Prostaglandin E2 stimulates sodium reabsorption in MDCK C7 cells, a principal cell model of the renal collecting duct (2023)

Mounting evidence has shown aldosterone generation in the collecting duct (CD), an important site for the synthesis and action of prostaglandin E.₂(PGE₂). Both aldosterone and PGE₂are stimulated by Na⁺exhaustion or K⁺charge or angiotensin II. However, whichever comes first and the correlation between PGE₂and aldosterone in the CD remains dark. PGE₂stimulates aldosterone release in adrenal zona glomerulosa cells via E-prostanoid (EP) receptors by activating the cAMP element-binding/cAMP-responsive pathway. Here, we further test the hypothesis that PGE stimulates aldosterone synthesis.₂in CD cells and the underlying mechanism. In mouse primary inner medullary CD cells, PGE₂incubation significantly stimulated aldosterone release in parallel with an increase in CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), expression of (pro)renin receptor (PRR) and prorenin protein and upregulation of Mean soluble PRR (sPRR), prorenin/renin, and cAMP levels, both attenuated by PE₁antagonist SC-19220 and the protein kinase C (PKC) inhibitor calfostin C. PGE₂The induced release of aldosterone, prorenin/renin, and sPRR was also abolished by the protein kinase A inhibitor H89. Both a PRR antagonist PRO20 and a β-catenin inhibitor ICG001 attenuated PGE₂or sPRR-induced aldosterone and prorenin/renin secretion. Incubation with exogenous sPRR protein not only stimulated aldosterone and prorenin/renin release, but also reversed aldosterone and prorenin/renin secretion attenuated by PF429242 (an inhibitor of subtilisin kexin isoenzyme-1, which can block endogenous generation from sPRR). Therefore, we conclude that PGE₂increases CD aldosterone synthesis via EP₁receptor via the PKC/cAMP/sPRR/β-catenin pathway.

Prostaglandin E₂(PGE₂) is a major lipid mediator involved in several biological processes, including immune responses and fluid secretion. As the host's first line of defense against infection, the vaginal epithelium plays orchestrated roles in vaginal innate immunity. However, the effect of PGE₂triggered by proinflammatory stimuli in the vaginal epithelium remains elusive. This study aimed to investigate the regulatory role of PGE₂in the vaginal epithelium after stimulation with lipopolysaccharide (LPS). RT-PCR and Western blot analysis revealed that E-prostanoid (EP) receptors EP2 and EP4 were expressed in the rat vagina. Basolateral application of PGE₂Cystic fibrosis transmembrane conductance regulator (CFTR)-mediated induced anion secretion via the EP-adenylate cyclase-cAMP signaling pathway in rat vaginal epithelial cells. The in vivo study showed that PGE₂promoted fluid secretion in the rat vagina. In addition, LPS stimulation facilitated cyclooxygenase-dependent PGE.₂synthesis and secretion of vaginal fluids in vivo. In conclusion, LPS stimulation elicited epithelium-derived PGE.₂production in the vaginal epithelium, leading to CFTR-mediated anion secretion and luminal redness. This study provides valuable information on the physiological role of PGE₂during vaginal bacterial infection.

Cardiovascular disease remains the leading cause of death worldwide, and hypertension is a major contributing factor to cardiovascular disease-associated mortality. At the population level, non-pharmacological approaches such as complementary/alternative medicine, including phytochemicals, have the potential to improve cardiovascular risk factors, including high blood pressure. Several epidemiological studies suggest an antihypertensive effect of garlic (Allium sativum) and many of its bioactive components. The aim of this review is to present an in-depth discussion on the molecular, biochemical and cellular rationales underlying the antihypertensive properties of garlic and its bioactive components, with a main focus on S-allylcysteine ​​and allicin. Key studies, mostly from PubMed, were selected and reviewed to develop a comprehensive understanding of the specific role of garlic and its bioactive components in the treatment of hypertension. We also review recent advances focused on the role of garlic bioactives, S-allylcysteine ​​and allicin, in the modulation of various parameters involved in the pathogenesis of hypertension. These parameters include oxidative stress, nitric oxide bioavailability, hydrogen sulfide production, angiotensin-converting enzyme activity, nuclear factor-κB expression, and vascular smooth muscle cell proliferation. This review suggests that garlic and garlic-derived bioactives have significant medicinal properties with the potential to ameliorate hypertension and associated morbidity; however, further clinical and epidemiological studies are required to fully determine the specific physiological and biochemical mechanisms involved in the prevention and management of the disease.

Human NHA2, a recently discovered cation proton antiporter, is implicated in essential hypertension by gene linkage analysis. We show that NHA2 mediates Na responsive to phloretin⁺-Li⁺countertransport activity (SLC), an established marker for hypertension. Unlike bacteria and fungi, where H⁺gradients drive uptake of metabolites, secondary transport at the plasma membrane of mammalian cells is coupled to Na⁺electrochemical gradient. Our findings challenge this paradigm by showing the coupling of NHA2 and H type V.⁺-ATPase in the plasma membrane of kidney-derived MDCK cells, resulting in a virtual Na⁺efflux pump Thus, NHA2 functionally recapitulates an ancient evolutionary origin shared with bacterial NhaA. Although the plasma membrane H⁺Gradients have been observed in some specialized mammalian cells, the ubiquitous tissue distribution of NHA2 suggests that H⁺-coupled transport is more widespread. The coexistence of Na⁺y H⁺Nucleotide-driven chemiosmotic circuits have implications for salt and pH regulation in the kidney.

Despite the identification twenty years ago of the gene responsible for cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis (CF), investigation of this monogenetic disease has not provided an explanation for the divergent symptoms. , and a breakthrough in treatment is still expected. expected This review looks at different aspects of the alterations in lipid metabolism seen in CF. These include increased release of arachidonic acid (AA) from cell membrane phospholipids and low status of linoleic and docosahexaenoic acids. Recent research has explored more complicated lipid associations. Alterations in annexins and ceramides could act in concert to explain the impact on inflammation and AA release. Connections with CFTR and between alterations in essential fatty acid metabolism are reviewed. Metabolic interactions, some of which might be compensatory, possibly explain the difficulties in understanding fatty acid disturbances in relation to different symptoms and their relationship to defective CFTR.

International Journal of Biological Macromolecules, Volume 69, 2014, pp. 532-541

Lung cancer, associated with upregulated epidermal growth factor receptor (EGFR), led to the development of EGFR-targeted cancer therapies. Biopolymeric nanoparticles form an exceptional system for the targeted delivery of therapeutic agents. The present work evaluated the in vitro effects of chitosan-crosslinked γ-polyglutamic acid (γ-PGA) nanoparticles (Nps) loaded with docetaxel (DTXL) and decorated with Cetuximab (CET), targeting non-overexpressing EGFRs. small cell lung cancer (NSCLC) cells (A549). CET-DTXL-γ-PGA Nps was prepared by ion gelation and CET conjugation by EDC/NHS chemistry. EGFR specificity of specific Nps was confirmed by the higher uptake rates of EGFR +ve A549 cells compared to EGFR -ve (NIH3T3) cells. Nps cytotoxicity quantified by cell-based (MTT/LDH) and flow cytometric assays (cell cycle analysis, annexin V/PI and JC-1) showed superior antiproliferative activity of CET-DTXL-γ-PGA Nps over DTXL-γ-PGA Nps. A549 cells treated with CET-DTXL-γ-PGA NP underwent G2/M phase cell cycle arrest followed by a reduction in the mitochondrial membrane potential of A549 cells, which induced apoptosis and necrosis, resulting in in increased death of cancer cells. CET-DTXL-γ-PGA Nps exhibited enhanced cellular internalization and therapeutic activity by actively targeting EGFR in NSCLC cells and thus could be an effective alternative to conventional non-specific chemotherapy by increasing its efficiency in many times.

Pulmonary Pharmacology & Therapeutics, Volume 28, Issue 1, 2014, pp. 68-76

Gene, Volume 627, 2017, pgs. 434-4

Kidney International, Volume 87, Number 2, 2015, pp. 382-395

Krüppel-like factor 2 (KLF2), a shear-inducible transcription factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular expression of Klf2 was reduced compared to non-diabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than in non-diabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothelial cells. To determine the role of KLF2 in streptozotocin-induced diabetic nephropathy, we used endothelial cell-specific Klf2 heterozygous knockout mice and found that diabetic knockout mice developed more renal/glomerular hypertrophy and proteinuria than wild-type diabetic mice. Glomerular expression of Vegfa, Flk1, and angiopoietin 2 was increased, but expression of Flt1, Tie2, and angiopoietin 1 was decreased in diabetic knockout mice compared with diabetic wild-type mice. The glomerular expression of ZO-1, glycocalyx, and eNOS was also decreased in diabetic knockout mice compared to diabetic wild-type mice. These data suggest that knockdown of Klf2 expression in endothelial cells induced more endothelial cell injury. Interestingly, podocyte injury was also more prominent in diabetic knockout mice compared to diabetic wild-type mice, indicating a cross-talk between these two cell types. Therefore, KLF2 may play a role in glomerular endothelial cell injury in early diabetic nephropathy.

Lung Cancer, Volume 107, 2017, pp. 1-13

Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an increasing number of drugs directed against a variety of specific tumor targets. Among these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are the most widely used. However, since only a sensitive subset of patients benefit from targeted drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker to predict the efficacy of therapy. Some of the TKIs and mAbs in clinical use can be radioactively labeled and used as markers. PET can visualize and quantify the tumor-specific uptake of radiolabeled targeted drugs, allowing characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET with radiolabeled TKIs (TKI-PET) and mAb (immuno-PET) in NSCLC is discussed, and an overview of the most relevant preclinical and clinical studies is provided.

Transplant Immunology, Volume 49, 2018, pp. 1-4

Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS) represent a powerful tool to identify causative genetic variants, through the simultaneous analysis of millions of single nucleotide polymorphisms scattered throughout the genome. GWAS in transplantation may indeed be useful in revealing new markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited, as already reflected in the fact that many parameters, significant in one study, cannot be confirmed in another.