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The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1–7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1–7)/MasR axis. However, due to the reported toxicity of DA, its application has been limited. In the current study, we synthesized a low toxicity DA derivative 3 (DAD3) and sought to determine whether DAD3 can also activate ACE2 in bovine mammary epithelial cells (BMEC) and regulate the RAS system to inhibit inflammation. We found that both DA and DAD3 can activate and promote ACE2 expression in BMEC. iRNA-mediated knockdown of ACE2 demonstrated that DAD3 activates the ACE2/Ang-(1–7)/MasR axis and plays an anti-inflammatory role in BMEC. Furthermore, the inhibitory effects of DA and DAD3 on the protein phosphorylation of MAPK and NF-κB pathways were reduced in ACE2-silenced BMEC. Our findings show that ACE2 is a target of DAD3, which leads to inhibition of the MAPK and NF-κB signalling pathways and protects against LPS-induced inflammation in BMEC. Thus, DAD3 may provide a new strategy to treat dairy cow mastitis.

The association between gut microbiota imbalance and depression is well known; however, its underlying mechanisms remain unclear. Angiotensin (Ang)-converting enzyme 2 (ACE2) transforms Ang II into Ang (1–7), which exerts antidepressant effects via the Mas receptor (MasR). However, the role of ACE2 in dysbiosis-related depression in the brain remains unclear. In this study, we assessed changes in brain ACE2 expression and whether diminazene aceturate (DIZE), an ACE2 activator, alleviates depression-like behavior in an antibiotic-induced (ABX) dysbiosis mouse model. The tail suspension test revealed depression-like behavior in ABX mice. Western blotting and immunohistochemistry revealed decreased expression levels of ACE2, Ang (1–7), p-CAMKII, p-CREB, BDNF, synaptophysin, p-PPARγ, CD206, TREM2, and IL-10 and reduced neurogenesis in the dentate gyrus of the hippocampus. Iba1, CD86, iNOS, IL-1β, TNF-α, and cleaved caspase-3 levels were increased, indicating microglial activation in the hippocampus. MasR staining was observed in neurons and microglia in the hippocampus of ABX mice. Furthermore, p-CAMKII and p-CREB staining was observed in neurons, while p-PPARγ staining was observed in microglia in the hippocampus of ABX mice treated with DIZE. DIZE administration prevented ABX-induced changes, whereas the effects of DIZE were abolished by co-administration with A779, a MasR inhibitor. These findings suggest that hippocampal ACE2 expression plays a crucial role in dysbiosis-related depression associated with gut microbiota imbalance, potentially offering a target for therapeutic interventions.

Background Retinal inflammation is a devastating pathological process in ocular diseases. Functional impairment of retinal pigment epithelium (RPE) is associated with inflammatory retinal diseases. Enhancing the protective axis namely ACE2/Ang-(1-7)/Mas by activation of ACE2 presents anti-inflammatory properties. We investigated whether diminazene aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, prevented lipopolysaccharide (LPS)-induced inflammatory response by activating the protective axis and whether the effect was mediated by inhibiting the mitogen-activated protein kinase (MAPK) and the nuclear factor-κB (NF-κB) pathways. Methods Cell counting kit-8 (CCK-8) assay and real-time PCR were used to determine the optimum concentration and incubation time of DIZE. ARPE-19 cells and primary cultured human retinal pigment epithelia (hRPE) were incubated with or without 10 μg/mL DIZE for 6 h before stimulated with 5 μg/mL LPS for 24 h. The mRNA expression of inflammatory cytokines, AT1R, and AT2R was analyzed. The protein level of inflammatory cytokines, Ang II, and Ang-(1-7) was detected. Phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphorylated transcription inhibition factor-κB-α (p-IκB-α) were measured. Inhibitors of MAPKs and NF-κB were added to verify the involvement of these pathways. A small interfering RNA (siRNA) targeted to ACE2 and a selective Ang-(1-7) antagonist A779 was used to confirm the role of ACE2 and the involvement of ACE2/Ang-(1-7)/Mas axis. Results DIZE remarkably increased the expression of ACE2 and inhibited the expression of IL-6, IL-8, and MCP-1 at both mRNA and protein levels in both RPE cell lines stimulated with LPS. Inhibitors of p38, ERK1/2, JNK, and NF-κB significantly decreased LPS-induced overproduction of IL-6, IL-8, and MCP-1. DIZE reduced the expression of Ang II and AT1R, whereas increased Ang-(1-7). Furthermore, DIZE downregulated the phosphorylation of p38MAPK, ERK1/2, JNK, and the activation of NF-κB upon stimulation with LPS. Downregulating ACE2 and pre-treatment with A779 abrogated the effects of DIZE on production of cytokines, the expression of Ang II, Ang-(1-7), AT1R, phosphorylation of MAPKs and activation of NF-κB. Conclusions DIZE inhibits LPS-induced inflammatory response by activating ACE2/Ang-(1-7)/Mas axis in human RPE cells. The protective effect is mediated by inhibiting the p38MAPK, ERK1/2, JNK, and NF-κB pathways.

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.

The efficacy of diminazene aceturate in three Nigerian breeds of sheep [West African Dwarf (WAD), Yankassa and Ouda] experimentally infected with Trypanosoma vivax was studied. Five rams of each breed were administered 0.5 ml of goat blood containing 2.5 × 106T. vivax per millilitre intravenously, while three rams of each breed served as uninfected controls. The treatment with diminazene aceturate was intramuscularly administered to the infected sheep, when their packed cell volume (PCV) fell to 15 %, at a dosage of 7 mg.kg−1 b. w. The parameters measured were parasitaemia, live weight gain and PCV. By 24 hours post treatment (pt.), no trypanosomes were detected by either the Haematocrit Concentration Technique (HCT) or the Polymerase Chain Reaction (PCR) in the blood of any of the treated sheep. However, a relapse of parasitaemia occurred 17 to 32 days pt. in 46.7 % of the treated rams and these were retreated with 14 mg.kg−1 b. w. diminazene aceturate. There were gradual increments in the live weight gain and the PCV of the treated rams until the resurgence of parasitaemia. Ouda had the highest cases of relapse (80 %), the least mean live weight gain and was the only breed in which mortality was recorded despite the treatment. In conclusion, diminazene aceturate administered at 7 mg.kg−1 b. w. cleared the trypanosomes in the blood of all the treated sheep within 24 hours and this was accompanied by the restoration of lost weight and the reversal of anaemia. However, the subsequent resurgence of parasitaemia indicated that a dosage of 7 mg.kg−1 b. w. was no longer reliable for complete elimination of trypanosomes from all the tissues of the host.

Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.

The implication of the tissue-localized renin-angiotensin system (RAS) in the pathogenesis of osteoarthritis (OA) has been documented in the last decades. A combination of intraarticular (IA) corticosteroid and hyaluronic acid (HYAL) is approved for pain relief in patients with mild to moderate OA. Combining HYAL with an activator of angiotensin-converting enzyme 2, diminazen aceturate (DIZE), was evaluated in this study for its therapeutic potential. Monosodium iodoacetate was used to induce OA. The effects of daily administration of DIZE versus once-per-week IA injection of HYAL and a combination of both drugs for 21 days on OA deformities in rats’ knees were observed. Evaluation of motor activities, pain, and inflammatory response was done using rotarod, knee bend, and knee swelling tests. RAS components, inflammatory biomarkers, and oxidative stress mediators were measured in the knee joint. X-ray radiological examination and histopathological investigations were used to assess joint degeneration and regeneration. Levels of both inflammatory and oxidative markers in knee joint homogenate of OA rats rose, and these increments were mostly improved by the three therapies with a more prominent effect of the drug combination, an effect that was also reflected in the behavioral tests. RAS markers have shown better responsiveness to the combination therapy over both drugs individually, showing a pronounced increase in the angiotensin 1–7 amount. Both radiological and histopathology investigations came to confirm the biochemical results, nominating a combination of HYAL and DIZE as a possible therapeutic option for OA.

Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N1-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI.

Trypanosomosis is a serious constraint to livestock productivity in sub-Saharan Africa. Chemotherapy which is the main means of control is unsatisfactory because of drug resistance and toxicity. Thus, the search for alternative antitrypanosomal agents has become imperative. The study was aimed at evaluating the effects of astaxanthin alone or in combination with diminazene aceturate (DZ) on parasitaemia and haematological parameters in Trypanosoma brucei brucei –infected Wistar rats. Eighty Wistar rats were divided into eight groups of ten rats each and treated as follows: I, DW (uninfected and treated with distilled water); II, S/OIL (uninfected and treated with soya oil); III, T (infected with 10 6 trypanosomes/mL); IV, PreA [pretreated with astaxanthin (100 mg/kg)] + T; V, PreA + T + DZ (3.5 mg/kg); VI, T + A (astaxanthin); VII, T + A + DZ; VIII, T + DZ. Parasitaemia was monitored daily, and blood was collected for evaluation of haematological parameters at the end of the experiment. Parasitaemia increased progressively in the T, PreA + T and T + A groups till the termination of the experiment, but was lower ( P  < 0.05) in the PreA group alone, compared to the T and T + A groups at days 6 and 8. There was a resurgence of parasitaemia in 10% of rats in the T + A + DZ group at day 7 post-treatment. The red blood cell counts, PCV and haemoglobin concentration were higher ( P  < 0.05), but lower neutrophil and total leucocyte counts ( P  < 0.05) in PreA and/or DZ groups compared to the T and T + A groups. Rats in the T and T + A groups had higher ( P  < 0.05) erythrocytic indices. Pre-treatment with astaxanthin and/or diminazene aceturate was more effective than post-treatment in decreasing parasitaemia and ameliorating the anaemia caused by T. brucei brucei infection in Wistar rats.

Introduction: Histone post-translational modification is one of the most studied factors influencing epigenetic regulation of protozoan parasite gene expression, which is mediated by histone deacetylases (KDACs) and acetyltransferases (KATs). Objective and methods: The present study investigated the role of resveratrol (RVT) as an activator of histone deacetylases in the control of various pathogenic Babesia sp. and Theileria equi in vitro , as well as B. microti infected mice in vivo using fluorescence assay. Its role in mitigating the side effects associated with the widely used antibabesial drugs diminazene aceturate (DA) and azithromycin (AZM) has also been investigated. Results: The in vitro growth of B. bovis , B. bigemina , B. divergens , B. caballi and Theileria equi ( T. equi ) was significantly inhibited (P < 0.05) by RVT treatments. The estimated IC50 values revealed that RVT has the greatest inhibitory effects on B. bovis growth in vitro , with an IC50 value of 29.51 ± 2.46 µM. Reverse transcription PCR assay showed that such inhibitory activity might be attributed to resveratrol’s stimulatory effect on B. bovis KDAC3 (BbKADC3) as well as its inhibitory effect on BbKATS. RVT causes a significant decrease (P < 0.05) in cardiac troponin T (cTnT) levels in heart tissue of B. microti - infected mice, thereby indicating that RVT may play a part in reducing the cardiotoxic effects of AZM. Resveratrol showed an additive effect with imidocarb dipropionate in vivo . Treatment of B. microti -infected mice with a combined 5 mg/kg RVT and 8.5 mg/kg ID resulted in an 81.55% inhibition at day 10 postinoculation (peak of parasitemia). Conclusion: Our data show that RVT is a promising antibabesial pharmacological candidate with therapeutic activities that could overcome the side effects of the currently used anti-Babesia medications.