Hypertension: A Continuing Public Healthcare Issue.

Hypertension is a cardiovascular disease defined by an elevated systemic blood pressure. This devastating disease afflicts 30-40% of the adult population worldwide. The disease burden for hypertension is great, and it greatly increases the risk of cardiovascular morbidity and mortality.

RNA Binding of GAPDH Controls Transcript Stability and Protein Translation in Acute Myeloid Leukemia.

Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukemia (AML) RBPs are key regulators of tumor proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear.

Long non-coding RNA GRASLND links melanoma differentiation and interferon-gamma response.

Melanoma is a highly malignant tumor, that stands as the most lethal form of skin cancer and is characterized by notable phenotypic plasticity and intratumoral heterogeneity. Melanoma plasticity is involved in tumor growth, metastasis and therapy resistance. Long non-coding RNAs (lncRNAs) could influence plasticity due to their regulatory function.

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats.

All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease.

CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis.

Unlabelled: Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy.

Profiling Cellular Morphological Changes Induced by Dual-Targeting PROTACs of Aurora Kinase and RNA-Binding Protein YTHDF2.

Proteolysis targeting chimeras (PROTACs) are new chemical modalities that degrade proteins of interest, including established kinase targets and emerging RNA-binding proteins (RBPs). Whereas diverse sets of biochemical, biophysical and cellular assays are available for the evaluation and optimizations of PROTACs in understanding the involved ubiquitin-proteasome-mediated degradation mechanism and the structure-degradation relationship, a phenotypic method profiling the cellular morphological changes is rarely used. In this study, first, we reported the only examples of PROTACs degrading the mRNA-binding protein YTHDF2 via screening of multikinase PROTACs.

Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis.

Introduction: Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model.

Methods: Male mice went through either UUO or sham surgery.

Kidney Injury by Unilateral Ureteral Obstruction in Mice Lacks Sex Differences.

Introduction: Renal fibrosis is a critical event in the development and progression of chronic kidney disease (CKD), and it is considered the final common pathway for all types of CKD. The prevalence of CKD is higher in females; however, males have a greater prevalence of end-stage renal disease. In addition, low birth weight and low nephron number are associated with increased risk for CKD.

Integrative CRISPR Activation and Small Molecule Inhibitor Screening for lncRNA Mediating BRAF Inhibitor Resistance in Melanoma.

The incidence of melanoma, being one of the most commonly occurring cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. The conventional targeted therapy is well defined and effective for advanced-stage melanomas for patients not responding to the standard-of-care immunotherapy.

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension.

Hypertension characterized by an elevated blood pressure is a cardiovascular disease that afflicts greater than one in every three adults worldwide. Nuclear receptors are large superfamily of DNA-binding transcription factors that target genes to regulate metabolic and cardiovascular function. Drugs have been developed for nuclear receptors such as peroxisome proliferator-activated receptors (PPARα and PPARγ) and farnesoid X receptor (FXR).

Bioactive lipids in hypertension.

Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction.

Salt-sensitive hypertension after reversal of unilateral ureteral obstruction.

The incidence of ureter obstruction is increasing and patients recovering from this kidney injury often progress to chronic kidney injury. There is evidence that a long-term consequence of recovery from ureter obstruction is an increased risk for salt-sensitive hypertension. A reversal unilateral ureteral obstruction (RUUO) model was used to study long-term kidney injury and salt-sensitive hypertension.

Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury.

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression.

Altered BAF occupancy and transcription factor dynamics in PBAF-deficient melanoma.

ARID2 is the most recurrently mutated SWI/SNF complex member in melanoma; however, its tumor-suppressive mechanisms in the context of the chromatin landscape remain to be elucidated. Here, we model ARID2 deficiency in melanoma cells, which results in defective PBAF complex assembly with a concomitant genomic redistribution of the BAF complex. Upon ARID2 depletion, a subset of PBAF and shared BAF-PBAF-occupied regions displays diminished chromatin accessibility and associated gene expression, while BAF-occupied enhancers gain chromatin accessibility and expression of genes linked to the process of invasion.

Multi-Target Drugs for Kidney Diseases.

Kidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets.

SARS-CoV-2 spike protein causes cardiovascular disease independent of viral infection.

The SARS-CoV-2 virus that results in COVID-19 has been found to damage multiple organs beyond the lung. Interestingly, the SARS-CoV-2 spike (S) protein can be found circulating in the blood of COVID-19 patients. Experimental findings are demonstrating that the circulating S protein can bind to receptors resulting in inflammation and cell, tissue, and organ damage.

Synthesis and evaluation of RNase L-binding 2-aminothiophenes as anticancer agents.

Aminothiophene is a scaffold that is widely present in drugs and biologically active small molecules as chemical probes. In this study, 43 compounds sharing a 2-aminothiophenone-3-carboxylate (ATPC) scaffold, known to activate the ribonuclease L (RNase L), were synthesized and selected ATPCs showed enhancement of thermal stability of RNase L upon binding. Screening of antiproliferation activities against human cancer cell lines revealed that ATPCs represented by compounds 4l and 50 showed potent single-digit micromolar antiproliferation activity against human cancer cell lines.

Epoxyeicosatrienoic Acid Analog and 20-HETE Antagonist Combination Prevent Hypertension Development in Spontaneously Hypertensive Rats.

Numerous studies indicate a significant role for cytochrome P-450-dependent arachidonic acid metabolites in blood pressure regulation, vascular tone, and control of renal function. Epoxyeicosatrienoic acids (EETs) exhibit a spectrum of beneficial effects, such as vasodilatory activity and anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that inhibits sodium reabsorption in the kidney.

Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath.

Introduction: In COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB ≫ PGE > PGD in the lungs, and 11-dehydro-TxB, a TxA metabolite, in the systemic circulation. While TxA stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA/TP and PGD/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization.

Dual sEH/COX-2 Inhibition Using PTUPB-A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity.

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects.