis of gut microbiota, gut epithelial dysfunction, and deranged input to the brain, contributes to hypertension via inflammatory mediators, metabolites, bacteria in the circulation, afferent information alterations, etc resulting in neuroinflammation and unbalanced autonomic nervous system activity that elevates blood pressure. This in turn negatively affects gut function and its microbiota exacerbating the problem. We focus this review on the gut-brain axis hypothesis for hypertension and possible contribution to racial disparities in hypertension. A novel idea, that immunoglobulin A-coated bacteria originating in the gut with access to the brain could be involved in hypertension, is raised. Finally, minocycline, with its anti-inflammatory and antimicrobial properties, is evaluated as a potential antihypertensive drug acting on this axis.

Recent evidence suggests pulmonary hypertension (PH), a disease of the pulmonary vasculature actually has multiorgan pathophysiology and perhaps etiology. Herein, we demonstrated that fecal matter transplantation from angiotensin-converting enzyme 2 overexpressing mice counteracted the effects of chronic hypoxia to prevent pulmonary hypertension, neuroinflammation, and gut dysbiosis in wild type recipients., Competing Interests: The authors declare that there are no conflict of interests., (© 2021 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Hypertension (HTN) is frequently linked with depression (DEP) in adults with cardiovascular disease (CVD), yet the underlying mechanism and successful management remain elusive. We approached this knowledge gap through the lens that humans are eukaryote-prokaryote "meta-organisms," such that cardiovascular disease dysregulation is a mosaic disorder involving dysbiosis of the gut. We hypothesized that patients diagnosed with hypertension plus depression harbor a unique gut microbial ecology with attending functional genomics engaged with their hosts' gut/brain axis physiology., Methods: Stool microbiome DNA was analyzed by whole metagenome shotgun sequencing in 54 subjects parsed into cohorts diagnosed with HTN only (N = 18), DEP only (N = 7), DEP plus HTN (DEP-HTN) (N = 8), or reference subjects with neither HTN nor DEP (N = 21). A novel battery of machine-learning multivariate analyses of de-noised data yielded effect sizes and permutational covariance-based dissimilarities that significantly differentiated the cohorts (false discovery rate (FDR)-adjusted P ≤ .05); data clustering within 95% confidence interval)., Results: Metagenomic significant differences extricated the four cohorts. Data of the cohort exhibiting DEP-HTN were germane to the interplay of central control of blood pressure concomitant with the neuropathology of depressive disorders. DEP-HTN gut bacterial community ecology was defined by co-occurrence of Eubacterium siraeum, Alistipes obesi, Holdemania filiformis, and Lachnospiraceae bacterium 1.1.57FAA with Streptococcus salivariu. The corresponding microbial functional genomics of DEP-HTN engaged pathways degrading GABA and beneficial short chain fatty acids (SCFA), and are associated with enhanced sodium absorption and inflammasome induction., Conclusions: These data suggest a new putative endotype of hypertension, which we denote "depressive-hypertension" (DEP-HTN), for which we posit a model that is distinctive from either HTN alone or DEP alone. An "endotype" is a subtype of a heterogeneous pathophysiological mechanism. The DEP-HTN model incorporates a unique signature of microbial taxa and functional genomics with crosstalk that putatively intertwines host pathophysiology involving the gastrointestinal tract with disruptions in central control of blood pressure and mood. The DEP-HTN endotype model engages cardiology with gastroenterology and psychiatry, providing a proof-of-concept foundation to explore future treatments, diagnosis, and prevention of HTN-coupled mood disorders., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Antihypertensive medication nonadherence is a prevalent issue but is very difficult to accurately assess. To clarify this problem among hypertensive patients attending a cardiovascular disease outpatient clinic, we utilized high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) to assess antihypertensive medication adherence and identify trends by sex and drug class., Methods: Serum was extracted from blood samples obtained from patients with either drug-controlled or drug resistant hypertension (RHTN) and analyzed via HPLC-MS for antihypertensive drugs which were categorized by drug class as beta blockers, aldosterone antagonists, diuretics, ACE inhibitor/ARBs, or calcium channel blockers. Clinic blood pressure (BP), sex, and prescription regimens were extracted from medical records at or near the time of blood collection. "Adherence" or "nonadherence" was determined by comparison of the patient's prescribed drug regimen and the presence/absence of prescribed drug(s) in their serum., Results: Among 76 patients (47 women; mean age 63; 53% white), nonadherence was confirmed in 29%. RHTN was more frequently identified in women than men (55% vs 38%) and nonadherence was higher in women than men (34% vs 21%). BP in those who were adherent to prescribed antihypertensive drugs was significantly lower than in those who were nonadherent (129/75 vs 145/83 mmHg, p  = 0.0015). Overall, ACE inhibitors/ARBs were associated with the least nonadherence. Among women, nonadherence was highest for aldosterone antagonists, whereas among men, nonadherence was highest for diuretics., Conclusion: We observed nonadherence was more frequent among older women in a cohort of HTN and RHTN patients with cardiovascular disease based on HPLC-MS confirmed drug levels., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that couple have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Hypertension is associated with gut bacterial dysbiosis and gut pathology in animal models and people. Butyrate-producing gut bacteria are decreased in hypertension. RNA-seq analysis of gut colonic organoids prepared from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to test the hypothesis that impaired interactions between the gut microbiome and gut epithelium are involved and that these would be remediated with butyrate supplementation. Gene expressions in immune responses including antigen presentation and antiviral pathways were decreased in the gut epithelium of the SHR in organoids and confirmed in vivo; these deficits were corrected by butyrate supplementation. Deficits in gene expression driving epithelial proliferation and differentiation were also observed in SHR. These findings highlight the importance of aligned interactions of the gut microbiome and gut immune responses to blood pressure homeostasis.

Purpose of Review: Rapidly emerging evidence implicates an important role of gut-brain-bone marrow (BM) axis involving gut microbiota (GM), gut epithelial wall permeability, increased production of pro-inflammatory BM cells and neuroinflammation in hypertension (HTN). However, the precise sequence of events involving these organs remains to be established. Furthermore, whether an impaired gut-brain-BM axis is a cause or consequence of HTN is actively under investigation. This will be extremely important for translation of this fundamental knowledge to novel, innovative approaches for the control and management of HTN. Therefore, our objectives are to summarize the latest hypothesis, provide evidence for and against the impaired gut, BM and brain interactions in HTN and discuss perspectives and future directions., Recent Findings: Hypertensive stimuli activate autonomic neural pathways resulting in increased sympathetic and decreased parasympathetic cardiovascular modulation. This directly affects the functions of cardiovascular-relevant organs to increase blood pressure. Increases in sympathetic drive to the gut and BM also trigger sequences of signaling events that ultimately contribute to altered GM, increased gut permeability, enhanced gut- and brain-targeted pro-inflammatory cells from the BM in perpetuation and establishment of HTN., Summary: In this review, we present the mechanisms involving the brain, gut, and BM, whose dysfunctional interactions may be critical in persistent neuroinflammation and key in the development and establishment of HTN., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications., (© 2021 The Author(s).)

The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin-angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein-coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Discovery of ACE2 (angiotensin-converting enzyme 2) revealed that the renin-angiotensin system has 2 counterbalancing arms. ACE2 is a major player in the protective arm, highly expressed in lungs and gut with the ability to mitigate cardiopulmonary diseases such as inflammatory lung disease. ACE2 also exhibits activities involving gut microbiome, nutrition, and as a chaperone stabilizing the neutral amino acid transporter, B 0 AT1, in gut. But the current interest in ACE2 arises because it is the cell surface receptor for the novel coronavirus, severe acute respiratory syndrome coronavirus-2, to infect host cells, similar to severe acute respiratory syndrome coronavirus-2. This suggests that ACE2 be considered harmful, however, because of its important other roles, it is paradoxically a potential therapeutic target for cardiopulmonary diseases, including coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2. This review describes the discovery of ACE2, its physiological functions, and its place in the renin-angiotensin system. It illustrates new analyses of the structure of ACE2 that provides better understanding of its actions particularly in lung and gut, shedding of ACE2 by ADAM17 (a disintegrin and metallopeptidase domain 17 protein), and role of TMPRSS2 (transmembrane serine proteases 2) in severe acute respiratory syndrome coronavirus-2 entry into host cells. Cardiopulmonary diseases are associated with decreased ACE2 activity and the mitigation by increasing ACE2 activity along with its therapeutic relevance are addressed. Finally, the potential use of ACE2 as a treatment target in COVID-19, despite its role to allow viral entry into host cells, is suggested.

The central dogma teaches us that DNA makes RNA, which in turn makes proteins, the main building blocks of the cell. But this over simplified linear transmission of information overlooks the vast majority of the genome produces RNAs that do not encode proteins and the myriad ways that RNA regulates cellular functions. Historically, one of the challenges in illuminating RNA biology has been the lack of tools for visualizing RNA in live cells. But clever approaches for exploiting RNA binding proteins, in vitro RNA evolution, and chemical biology have resulted in significant advances in RNA visualization tools in recent years. This review provides an overview of current tools for tagging RNA with fluorescent probes and tracking their dynamics, localization andfunction in live mammalian cells., Competing Interests: Declaration of Interests A.E.P. and E.B. are listed as inventors on a patent (U.S. application no. 16/526,835, Compositions and Methods for Tagging Ribonucleic Acids). The patent was filed July 31, 2019; it has not been awarded yet. One technology mentioned in the article (Riboglow) is mentioned in this patent., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Emerging evidence implicates an interplay among multiple organs such as brain, vasculature, gut and lung in the development of established pulmonary arterial hypertension (PAH). This has led us to propose that activated microglia mediated-enhanced sympathetic activation contributes to PAH pathophysiology. Since enhanced sympathetic activity is observed in human PAH and the gut is highly innervated by sympathetic nerves that regulate its physiological functions, we hypothesized that PAH would be associated with gut pathophysiology. A monocrotaline rat model of PAH was utilized to investigate the link between gut pathology and PAH. Haemodynamics, histology, immunocytochemistry and 16S RNA gene sequencing were used to assess cardiopulmonary functions, gut pathology and gut microbial communities respectively. Monocrotaline treatment caused increased right ventricular systolic pressure, haemodynamics and pathological changes associated with PAH. PAH animals also showed profound gut pathology that included increased intestinal permeability, increased muscularis layer, decreased villi length and goblet cells. These changes in gut pathology were associated with alterations in microbial communities, some unique to PAH animals. Furthermore, enhanced gut-neural communication involving the paraventricular nucleus of the hypothalamus and increased sympathetic drive were observed. In conclusion, our data show the presence of gut pathology and distinct changes in gut microbiota and increased sympathetic activity in PAH. They suggest that dysfunctional gut-brain crosstalk could be critical in PAH and considered a future therapeutic target for PAH., Competing Interests: Conflict of interest: R.K. Sharma has nothing to disclose. Conflict of interest: A.C. Oliveira has nothing to disclose. Conflict of interest: T. Yang has nothing to disclose. Conflict of interest: S. Kim has nothing to disclose. Conflict of interest: J. Zubcevic has nothing to disclose. Conflict of interest: V. Aquino has nothing to disclose. Conflict of interest: G.O. Lobaton has nothing to disclose. Conflict of interest: R. Goel has nothing to disclose. Conflict of interest: E.M. Richards has nothing to disclose. Conflict of interest: M.K. Raizada reports grants from the NIH outside the submitted work., (Copyright ©ERS 2020.)

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH. ACE2 knockin and wild-type (WT; C57BL/6) mice were subjected to chronic hypoxia (10% FIO2) or room air for 4 weeks. Cardiopulmonary hemodynamics, histology, immunohistochemistry, and fecal 16S rRNA microbial gene analyses were evaluated. Hypoxia significantly increased right ventricular systolic pressure, sympathetic activity as well as the number and activation of microglia in the paraventricular nucleus of the hypothalamus in WT mice. This was associated with a significant increase in muscularis layer thickening and decreases in both villi length and goblet cells and altered gut microbiota. Global overexpression of ACE2 prevented changes in hypoxia-induced pulmonary and gut pathophysiology and established distinct microbial communities from WT hypoxia mice. Furthermore, WT mice subjected to fecal matter transfer from ACE2 knockin mice were resistant to hypoxia-induced PH compared with their controls receiving WT fecal matter transfer. These observations demonstrate that ACE2 ameliorates these hypoxia-induced pathologies and attenuates PH. The data implicate dysfunctional brain-gut-lung communication in PH and provide novel avenues for therapeutic interventions.

Maternal-fetal crosstalk has been implicated in long-term control of the health of offspring, including transgenerational hypertension. However, current knowledge is limited regarding maternal influences on the gut and its microbiome in blood pressure control in offspring. Therefore, the current study was designed to test the hypothesis that maternal factors influence the gut-brain axis impacting hypertension in offspring. We elected to use captopril, an antihypertensive angiotensin-converting enzyme inhibitor that possesses antibacterial properties, for the study. Pregnant female spontaneously hypertensive rats and normotensive Wistar Kyoto rats were treated with captopril water (100 mg/[kg·day]) or sterile water throughout pregnancy and lactation. At weaning, the pups from dams drinking sterile water were continued with sterile water until 12 weeks of age. The male pups from dams drinking captopril water were divided at weaning into 2 groups: offspring drinking captopril water and offspring withdrawn from captopril water, then drinking sterile water until 12 weeks of age. Captopril changed gut microbiota of spontaneously hypertensive rat dams, and some of these changes were reflected in their 12-week-old male offspring. These 12-week-old spontaneously hypertensive rat male offspring exposed to captopril via dams demonstrated persistently decreased systolic blood pressure, decreased number of activated microglia and neuroinflammation, as well as improvement of gut inflammation and permeability. Therefore, maternal captopril treatment improves the dysregulated gut-brain axis in spontaneously hypertensive rat male offspring, providing conceptual support that targeting the gut-brain axis via the mother may be a viable strategy for control of hypertension in the offspring.

We have previously found that in utero exposure to excess maternal cortisol (1 mg/kg/day) in late gestation increases the incidence of stillbirth during labor and produces fetal bradycardia at birth. In the interventricular septum, mitochondrial DNA (mt-DNA) was decreased, and transcriptomics and metabolomics were consistent with altered mitochondrial metabolism. The present study uses transcriptomics to model effects of increased maternal cortisol on fetal biceps femoris. Transcriptomic modeling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways for regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mt-DNA and the protein levels of cytochrome C were significantly decreased in the biceps femoris. RT-PCR validation of the pathways confirmed a significant decrease in SLC2A4 mRNA levels and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, suggesting that insulin sensitivity of the biceps femoris muscle may be reduced in cortisol offspring. We also tested for changes in gene expression in diaphragm by rt-PCR. PDK4, TXNIP, and ANGPTL4 mRNA were also increased in the diaphragm, but SLC2A4, cytochrome C protein, and mt-DNA were unchanged. Comparison of the change in gene expression in biceps femoris to that in cardiac interventricular septum and left ventricle showed few common genes and little overlap in specific metabolic or signaling pathways, despite reduction in mt-DNA in both heart and biceps femoris. Our results suggest that glucocorticoid exposure alters expression of nuclear genes important to mitochondrial activity and oxidative stress in both cardiac and skeletal muscle tissues, but that these effects are tissue-specific.

Pulmonary arterial hypertension (PAH) is considered a disease of the pulmonary vasculature. Limited progress has been made in preventing or arresting progression of PAH despite extensive efforts. Our previous studies indicated that PAH could be considered a systemic disease since its pathology involves interplay of multiple organs. This, coupled with increasing implication of the gut and its microbiome in chronic diseases, led us to hypothesize that patients with PAH exhibit a distinct gut microbiome that contributes to, and predicts, the disease. Fecal microbiome of 18 type 1 PAH patients (mean pulmonary arterial pressure, 57.4, SD 16.7 mm Hg) and 13 reference subjects were compared by shotgun metagenomics to evaluate this hypothesis. Significant taxonomic and functional changes in microbial communities in the PAH cohort were observed. Pathways for the synthesis of arginine, proline, and ornithine were increased in PAH cohort compared with reference cohort. Additionally, groups of bacterial communities associated with trimethylamine/ trimethylamine N-oxide and purine metabolism were increased in PAH cohort. In contrast, butyrate-and propionate-producing bacteria such as Coprococcus, Butyrivibrio, Lachnospiraceae, Eubacterium, Akkermansia, and Bacteroides were increased in reference cohort. A random forest model predicted PAH from the composition of the gut microbiome with 83% accuracy. Finally, virome analysis showed enrichment of Enterococcal and relative depletion of Lactococcal phages in the PAH cohort. In conclusion, patients with PAH exhibit a unique microbiome profile that has the high predictive potential for PAH. This highlights previously unknown roles of gut bacteria in this disease and could lead to new therapeutic, diagnostic, or management paradigms for PAH.

Fecal matter transfer from hypertensive patients and animals into normotensive animals increases blood pressure, strengthening the evidence for gut-microbiota interactions in the control of blood pressure. However, cellular and molecular events involved in gut dysbiosis-associated hypertension remain poorly understood. Therefore, our objective in this study was to use gene expression profiling to characterize the gut epithelium layer in the colon in hypertension. We observed significant suppression of components of T cell receptor (TCR) signaling in the colonic epithelium of spontaneously hypertensive rats (SHR) when compared with Wistar Kyoto (WKY) normotensive rats. Western blot analysis confirmed lower expression of key proteins including T cell surface glycoprotein CD3 gamma chain (Cd3g) and lymphocyte cytosolic protein 2 (Lcp2). Furthermore, lower expression of cytokines and receptors responsible for lymphocyte proliferation, differentiation, and activation (e.g., Il12r , Il15ra , Il7 , Il16 , Tgfb1 ) was observed in the colonic epithelium of the SHR. Finally, Alpi and its product, intestinal alkaline phosphatase, primarily localized in the epithelial cells, were profoundly lower in the SHR. These observations demonstrate that the colonic epithelium undergoes functional changes linked to altered immune, barrier function, and dysbiosis in hypertension.

Pulmonary hypertension (PH) is classically considered a disease of pulmonary vasculature which has been the predominant target for drug development and PH therapy. Despite significant advancement in recent years in identification of new drug targets and innovative treatment strategies, the prognosis of PH remains poor, with median survival of 5 years. Recent studies have demonstrated involvement of neuroinflammation, altered autonomic and gastrointestinal functions and increased trafficking of bone marrow-derived cells in cardiopulmonary pathophysiology. This has led to the proposal that PH could be considered a systemic disease involving complex interactions among many organs. Our objectives in this review is to summarize evidence for the involvement of the brain, bone marrow and gut in PH pathophysiology. Then, to synthesize all evidence supporting a brain-gut-lung interaction hypothesis for consideration in PH pathophysiology and finally to summarize unanswered questions and future directions to move this novel concept forward. This forward-thinking view, if proven by further experiments, would provide new opportunities and novel targets for the control and treatment of PH., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cortisol administration during late gestation in ewes, modeling maternal stress, resulted in transcriptomic changes suggesting altered maturation and metabolic changes to the offspring heart. This study investigates the effects of cortisol on epicardial adipose tissue (EAT), a visceral fat pad associated with adverse cardiovascular conditions in adults. Pregnant ewes were treated with either 1 mg·kg -1 ·day -1 cortisol from 115 days gestation to term and EAT collected from term fetuses (control: n = 8, maternal cortisol 1 mg·kg -1 ·day -1 : n = 6). To compare the effects of cortisol to the normal maturation in EAT, we also modeled the normal changes in gene expression in EAT at the transition from in utero to postnatal life using the EAT from control fetuses and from two-week-old lambs (control: n = 7). Transcriptomic modeling was used to identify pathways altered by maternal cortisol overexposure. Transcriptomic modeling confirmed the brown fat phenotype of EAT at term and a transition toward white fat at 2 wk of age in EAT of control fetuses/lambs and highlighted a role of immune responses, including complement coagulation, and serotonin in this transition. Maternal cortisol (1 mg·kg -1 ·day -1 ) increased the lipid peroxidation product 4-hydroxynonenal in EAT of term fetuses but did not affect the number of activated macrophages or size of the lipid droplets in the depot; transcriptomics suggested an earlier metabolic maturation of EAT via, in part, increased immune responses.

In utero treatment with glucocorticoids have been suggested to reprogram postnatal cardiovascular function and stress responsiveness. However, little is known about the effects of prenatal exposure to the natural corticosteroid, cortisol, on postnatal cardiovascular system or metabolism. We have demonstrated an increased incidence of stillbirth in sheep pregnancies in which there is mild maternal hypercortisolemia caused by infusion of 1 mg/kg/d cortisol. In order to model corticosteroid effects in the neonate, we created a second model in which cortisol was infused for 12 h per day for a daily infusion of 0.5 mg/kg/d. In this model we had previously found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group, and that neonatal ponderal index and kidney weight were reduced and left ventricular wall thickness was increased in the 2 week old lamb. In this study, we have used transcriptomic modeling to better understand the programming effect of this maternal hypercortisolemia in these hearts. This is a time when both terminal differentiation and a shift in the metabolism of the heart from carbohydrates to lipid oxidation are thought to be complete. The transcriptomic model indicates suppression of genes in pathways for fatty acid and ketone production and upregulation of genes in pathways for angiogenesis in the epicardial adipose fat (EAT). The transcriptomic model indicates that RNA related pathways are overrepresented by downregulated genes, but ubiquitin-mediated proteolysis and protein targeting to the mitochondria are overrepresented by upregulated genes in the intraventricular septum (IVS) and left ventricle (LV). In IVS the AMPK pathway and adipocytokine signaling pathways were also modeled based on overrepresentation by downregulated genes. Peroxisomal activity is modeled as increased in EAT, but decreased in LV and IVS. Our results suggest that pathways for lipids as well as cell proliferation and cardiac remodeling have altered activity postnatally after the in utero cortisol exposure. Together, this model is consistent with the observed increase in cardiac wall thickness at necropsy and altered glucose metabolism observed in vivo , and predicts that in utero exposure to excess maternal cortisol will cause postnatal cardiac hypertrophy and altered responses to oxidative stress.

Hypertension affects an estimated 103 million Americans, yet gaps in knowledge continue to limit its successful management. Rapidly emerging evidence is linking gut dysbiosis to many disorders and diseases including hypertension. The evolution of the -omics techniques has allowed determination of the abundance and potential function of gut bacterial species by next-generation bacterial sequencing, whereas metabolomics techniques report shifts in bacterial metabolites in the systemic circulation of hypertensive patients and rodent models of hypertension. The gut microbiome and host have evolved to exist in balance and cooperation, and there is extensive crosstalk between the 2 to maintain this balance, including during regulation of blood pressure. However, an understanding of the mechanisms of dysfunctional host-microbiome interactions in hypertension is still lacking. Here, we synthesize some of our recent data with published reports and present concepts and a rationale for our emerging hypothesis of a dysfunctional gut-brain axis in hypertension. Hopefully, this new information will improve the understanding of hypertension and help to address some of these knowledge gaps.

Translocator protein 18 kDa (TSPO) has been widely imaged as a marker of neuroinflammation using several radioligands, including [ 11 C]PBR28. In order to study the effects of age, sex, and obesity on TSPO binding and to determine whether this binding can be accurately assessed using fewer radio high-performance liquid chromatography (radio-HPLC) measurements of arterial blood samples, we created a database of 48 healthy subjects who had undergone [ 11 C]PBR28 scans (23 high-affinity binders (HABs) and 25 mixed-affinity binders (MABs), 20 F/28 M, age: 40.6 ± 16.8 years). After analysis by Logan plot using 23 metabolite-corrected arterial samples, total distribution volume ( V T ) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( V ND ) as 1.40 mL · cm -3 , which generated a specific-to-nondisplaceable ratio ( BP ND ) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. V T increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, V T did not correlate with body mass index and was not affected by sex. These results underscore which patient characteristics should be accounted for during [ 11 C]PBR28 studies and suggest ways to perform such studies more easily and with fewer blood samples.

We have identified effects of elevated maternal cortisol (induced by maternal infusion 1 mg·kg -1 ·day -1 ) on fetal cardiac maturation and function using an ovine model. Whereas short-term exposure (115-130-day gestation) increased myocyte proliferation and Purkinje fiber apoptosis, infusions until birth caused bradycardia with increased incidence of arrhythmias at birth and increased perinatal death, despite normal fetal cortisol concentrations from 130 days to birth. Statistical modeling of the transcriptomic changes in hearts at 130 and 140 days suggested that maternal cortisol excess disrupts cardiac metabolism. In the current study, we modeled pathways in the left ventricle (LV) and interventricular septum (IVS) of newborn lambs after maternal cortisol infusion from 115 days to birth. In both LV and IVS the transcriptomic model indicated over-representation of cell cycle genes and suggested disruption of cell cycle progression. Pathways in the LV involved in cardiac architecture, including SMAD and bone morphogenetic protein ( BMP) were altered, and collagen deposition was increased. Pathways in IVS related to metabolism, calcium signaling, and the actin cytoskeleton were altered. Comparison of the effects of maternal cortisol excess to the effects of normal maturation from day 140 to birth revealed that only 20% of the genes changed in the LV were consistent with normal maturation, indicating that chronic elevation of maternal cortisol alters normal maturation of the fetal myocardium. These effects of maternal cortisol on the cardiac transcriptome, which may be secondary to metabolic effects, are consistent with cardiac remodeling and likely contribute to the adverse impact of maternal stress on perinatal cardiac function.

Rationale: Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension, and their inhibition by minocycline-an anti-inflammatory antibiotic-produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for hypertension. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in hypertension. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3)-a derivative of tetracycline that has potent anti-inflammatory activity-to address this question., Objective: Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing hypertension-associated pathology, and attenuate hypertension., Methods and Results: Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall., Conclusions: These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes in gut microbial communities and profound attenuation of gut pathology. They suggest, for the first time, a link between microglia and certain microbial communities that may have implications for treatment of hypertension.

Background We have demonstrated that the antihypertensive effect of the angiotensin-converting enzyme inhibitor, captopril ( CAP ), is associated with beneficial effects on gut pathology. Coupled with the evidence that CAP exerts prolonged reduction in blood pressure ( BP ) after discontinuation of treatment, we investigate whether persistent beneficial actions of CAP are linked to alterations of gut microbiota and improvement of hypertension-induced gut pathology. Methods and Results Spontaneously hypertensive rats ( SHR ) and Wistar Kyoto rats were treated with CAP (250 mg/kg/day) for 4 weeks followed by withdrawal for 16 weeks. Gut microbiota, gut pathology, BP, and brain neuronal activity were assessed. CAP resulted in a ≈60 mm Hg decrease in systolic BP after 3 weeks of treatment in SHR , and the decrease remained significant at least 5 weeks after CAP withdrawal. In contrast, CAP caused modest decrease in systolic BP in Wistar Kyoto. 16S rRNA gene-sequencing-based gut microbial analyses in SHR showed sustained alteration of gut microbiota and increase in Allobaculum after CAP withdrawal. Phylogenetic investigation of communities by reconstruction of unobserved states analysis revealed significant increase in bacterial sporulation upon CAP treatment in SHR . These were associated with persistent improvement in gut pathology and permeability. Furthermore, manganese-enhanced magnetic resonance imaging showed significantly decreased neuronal activity in the posterior pituitary of SHR 4 weeks after withdrawal. Conclusions Decreased BP , altered gut microbiota, improved gut pathology and permeability, and dampened posterior pituitary neuronal activity were maintained after CAP withdrawal in the SHR . They suggest that CAP influences the brain-gut axis to maintain the sustained antihypertensive effect of CAP after withdrawal.

The physiological response to hypoxia in the fetus has been extensively studied with regard to redistribution of fetal combined ventricular output and sparing of oxygen delivery to fetal brain and heart. Previously, we have shown that the fetal brain is capable of mounting changes in gene expression that are consistent with tissue inflammation. The present study was designed to use transcriptomics and systems biology modeling to test the hypothesis that ketamine reduces or prevents the upregulation of inflammation-related pathways in hypothalamus and hippocampus after transient hypoxic hypoxia. Chronically catheterized fetal sheep (122 ± 5 days gestation) were subjected to 30 min hypoxia (relative reduction in P a O 2 ∼50%) caused by infusion of nitrogen into the inspired gas of the pregnant ewe. RNA was isolated from fetal hypothalamus and hippocampus collected 24 h after hypoxia, and was analyzed for gene expression using the Agilent 15.5 k ovine microarray. Ketamine, injected 10 min prior to hypoxia, reduced the cerebral immune response activation to the hypoxia in both brain regions. Genes both upregulated by hypoxia and downregulated by ketamine after hypoxia were significantly associated with gene ontology terms and KEGG pathways that are, themselves, associated with the tissue response to exposure to bacteria. We conclude that the results are consistent with interruption of the cellular response to bacteria by ketamine.

Background: Black Americans have greater rates, severity and resistance to treatment of hypertension than White Americans. The gut microbiota and its metabolites may contribute to this. This concept was tested in a pilot study., Methods: Subjects with high (HBP, >140/80 mm Hg) and normal (NBP, <120/80 mm Hg) blood pressure (BP) provided stool and blood samples for whole genome sequencing (WGS) of gut microbiota and global untargeted metabolomics of serum. Patients were either black (B) with NBP (n = 10 for WGS, 5 for metabolomics) and HBP (n = 10 and 9, BHBP) or white (W) with NBP (n = 20 and 13, WNBP) and HBP (n = 12 and 8, WHBP)., Results: All four subject groups had distinct gut microbiota taxonomy by partial least squares discriminant analysis (PLS-DA). More importantly, linear discriminant analysis effect size showed marked differences in function of the microbiota of BHBP and WHBP (PLS-DA) with LDA scores <1. This included pathways for synthesis and interconversion of amino acids and inflammatory antigens. Similarly, metabolites differed (PLS-DA) with BHBP having significantly higher sulfacetaldehyde, quinolinic acid, 5-aminolevulinic acid, leucine and phenylalanine and lower 4-oxoproline and l-anserine., Discussion: Combination analyses of functional gut metabolic pathways and metabolomics data in this small pilot study suggest that BHBP may have greater oxidative stress markers in plasma, greater inflammatory potential of the gut microbiome and altered metabolites with gut microbial functions implying insulin resistance. A fuller understanding of these potential differences could lead to race-based treatments for hypertension., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11 C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11 C-PBR28. Total distribution volume (V T , proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression., Results: TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04-1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001-1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers., Conclusions: This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy. However, little is known about this interplay. This study was undertaken to examine the concept that altered autonomic-pulmonary communication is important in PH pathophysiology. Therefore, we hypothesize that activation of microglial cells in the paraventricular nucleus of hypothalamus and neuroinflammation is associated with increased sympathetic drive and pulmonary pathophysiology contributing to PH. We utilized the monocrotaline rat model for PH and intracerebroventricular administration of minocycline for inhibition of microglial cells activation to investigate this hypothesis. Hemodynamic, echocardiographic, histological, immunohistochemical, and confocal microscopic techniques assessed cardiac and pulmonary function and microglial cells. Monocrotaline treatment caused cardiac and pulmonary pathophysiology associated with PH. There were also increased activated microglial cells and mRNA for proinflammatory cytokines (IL [interleukin]-1β, IL-6, and TNF [tumor necrosis factor]-α) in the paraventricular nucleus. Furthermore, increased sympathetic drive and plasma norepinephrine were observed in rats with PH. Intracerebroventricular infusion of minocycline inhibited all these parameters and significantly attenuated PH. These observations implicate a dysfunctional autonomic-lung communication in the development and progression of PH providing new therapeutic targets, such as neuroinflammation, for PH therapy., (© 2018 American Heart Association, Inc.)

Plasticity, the capacity of an organism to respond to its environment, is thought to evolve through changes in development altering the integration of environmental cues. In polyphenism, a discontinuous plastic response produces two or more phenotypic morphs. Here we describe evolutionary change in wing polyphenism and its underlying developmental regulation in natural populations of the red-shouldered soapberry bug, Jadera haematoloma (Insecta: Hemiptera: Rhopalidae) that have adapted to a novel host plant. We find differences in the fecundity of morphs in both sexes and in adult expression of insulin signaling components in the gonads. Further, the plastic response of ancestral-state bugs can be shifted to resemble the reaction norm of derived bugs by the introduction of exogenous insulin or RNA interference targeting the insulin signaling component encoded by FoxO. These results suggest that insulin signaling may be one pathway involved in the evolution of this polyphenism, allowing adaptation to a novel nutritional environment.

Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R 2 = 0.5301, P <0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R 2 = 0.4608, P <0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)