Farrellvelazquez9761

The kidney is one of the major targets of the RAS, which is responsible in maintaining fluid, electrolyte balance, and blood pressure. In this review we will discuss the role of AT1Rs in the kidney, vasculature, and immune cells and address their effects on hypertension and kidney disease.The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), has been identified as the receptor for the SARS-CoV-2. Several RAS components including ACE2 and its substrate Ang II are present in both eye and skin, two stratified squamous epithelial tissues that isolate organisms from external environment. Our recent findings in cornea and others in both skin and eye suggest contribution of this system, and specifically of ACE2 in variety of physiological and pathological responses of these organ systems. This review will focus on the role RAS system plays in both skin and cornea, and will specifically discuss our recent findings on ACE2 in corneal epithelial inflammation, as well as potential implications of ACE2 in patients with COVID-19.Long non-coding RNAs (lncRNAs) are a large and diverse class of RNA molecules that are transcribed but not translated into proteins, with a length of more than 200 nucleotides. LncRNAs are involved in gene expression and regulation. The abnormal expression of lncRNAs is associated with disease pathogenesis. Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that plays a pivotal role in many biological processes by acting as a transcriptional repressor. In this review, we present the critical roles of SHP and summarize recent findings demonstrating the regulation between lncRNAs and SHP in liver disease.Parathyroid hormone-related peptide (PTHrP) exerts its effects on cells derived from colorectal cancer (CRC) and tumor microenvironment and is involved in processes requiring the epithelial-mesenchymal transition (EMT). Here, we report that PTHrP modulates factors expression and morphological changes associated with EMT in HCT116 cells from CRC. PTHrP increased the protein expression of SPARC, a factor involved in EMT, in HCT116 cells but not in Caco-2 cells also from CRC but with less aggressiveness. PTHrP also increased SPARC expression and its subsequent release from endothelial HMEC-1 cells. The conditioned media of PTHrP-treated HMEC-1 cells induced early changes related to EMT in HCT116 cells. Moreover, SPARC treatment on HCT116 cells potentiated PTHrP modulation in E-cadherin expression and cell migration. In vivo PTHrP also increased SPARC expression and decreased E-cadherin expression. These results suggest a novel PTHrP action on CRC progression involving the microenvironment in the modulation of events associated with EMT.Impactors have hit the Earth since its formation and have continued to be infrequent guests throughout the Earth's history. Although the early part of the Earth's history was marked by these violent events, life was present early, possibly existing already in the Hadean Eon. It is possible that life has been, and still is, transported between the worlds of the solar system, owing to impacts leading material away from the impact region. Beyond this lithopanspermia hypothesis, in the so-called 'refugium hypothesis', ejected material has been suggested to also return to its home planet and 'reseed' life after the world has recovered after a global impactor, thus restarting evolution. In addition to such impactors, more frequent impacts from smaller non-sterilizing impactors existed during the Heavy Bombardment epoch, feeding material potentially harbouring viable organisms into near Earth space. During the three stages of planetary self-reseeding, the encapsulated microbial population experiences abiotic stresso of planetary self-reseeding can themselves be considered facilitators of a process that enhances the stress capacity of the collected microbial organisms and thus their survival capacity. This process may have played a role in the survival of life through violent periods of Earth's history and thus may affect inhabited worlds in general.Recent overarching frameworks propose that various human social interactions are commonly supported by a set of fundamental neuropsychological processes, including social cognition, motivation, and cognitive control. However, it remains unclear whether brain networks implicated in these functional constructs are consistently engaged in diverse social interactions. Based on ample evidence from human brain imaging studies (342 contrasts, 7234 participants, 3328 foci), we quantitatively synthesized brain areas involved in broad domains of social interactions, including social interactions versus non-social contexts, positive/negative aspects of social interactions, social learning, and social norms. We then conducted brain network analysis on the ensuing brain regions and characterized the psychological function profiles of identified brain networks. Our findings revealed that brain regions consistently involved in diverse social interactions mapped onto default mode network, salience network, subcortical network and central executive network, which were respectively implicated in social cognition, motivation and cognitive control. These findings implicate a heuristic integrative framework to understand human social life from the perspective of component process and network integration.

Inflammation plays a key role in peripheral nerve adhesion and often leads to severe pain and nerve dysfunction. PRI-724 Minocycline was reported to have potent anti-inflammatory effects and might be a promising drug to prevent or attenuate peripheral nerve adhesion. The present study aimed to clarify whether minocycline contributes to nerve adhesion protection and its underlying mechanism.

Rats with sciatic nerve adhesion induced by glutaraldehyde glue (GG) were intraperitoneally injected with minocycline or saline every 12h for 7 consecutive days. After that, the adhesion score, Ashcroft score, demyelination, macrophage polarization and inflammatory factors in peripheral nerve adhesion tissues or tissues in sham group were determined with histological staining, western blot and real time-PCR. Murine macrophage RAW264.7 cells were stimulated by LPS alone or together with minocycline at different concentrations and time duration to study the mechanism of minocycline in alleviating nerve adhesion.

We found that minocycline treatment reduced the adhesion score, Ashcroft score, the growth of scar tissue, demyelination, and macrophage recruitment. Moreover, minocycline significantly and dose-dependently promoted regulatory macrophage polarization but decreased pro-inflammatory macrophage polarization. Furthermore, mechanism studies showed that TAK1 and its downstream pathway p38/JNK/ERK1/2/p65 were inhibited by minocycline, which led to lower IL-1β and TNFα expression, but increased IL-10 expression.

Altogether, these results suggest that minocycline is highly effective against peripheral nerve adhesion through anti-fibrosis, anti-inflammation, and myelination protection, making it a highly promising candidate for treating adhesion-related disorders.

Altogether, these results suggest that minocycline is highly effective against peripheral nerve adhesion through anti-fibrosis, anti-inflammation, and myelination protection, making it a highly promising candidate for treating adhesion-related disorders.

Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored.

To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R).

Langendorff-perfused rabbit hearts were subjected to 30min of complete perfusion arrest and reperfusion. Either EMPA (1μM) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting.

Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction 16.7±3.3% vs. 60±8.7% in control hearts, p=0.003), improvement of LV developed pressure (LVDP; 68.10±9.02% vs. 47.61±5.15% in controls, p=0.03) and reduction of NADH fluorescence (87.42±2.79% vs. 112.88±2.27% in control hearts, p=0.04) along with an increase in NAD+/NADH ratio (2.75±0.55 vs. 1.09±0.32 in the control group, p=0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42±0.1Hz vs. 4.75±0.1Hz in controls, p=0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues.

EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.

EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.

MicroRNAs are well-established players in post-transcriptional gene modulation. We aim to explore the role of microRNA-15a-5p (miR-15a-5p)/sex determining region Y-box 9 (Sox9)/nuclear factor-κB (NF-κB) axis in inflammation and apoptosis of murine nucleus pulposus cells (NPCs) in intervertebral disc degeneration (IVDD).

Expression levels of miR-15a-5p and Sox9 in disc tissues from IVDD patients were determined. The IVDD mouse models were established by disc puncture, and the modeled mice were accordingly injected with miR-15a-5p antagomir and/or overexpressed Sox9 plasmid, or their negative controls. Then, the expression of miR-15a-5p, Sox9 and p-p65, pathological changes and the apoptosis of NPCs in IVDD mouse intervertebral disc tissues were measured. The NPCs were isolated and cultured, which were then transfected with miR-15a-5p inhibitor, overexpressed or silenced Sox9 plasmids, or the NCs. Next, the expression of miR-15a-5p and Sox9, apoptosis, proliferation and cell cycle distribution of NPCs, and the contents of inflammatory factors in the NPCs were evaluated.