Citations

Abstract BACKGROUND Renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS) as well. Coexisting MetS and hypertension increases cardiovascular morbidity and mortality, but the mechanisms underlying cardiac injury remain unknown. We hypothesized that superimposition of MetS induces myocardial mitochondrial damage, leading to cardiac injury and dysfunction in swine RVH. METHODS Pigs were studied after 16 weeks of diet-induced MetS with or without RVH (unilateral renal artery stenosis), and Lean controls (n = 6 each). Systolic and diastolic cardiac function were assessed by multidetector CT, and cardiac mitochondrial morphology (electron microscopy) and myocardial function in tissue and isolated mitochondria. RESULTS Body weight was similarly higher in MetS groups vs. Lean. RVH groups achieved significant stenosis and developed hypertension. Mitochondrial matrix density and adenosine triphosphate production were lower and H2O2 production higher in RVH groups vs. Lean and MetS. Lean + RVH (but not MetS + RVH) activated mitophagy, which was associated with decreased myocardial expression of mitophagy-related microRNAs. MetS groups exhibited higher numbers of intermitochondrial junctions, which could have prevented membrane depolarization/activation of mitophagy in MetS + RVH. Cardiac fibrosis, hypertrophy (increased left ventricular muscle mass), and diastolic function (decreased E/A ratio) were greater in MetS + RVH vs. Lean + RVH. CONCLUSIONS MetS+RVH induces myocardial mitochondrial damage and dysfunction. MetS + RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and therapeutic targets to ameliorate cardiac damage and dysfunction in patients with coexisting MetS and RVH.

Abstract The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, ‘improving efficiency’, ‘improving planning and delivery’, ‘improving imaging’, and ‘improving patient selection’.

The microbiome plays an important role in human health by mediating the path from environmental exposures to health outcomes. The relative abundances of the high‐dimensional microbiome data have an unit‐sum restriction, rendering standard statistical methods in the Euclidean space invalid. To address this problem, we use the isometric log‐ratio transformations of the relative abundances as the mediator variables. To select significant mediators, we consider a closed testing‐based selection procedure with desirable confidence. Simulations are provided to verify the effectiveness of our method. As an illustrative example, we apply the proposed method to study the mediation effects of murine gut microbiome between subtherapeutic antibiotic treatment and body weight gain, and identify Coprobacillus and Adlercreutzia as two significant mediators.

The cross-talk between apoptosis and autophagy influences anticancer drug sensitivity and cellular death in various cancer cell lines. However, the fundamental mechanisms behind this phenomenon are still unidentified. We demonstrated anti-cancerous role of cisplatin (CP) and morin hydrate (Mh) as an individual and/or in combination (CP-Mh) in hepatoma cells and tumor model. Exposure of CP resulted in the production of intracellular reactive oxygen species (ROS)-mediated cellular vacuolization, expansion of mitochondria membrane and activation of endoplasmic reticulum (ER)-stress. Consequently, Cyt c translocation led to the increase of Bax/Bcl-2 ratio, which simultaneously triggered caspase-mediated cellular apoptosis. In addition, CP-induced PARP-1 activation led to ADP-ribosylation of HMGB1, which consequently developed autophagy as evident by the LC3I/II ratio. Chemically-induced inhibition of autophagy marked by increased cell death signified a protective role of autophagy against CP treatment. CP-Mh abrogates the PARP-1 expression and significantly reduced HMGB1-cytoplasmic translocation with subsequent inhibition of the HMGB1-Beclin1 complex formation. In the absence of PARP-1, a reduced HMGB1 mediated autophagy was observed followed by induced caspase-dependent apoptosis. To confirm the role of PARP-1-HMGB1 signaling in autophagy, we used the PARP-1 inhibitor, 4-amino-1,8-naphthalimide (ANI), HMGB1 inhibitor, ethyl pyruvate (EP), autophagy inhibitors, 3-methyl adenine (3-MA) and bafilomycin (baf) and small interfering RNAs (siRNA) to target Atg5 in combination of CP and Mh. Exposure to these inhibitors enhanced the sensitivity of HepG2 cells to CP. Collectively, our findings indicate that CP-Mh in combination served as a prominent regulator of autophagy and significant inducer of apoptosis that maintains a homeostatic balance towards HepG2 cells and the subcutaneous tumor model.

Hypoplastic left heart syndrome (HLHS) is a single ventricle congenital heart disease that results in severe underdevelopment of the left ventricle, mitral valve, aortic valve, and ascending aorta. Early serial postmortem examinations also revealed a high rate of coronary anomalies in HLHS, which included multiple ventriculo-coronary arterial connections as well as thick-walled and kinked coronary arteries. A previous study showed that fetal hypoplastic left hearts had a reduced endothelial cell (EC) population and lower capillary density compared with normal hearts. However, the mechanism underlying coronary abnormalities associated with HLHS remains unknown. Thus, we generated induced pluripotent stem cells derived ECs (iPSC-ECs) from three HLHS patients and three age-matched controls. Single Cell RNA-Seq (scRNA-seq) profiling identified both endocardial (NPR3 + /CDH5 + ) and coronary endothelial populations (APLN + /CDH5 + ) from the heterogeneous iPSC-ECs. Intriguingly, a subcluster of the coronary endothelial cells (CECs) with cell cycle arrest was specifically enriched in HLHS patients. Further cell cycle analysis showed that 30.6% of the HLHS cells were trapped in the G1 phase, while the majority of the control CECs entered cell cycle normally. Additionally, the cell cycle differences between control and HLHS was only seen in CECs, not in the endocardial population. To verify our transcriptomic analysis, we applied negative cell sorting (NPR3 - /CDH5 + ) on iPSC-ECs to purify CECs (iCECs) and confirmed that HLHS iCECs showed profound reduction of cell cycle/proliferative genes ( KI67, PCNA, CCNA2, CCNB1 ) and abnormal induction of CCND2 , which is the hallmark of G1 phase. BrdU assays also indicated suppressed proliferation in HLHS iCECs. Furthermore, we profiled the transcriptome from a human heart with an underdevelopment left ventricle (ULV) at single cell resolution. When compared to the normal human heart, pathway enrichment analysis of differentially expressed genes in ULV hearts demonstrated reduced cell proliferation in the CEC subpopulation. Here, we identified that CECs from HLHS patients exerted proliferative defects that can potentially impede the development of vascular/capillary structure and cause related functional deficiencies. Reformation of the coronary defect provides a promising therapeutic strategy to prevent HLHS deterioration.

AbstractBackground and AimMuscularis macrophages (MMs) not only mediate the innate immunity, but also functionally interact with cells important for gastrointestinal motility. The aim of this study was to determine the spatial relationship and types of contacts between the MMs and neighboring cells in the muscularis propria of human and mouse stomach, small intestine, and large intestine.MethodsThe distribution and morphology of MMs and their contacts with other cells were investigated by immunohistochemistry and transmission electron microscopy.Key ResultsImmunohistochemistry showed variable shape and number of MMs according to their location in different portions of the muscle coat. By double labeling, a close association between MMs and neighboring cells, that is, neurons, smooth muscle cells, interstitial cells of Cajal (ICCs), telocytes (TCs)/PDGFRα‐positive cells, was seen. Electron microscopy demonstrated that in the muscle layers of both animal species, MMs have similar ultrastructural features and have specialized cell‐to‐cell contacts with smooth muscle cells and TCs/PDGFRα‐positive cells but not with ICCs and enteric neurons.Conclusion & InferencesThis study describes varying patterns of distribution of MMs between different regions of the gut, and reports the presence of distinct and extended cell‐to‐cell contacts between MMs and smooth muscle cells and between MMs and TCs/PDGFRα‐positive cells. In contrast, MMs, although close to ICCs and nerve elements, did not make contact with them. These findings indicate specialized and variable roles for MMs in the modulation of gastrointestinal motility whose significance should be more closely investigated in normal and pathological conditions.