Sodium pumps,ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure

Accumulating evidence obtained over the last three decades has revealed a neuroendocrine system in the brain that mediates long term increases in blood pressure. The system involves distinct ion transport pathways including the alpha-2 isoform of the Na,K pump and epithelial sodium channels, as well as critical hormone elements such as angiotensin II, aldosterone, mineralocorticoid receptors and endogenous ouabain. Activation of this system either by circulating or central sodium ions and/or angiotensin II leads to a cascading sequence of events that begins in the hypothalamus and involves the participation of several brain nuclei including the subfornical organ, supraoptic and paraventricular nuclei and the rostral ventral medulla. Key events include heightened aldosterone synthesis and mineralocorticoid receptor activation, upregulation of epithelial sodium channels, augmented synthesis and secretion of endogenous ouabain from hypothalamic magnocellular neurons, and sustained increases in sympathetic outflow. The latter step depends upon increased production of angiotensin II and the primary amplification of angiotensin II type I receptor signaling from the paraventricular nucleus to the rostral ventral lateral medulla. The transmission of sympathetic traffic is secondarily amplified in the periphery by increased short- and long-term potentiation in sympathetic ganglia and by sustained actions of endogenous ouabain in the vascular wall that augment expression of sodium calcium exchange, increase cytosolic Ca²⁺ and heighten myogenic tone and contractility. Upregulation of this multi-amplifier system participates in forms of hypertension where salt, angiotensin and/or aldosterone are elevated and contributes to adverse outcomes in heart failure.     

阿魏酸钠联合缬沙坦对糖尿病肾病患者的疗效及对肾脏纤维化的影响

目的:研究阿魏酸钠联合缬沙坦对糖尿病肾病(diabetic kidney disease,DKD)患者的治疗效果及对肾脏纤维化的影响。方法:选择2017年1月～2018年12月山西医科大学附属晋中医院收治的101例糖尿病肾病患者,随机分为两组。两组均低蛋白饮食,口服他汀类药物调脂,口服降糖药和(或)胰岛素控制血糖。对照组加服缬沙坦8 0 mg/d治疗,观察组服缬沙坦联合静脉滴注0.3 g的阿魏酸钠,每天1次。两组均连续治疗1个月。观察两组肾功能指标、血糖指标以及肾脏纤维化指标的变化。结果:治疗后,观察组的治疗总有效率92.00%(46/50),显著高于对照组[68.63%(35/51)](P0.05)。治疗后,两组患者血清的纤维化相关指标Ⅲ型前胶原(procollagen typeⅢ,PCⅢ)和Ⅳ型胶原(typeⅣCollagen,CⅣ)均明显降低(P0.05),且观察组的明显低于对照组(P0.05);治疗后,两组的空腹血糖(fasting plasma glucose,FPG)、餐后2 h血糖(2 h plasma glucose,2 h PG)、血尿素氮(blood urea nitrogen,BUN)、血肌酐(serum creatinine,SCr)、β2-微球蛋白(β2-Microglobulin,β2-MG)、24 h尿白蛋白排泄率(24 h urine microalbumin excretion,24 h UAER)均明显降低(P0.05),且观察组的指标均显著低于对照组(P0.05),两组肾小球滤过率(GFR)增高(P0.05),且观察组指标明显高于对照组(P0.05)。结论:阿魏酸钠联合缬沙坦对DKD患者有较好的疗效,能明显延缓机体肾脏纤维化的进展速度,进而有效改善肾功能。     

免疫球蛋白联合磷酸肌酸钠对病毒性心肌炎患儿心肌重塑和心肌损伤的影响

摘要 目的：研究免疫球蛋白联合磷酸肌酸钠对病毒性心肌炎患儿心肌重塑和心肌损伤的影响。方法：选择2017年1月～2019年12月我院收治的143例病毒性心肌炎患儿,随机分为两组。对照组静脉输注磷酸肌酸钠治疗,每次0.5～1.0 g,每天1次,连用14 d。观察组联合静脉注射人免疫球蛋白,剂量1 g/(kg?d),每天1次,连用2 d。检测两组治疗前后的心肌重塑指标和心肌损伤指标变化情况。结果：观察组的有效率明显高于对照组（P<0.05）;治疗前,两组的血清血清转化生长因子β1(transforming growth factor-β1,TGFβ1）、I型前胶原氨基端肽(nitrogen terminal propeptide of type I procollagen,PINP）、基质金属蛋白酶(matrix metalloproteinase-2,MMP2）、I型胶原吡啶交联终肽(type I collagen carboxy terminal telopeptide,ICTP）、MMP9水平无明显差异（P>0.05）,治疗后,两组的血清TGFβ1、PINP、MMP2、ICTP、MMP9水平均明显降低（P<0.05）,且观察组的血清TGFβ1、PINP、MMP2、ICTP、MMP9水平明显低于对照组（P<0.05）;治疗前,两组的血清血清丙二醛(malondialdehyde,MDA）、心肌肌钙蛋白I(Cardiac troponini,cTnI）、脑利钠肽(B -type natriuretic peptide,BNP）、肌酸激酶同工酶(Creatine kinase isoenzyme,CK-MB）水平无明显差异（P>0.05）,治疗后,两组的血清MDA、CK-MB、BNP和cTnI水平均明显降低（P<0.05）,且观察组的血清MDA、CK-MB、BNP和cTnI水平明显低于对照组（P<0.05）。结论：免疫球蛋白联合磷酸肌酸钠对病毒性心肌炎患儿有显著的疗效,能有效抑制心肌重塑、减轻心肌损伤,值得进行推广。     

Alterations of 3,4-dihydroxyphenylethylamine and its metabolite 3,4-dihydroxyphenylacetic produced in rat brain tissues after systemic administration of saxitoxin

We have measured the dopamine levels in some discrete rat brain regions after acute intraperitoneal administration of saxitoxin (STX). STX is one of the several toxins that causes paralytic shellfish poisoning (PSP). PSP is a serious public health concern through the world. Certain dinoflagellates are able of producing STX, a powerful neurotoxic compound, which blocks the voltage sensitive sodium channels, entailing to the appearance of the main symptoms of poisoning by PSP: muscular paralysis and respiratory depression. The goal in this study was to analyze the effect of STX on dopamine levels in discrete rat brain regions after its acute intraperitoneal administration. Different experimental periods were analyzed for STX doses (5 and 10 μg kg⁻¹ body weight). With low dose, experimental periods were: 30, 60 and 120 min. With high dose, experimental period was just 30 min. At the end of each experimental period, animals were sacrificed by cervical dislocation. Brains were removed and dissected in: hypothalamus, striatum, midbrain, brain stem, right and left hemispheres. This is to our knowledge, the first report in which a sublethal dose of STX administered intraperitoneally results in an acute alteration of dopamine (DA) production and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC).     

Immunohistological localization of serotonin in the CNS and feeding system of the stable fly Stomoxys calcitrans L. (Diptera: Muscidae)

Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR) to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stable fly, Stomoxys calcitrans, using an immunohistological technique. The location and pattern of the 5-HT IR neurons are described and compared for these two different developmental stages. Anatomical features of the fly feeding system were analyzed in third instar larvae and adult flies using a combination of histological and immunohistological techniques. In third instar larvae, the cibarial dilator muscles were observed within the cibarial pump skeleton and innervated by 5-HT IR neurons in nerves arising from the brain. There were four pairs of nerves arising from the frontal surface of the larval brain that innervate the cibarial pump muscles, pharynx, and muscles controlling the mouth hooks. A strong serotoninergic innervation of the anterior stomatogastric system was observed, which suggests 5-HT may play a role in the coordination of different phases of food ingestion by larvae. Similarly, many 5-HT IR neurons were found in both the brain and the thoracico-abdominal ganglia in the adult, some of which innervate the cibarial pump dilator muscles and the stomatogastric muscles. This is tnhe first report describing neuromuscular structures of the stable fly feeding system. The results reported here suggest 5-HT may play a critical role in feeding behaviors of stable fly larvae and adults.     

Effect of reduced sulfur compounds on the fermentation of phosphoric acid pretreated sugarcane bagasse by ethanologenic Escherichia coli

The addition of reduced sulfur compounds (thiosulfate, cysteine, sodium hydrosulfite, and sodium metabisulfite) increased growth and fermentation of dilute acid hydrolysate of sugarcane bagasse by ethanologenic Escherichia coli (strains LY180, EMFR9, and MM160). With sodium metabisulfite (0.5 mM), toxicity was sufficiently reduced that slurries of pretreated biomass (10% dry weight including fiber and solubles) could be fermented by E. coli strain MM160 without solid-liquid separation or cleanup of sugars. A 6-h liquefaction step was added to improve mixing. Sodium metabisulfite also caused spectral changes at wavelengths corresponding to furfural and soluble products from lignin. Glucose and cellobiose were rapidly metabolized. Xylose utilization was improved by sodium metabisulfite but remained incomplete after 144 h. The overall ethanol yield for this liquefaction plus simultaneous saccharification and co-fermentation process was 0.20 g ethanol/g bagasse dry weight, 250 L/tonne (61 gal/US ton).     

Solid phase microbial fuel cell (SMFC) for harnessing bioelectricity from composite food waste fermentation: influence of electrode assembly and buffering capacity

Solid phase microbial fuel cells (SMFC; graphite electrodes; open-air cathode) were designed to evaluate the potential of bioelectricity production by stabilizing composite canteen based food waste. The performance was evaluated with three variable electrode-membrane assemblies. Experimental data depicted feasibility of bioelectricity generation from solid state fermentation of food waste. Distance between the electrodes and presence of proton exchange membrane (PEM) showed significant influence on the power yields. SMFC-B (anode placed 5 cm from cathode-PEM) depicted good power output (463 mV; 170.81 mW/m²) followed by SMFC-C (anode placed 5 cm from cathode; without PEM; 398 mV; 53.41 mW/m²). SMFC-A (PEM sandwiched between electrodes) recorded lowest performance (258 mV; 41.8 mW/m²). Sodium carbonate amendment documented marked improvement in power yields due to improvement in the system buffering capacity. SMFCs operation also documented good substrate degradation (COD, 76%) along with bio-ethanol production. The operation of SMFC mimicked solid-sate fermentation which might lead to sustainable solid waste management practices.     

Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930

The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with heteroatom substituted pyridyl and phenyl ring systems was synthesized and evaluated against a panel of kinases including c-Kit and KDR. Aminopyridyl derivative 6 was found to be the most active member of the series with 91% and 57% inhibition of c-Kit at 10μM and 1μM, respectively and 88% and 50% inhibition of KDR at 10μM and 1μM, respectively. The target compounds were also tested for their ability to inhibit efflux of mitoxantrone through inhibition of ATP dependent ABCG2 pump. Nitropyridyl derivative 5 and o-nitrophenyl derivative 7 exhibited complete inhibition of the ABCG2 pump with IC(50) values of 13.67μM and 16.67μM, respectively.     

Synthesis and DNA photocleavage by a pyridine-linked bis-acridine chromophore in the presence of copper(II): ionic strength effects

We report the synthesis of photonuclease 3 consisting of two acridine rings joined by a 2,6-bis(aminomethyl)pyridine copper-binding linker. In reactions containing micromolar concentrations of 3, irradiation at 419 nm produces efficient, copper(II)-dependent cleavage of plasmid DNA in the presence of the high concentrations of salt that exist in the cell nucleus (150 mM NaCl and 260 mM KCl). The DNA interactions of 3 are compared to an analogous bis-acridine (4) containing a more flexible 2,6-bis{[(methoxycarbonylamino)-ethyl]methylaminomethyl}pyridine unit.