Effect of the renal natriuretic peptide, ularitide, alone or combined with Vasopeptidase inhibitor, Omapatrilat, on experimental volume overloadinduced congestive heart failure in rats (Ularitide/ Omapatrilat in Congestive Heart Failure)

Introduction: Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF).Aim: This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) – induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity).Experimental protocol: Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium (FNa), absolute urinary sodium excretion (UNaV), urine volume, plasma cystin C level and urinary cyclic 30, 50-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded.Results: Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival.Conclusion: OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF.Keywords: Congestive heart failure; Aorto-caval fistula; Ularitide; Omapatrilat; Renin-angiotensin system; Vasopeptidase inhibitio

Promoting effect of adipocytokine, apelin, on hepatic injury in caerulein-induced acute pancreatitis in rats Apelin on AP-induced hepatic injury

Objective: To evaluate the potential apelin effect on hepatic injury in caerulein (Cn) - induced AP in rats.Experimental protocol: Thirty male albino rats were divided into three groups, 10 rats each: control group: received 0.9% NaCl solution. AP group: received (Cn, 50 lg/kg/h, i.p.) for 6 h. Apelin-13 treated AP group: received apelin 13, 50 nmol/kg/h, i.p, immediately after each Cn injection, starting after the second Cn dose. 12 h after the last Cn injection, the rats were sacrificed, and serum amylase, lipase, phospholipase A2 (PLA2), interleukin (IL)-6, IL-1b, IL-10, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase activity (LDH) were assayed. The hepatic malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels, caspase-3 activity and tumor necrosis factor-alpha (TNF-a) were assessed, while myeloperoxidase (MPO) was determined in pancreatic and hepatic tissues.Results: Cn injection caused severe AP, with marked hepatic damage. The exogenous apelin reduced Cn-induced pancreatic and hepatic injury with reduction in hepatic oxidative, apoptotic and inflammatory markers, pancreatic and hepatic MPO activity with modulation of inflammatory cytokines.Conclusion: Apelin could be protective in AP associated liver damage, possibly through antioxidant, anti-apoptotic mechanisms with modulating the inflammatory mediators

New treatment paradigm of combined raloxifene and conjugated estrogen for postmenopausal symptoms in VCD-ind

Introduction: The decreased ovarian estrogen production that occurs at menopause, results in osteoporosis and climacteric manifestations, and decreases women’s quality of life. The hormone replacement therapy (HRT) is the primary treatment options but has been associated with increased oncogenic potential. The tissue selective estrogen complex (TSEC) is a novel therapy, partnering a selective estrogen receptor modulator (SERM) with one or more estrogens. Aim: Our study was done to evaluate the potential relative estrogenic agonist activities of a SERM, raloxifene (RLX), when dosed alone and its antagonist activities when paired with conjugated estrogen (CE), as a TSEC and its potential use for the postmenopausal osteoporosis, vulvar/vaginal atrophy (VVA) in VCD induced menopausal rat model. Material and methods: Female rats were dosed daily with 4-vinylcyclohexene diepoxide (VCD) (80 mg/kg/d, IP) for 15 days to induce ovarian failure, followed by one month free drug. VCD injected rats received 12 weeks of RLX, CE, or combined RLX/CE with 17β-estradiol (E2), vehicle treated groups used as positive and negative controls, respectively. The bone turnover markers (BTM) were measured. The uterotropic activity was assessed by the uterine index and peroxidase assay. Vaginal wet weight (wt.) and glycogen were measured to evaluate the vaginotropic effects. Uterine and vaginal (ER) protein levels were assayed. Results: Our findings showed that the appropriate RLX/CE dose combination exhibits significant bone sparing with minimal vaginal stimulation and neutral uterine effect. Conclusion: We can conclude that appropriate RLX/CE combination could effectively be a promising alternative for the prevention of postmenopausal osteoporosis and VVA with no oncogenic risk

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis

Diabetic neuropathic pain (DNP) is a common diabetic complication that currently lacks an efficient therapy. The aim of the current work was to uncover the anti-allodynic and neuroprotective effects of memantine in a model of mouse diabetic neuropathy and its ameliorative effect on the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/nuclear factor-k B (NF-kB) inflammatory axis. Diabetes was prompted by an alloxan injection (180 mg/kg) to albino mice. On the ninth week after diabetes induction, DNP was confirmed. Diabetic mice were randomly allocated to two groups (six mice each); a diabetes mellitus (DM) group and DM+memantine group (10 mg/kg, daily) for five weeks. DNP-related behaviors were assessed in terms of thermal hyperalgesia and mechanical allodynia by hot-plate and von Frey filaments. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure the spinal glutamate, interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α). The spinal levels of N-methyl-D-aspartate type 1 receptor (NMDAR1), HMGB1, TLR4, and phosphorylated NF-kB were assessed using Western blotting. Histopathological investigation of the spinal cord and sciatic nerves, together with the spinal cord ultrastructure, was employed for assessment of the neuroprotective effect. Memantine alleviated pain indicators in diabetic mice and suppressed excessive NMDAR1 activation, glutamate, and pro-inflammatory cytokine release in the spinal cord. The current study validated the ability of memantine to combat the HMGB1/TLR4/NF-kB axis and modulate overactive glutamate spinal transmission, corroborating memantine as an appealing therapeutic target in DNP

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM’s antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity