Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Many advances have been made in the cardiovascular field in the last several decades. Among them is the progress completed to date on the heptapeptide member of the renin–angiotensin system (RAS), angiotensin‐(1‐7) [Ang‐(1‐7)]. The peptide's beneficial actions against pathophysiological processes, such as cardiac arrhythmia, heart failure, hypertension, renal disease, preeclampsia, and even cancer are continuously being uncovered. This review encompasses the pharmacology of Ang‐(1‐7) and expounds upon the peptide's potential as a therapeutic agent against pathological processes both within and outside the cardiovascular continuum.     

Lower urinary α‐Klotho is associated with lower angiotensin‐(1‐7) and higher blood pressure in young adults born preterm with very low birthweight

Early‐life factors including preterm birth and VLBW increase the risk of hypertension, but the mechanisms remain poorly understood. Reductions in the anti‐aging protein α‐klotho are associated with hypertension, possibly due to angiotensin (Ang) II activation, but the mechanisms are incompletely understood and clinical evidence is lacking. The association of α‐klotho with the alternative Ang‐(1‐7) pathway, which counteracts Ang II to lower BP, is undescribed. We hypothesized that lower urinary α‐klotho is associated with higher BP and lower urinary Ang‐(1‐7) in preterm‐born VLBW young adults. In a cross‐sectional analysis of data from a prospective cohort of 141 preterm‐born VLBW young adults, we assessed the associations among urinary α‐klotho/creatinine, Ang II/creatinine, Ang‐(1‐7)/creatinine, Ang II/Ang‐(1‐7), and BP using generalized linear models adjusted for age and hypertensive pregnancy and conducted a sensitivity analysis in 32 term‐born young adults. Among those born preterm, lower α‐klotho/creatinine was associated with higher systolic BP (adjusted β (aβ): −2.58 mm Hg, 95% CI −4.99 to −0.17), lower Ang‐(1‐7)/creatinine (ln aβ: 0.1, 0.04‐0.16), and higher Ang II/Ang‐(1‐7) (ln aβ: −0.14, −0.21 to −0.07). In term‐born participants, α‐klotho/creatinine was inversely associated with Ang II/creatinine (ln aβ: −0.15, −0.27 to −0.03) and Ang II/Ang‐(1‐7) (ln aβ: −0.15, −0.27 to −0.03). In preterm‐born young adults with VLBW, lower urinary α‐klotho/creatinine was associated with higher SBP, lower urinary Ang‐(1‐7)/creatinine, and higher urinary Ang II/Ang‐(1‐7). Reduced renal α‐klotho expression could lead to renal Ang‐(1‐7) suppression as a novel mechanism for the development of hypertension among individuals born preterm with VLBW.     

Dipeptidyl peptidase‐4 inhibitors: Multitarget drugs,not only antidiabetes drugs (D ipeptidyl peptidase ‐4抑制剂：多靶点药物，不仅仅是降糖药)

Dipeptidyl peptidase (DPP)‐4 inhibitors are a new class of antidiabetic agents that reduce blood glucose by preventing the degradation of the endogenous incretin hormones glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. Protection by DPP‐4 inhibitors of β‐cell function has been demonstrated in patients with type 2 diabetes. Because DPP‐4 is an enzyme widely expressed in humans, DPP‐4 inhibitors are speculated to be multitarget agents. However, other potential therapeutic benefits of DPP‐4 inhibitors remain unknown. Recently, some therapeutic effects of DPP‐4 inhibitors, such as immune regulation, cardiovascular protection, and anti‐inflammatory effects, have been observed. This article provides a systematic and comprehensive review of current research into the newly found effects and mechanism of action of DPP‐4 inhibitors in a therapeutic context.     

Leishmania braziliensis amastigotes stimulate production of IL‐1β, IL‐6, IL‐10 and TGF‐β by peripheral blood mononuclear cells from nonendemic area healthy residents

Leishmania (Viannia) braziliensis causes cutaneous and mucosal leishmaniasis in several countries in Latin America. In mammals, the parasites live as amastigotes, interacting with host immune cells and stimulating cytokine production that will drive the type of the specific immune responses. Generation of Th17 lymphocytes is associated with tissue destruction and depends on IL‐1β, IL‐6, TGF‐β and IL‐23 production, whereas IL‐10 and TGF‐β are associated with tissue protection. Here, we evaluate whether amastigotes stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors to produce the major cytokines responsible for the generation of Th17. Seven L. (V.) braziliensis isolates from patients with different clinical forms of leishmaniasis were expanded in interferon‐γ knockout mice to obtain amastigotes and in culture to get promastigotes. The parasites were used to stimulate PBMCs from healthy donors, and cytokine production was evaluated by ELISA or qPCR. Amastigotes and promastigotes induced IL‐10 production in PBMCs; however, only amastigotes induced IL‐1β, IL‐6 and TGF‐β. These data demonstrate for the first time that L. (V.) braziliensis amastigotes directly stimulate production of a unique pattern of cytokines that could contribute to the generation of Th17.     

Antioxidant potential of zinc–flavonol complex studied in streptozotocin‐diabetic rats (锌黄酮醇复合物在链脲霉素‐糖尿病大鼠中的抗氧化作用)

Background: Diabetic oxidative stress coexists with a reduction in the antioxidant status, which can further increase the deleterious effects of free radicals. Zinc is an essential trace element with significant antidiabetic activity. However, the acceptance of zinc compounds as promising therapeutic antidiabetic agents has been slowed due to concerns regarding chronic toxicity. Recently, we have designed, synthesized and characterized a novel zinc–flavonol complex and evaluated its antidiabetic efficacy in streptozotocin (STZ)‐diabetic rats. The aim of the present study was to evaluate the role of the zinc–flavonol complex in the antioxidant status of diabetic rats. Methods: Diabetes was induced in rats by i.p. injection of STZ. Diabetic rats were then treated with the zinc–flavonol complex (5 mg/kg, p.o.) for 30 days. The extent of oxidative stress was assessed by determining lipid peroxide levels, pancreatic tissue antioxidant enzyme activities and plasma concentrations of non‐enzymatic antioxidants. In addition, nuclear levels of nuclear factor (NF)‐κB p65, pancreatic nitric oxide (NO), and plasma levels of tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β and IL‐6 were determined. Pancreatic tissues were examined histologically. Results: Oral treatment with the zinc–flavonol complex significantly improved antioxidant levels and alleviated levels of oxidative stress markers. Furthermore, significant increases were seen in NF‐κB p65, NO, TNF‐α, IL‐1β and IL‐6 levels. Histological observations revealed that the zinc–flavonol complex effectively protects pancreatic β‐cells against oxidative damage. Conclusion: The results of the present study indicate that the zinc–flavonol complex has an antioxidative and anti‐inflammatory role in the diabetic milieu.     

A new unstable variant of the fetal hemoglobin HBG2 gene: Hb F‐Turritana [Gγ64(E8)Gly→Asp,HBG2:c.194G>A] found in cis to the Hb F‐Sardinia gene [Aγ(E19)Ile→Thr,HBG1:c.227T>C]

A new variant of the fetal hemoglobin (Hb) was observed in a newborn baby subjected to phototherapy due to jaundice, by means of electrophoretic and chromatographic techniques. The variant Hb resulted unstable by the isopropanol stability test. After HBG2 gene sequencing, the G to A transversion at codon 64, position eight of the E helix, was found, which corresponds to the Asp for Gly amino acid substitution. The new variant was called Hb F‐Turritana [^Gγ64(E8)Gly→Asp, HBG2:c.194G>A]. Incoming aspartic acid residue, bulky and negatively charged, may be responsible for alteration of the heme pocket steric configuration and for instability. The new abnormal HBG2 gene was found to be associated in cis with the mutated HBG1 gene, which characterizes the Hb F‐Sardinia [^Aγ (E19)Ile→Thr, HBG1:c.227T>C] variant.