Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid‐β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid‐β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β‐sheet breaker α/β‐hybrid peptide (BSBHp) and the underlying mechanisms against Aβ₄₀‐induced neurotoxicity in human neuroblastoma SH‐SY5Y cells. Cells were pretreated with the peptide Aβ₄₀ to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca²⁺, and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ₄₀‐induced toxicity by retaining cell viability, suppressing generation of ROS, Ca²⁺ levels, and effectively protects neuronal apoptosis by suppressing pro‐apoptotic protein Bax and up‐regulating antiapoptotic protein Bcl‐2. These results suggest that α/β‐hybrid peptide has neuroprotective effects against Aβ₄₀‐induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.     

Oxymatrine Induces Liver Injury through JNK Signalling Pathway Mediated by TNF‐α In Vivo

Oxymatrine (OMT) is a traditional Chinese medicine monomer and has been used for the treatment of chronic viral hepatitis and many other diseases. We aimed to investigate whether OMT could induce hepatotoxicity in mice and explored the preliminary mechanisms of toxic effects. Twenty‐four Institute for Cancer Research male mice were randomly divided into four groups: control group, 40, 160 and 320 mg/kg OMT‐treated group. OMT was orally administered once daily for 7 days. The OMT‐treated group exhibited an improved liver index and increase in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase,augmented liver histological injury, elevated levels of malondialdehyde and tumour necrosis factor alpha (TNF‐α) accompanied by the activation of caspase‐9/‐8/‐3, up‐regulated expressions of tumour necrosis factor receptor l (TNFR1), TNF receptor‐associated structure domain (TRADD) and phosphorylation of stress‐activated protein kinase/c‐jun N‐terminal protein kinases (p‐SAPK/JNK). Altogether, these results suggest that OMT at a dose of 320 mg/kg leads to liver damage and is related to the activation of JNK signalling pathway mediated by TNF‐α in the liver of mice.     

MMI-0100对DDC诱导的胆汁淤积性肝损伤的治疗作用研究

目的 探讨MMI-0100对3,5-二乙氧基羰基-1,4-二氢-2,4,6-三甲基吡啶（DDC）诱导的小鼠胆汁淤积性肝损伤的治疗作用。方法 15只Balb/c小鼠随机分为对照组、模型组（DDC）,治疗组（DDC+MMI-0100）,每组5只。对照组小鼠给予正常饮食2 周,其余2组小鼠给予0.1% DDC饮食喂养1周后,再给予正常饮食1周,同时治疗组小鼠在DDC饲养1周后,每天经腹腔注射MMI-0100进行治疗,注射量剂量为500 μg·kg^-1,连续注射1 周;对照组和模型组小鼠给予等量无菌生理盐水。观察并记录各组小鼠肝脏大体情况,HE和Masson染色观察肝脏的病理改变,免疫组化检测胆管增生指标CK19和Ki67,实时定量PCR检测肝脏纤维化相关基因α-SMA的表达。结果 与模型组相比,治疗组小鼠肝脏纤维化病变减轻（P<0.01）,炎症细胞浸润减少（P<0.01）,肝脏组织Knodell Score评分降低（P<0.01）,同时胆管增生相关指标CK19和Ki67表达降低（P<0.05）,肝脏α-SMA的mRNA表达水平降低（P<0.01）。结论 MMI-0100对DDC诱导的小鼠原发性硬化性胆管炎有良好的治疗作用。     

Synthesis of [3α‐3H] 17α‐Hydroxy pregnenolone and [3α‐3H] Pregnenolone

For the first time, [3α‐³H] 17α‐hydroxy pregnenolone (1) was synthesized through a multiple step sequence. The presence of [3β‐³H] isomer in RP‐HPLC purified product was identified by tritium NMR. The [3β‐³H] isomer was then separated from [3α‐³H] 17α‐hydroxy pregnenolone with chiralPAK AD‐H column. [3α‐³H] pregnenolone (2) was synthesized from commercial available 5‐pregnen‐3,20‐dione in one step with an improved procedure.     

The α‐adrenoceptor antagonist,zolertine, inhibits α1D‐ and α1A‐adrenoceptor‐mediated vasoconstriction in vitro

1 The antagonist effect of zolertine (4‐phenyl‐1‐[2‐(5‐tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (α1D‐adrenoceptors), mesenteric (α1A/D‐adrenoceptors) and caudal arteries (α1A‐adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (α1B‐adrenoceptors), was investigated in endothelium‐denuded arterial rings.
2 The selective α1D‐adrenoceptor agonist, noradrenaline, elicited concentration‐dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid=aorta>>.Gt;mesenteric=rabbit aorta>caudal arteries.
3 The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values of WKY, 7.48±0.18; SHR, 7.43±0.13 and WKY, 7.57±0.24; SHR, 7.40±0.08, respectively. Zolertine was a non‐competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pKb estimates for zolertine were WKY, 6.98±0.16; SHR, 6.81±0.18 in the mesenteric artery, WKY, 5.73±0.11; SHR, 5.87±0.25 in the caudal artery and 6.65±0.09 in rabbit aorta.
4 Competition binding experiments using the α1‐adrenoceptor antagonist [³H]prazosin showed a zolertine pKi of 6.81±0.02 in rat liver (α1B‐adrenoceptors) and 6.35±0.04 in rabbit liver (α1A‐adrenoceptors) membranes.
5 Zolertine showed higher affinity for α1D‐adrenoceptors compared to α1A‐adrenoceptors, while it had an intermediate affinity for α1B‐adrenoceptors. The ability of the α1‐adrenoceptor antagonist zolertine to block α1D‐adrenoceptor‐mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency.     

A simple and efficient synthesis of [3α‐3H]5α‐androst‐16‐en‐3β‐ol

An efficient one step synthesis of [3α‐³H]5α‐androst‐16‐en‐3β‐ol by NaBT₄ reduction of a ketone precursor is described. The specific activity of the product was 21.6 Ci/mmol with a radiochemical purity >99%. Synthesis of the precursor, 5α‐androst‐16‐en‐3‐one, from commercially available 5α‐androst‐16‐en‐3α‐ol is also presented. Copyright © 2006 John Wiley & Sons, Ltd.     

5‐Trideuteromethyl‐α‐tocotrienol and 5‐14CH3‐α‐tocotrienol as biological tracers of tocotrienols

The tocotrienols have attracted increased attention recently as evidence has accrued that their biological activities are significantly different from tocopherols. The biokinetics and metabolic fate of tocopherols have long been studied using deuteromethylated forms of α‐tocopherol prepared by a stannous chloride catalysed paraformaldehyde methylation of γ‐ and δ‐tocopherols. We show here that his methodology is not an efficient route to deuterated α‐tocotrienol because of low yields and extensive exchange of allylic hydrogens under the prolonged acidic conditions of the deuteromethylation. Instead, we have prepared deuteromethylated and ¹⁴C‐radiolabelled α‐tocotrienol by aminomethylation at C‐5 of γ‐tocotrienol (available from palm oil), followed by reduction with NaCNBD₃ in refluxing iso‐butanol. The deuteromethylation procedure is amenable to multi‐gram scale reactions. Copyright © 2006 John Wiley & Sons, Ltd.     

Detection and metabolic investigations of a novel designer steroid: 3‐chloro‐17α‐methyl‐5α‐androstan‐17β‐ol

In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid‐related compounds. Subsequent gas chromatography–mass spectrometry (GC‐MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α‐ and 3β‐ isomers of the novel compound; 3‐chloro‐17α‐methyl‐5α‐androstan‐17β‐ol. Synthesis of authentic reference materials followed by comparison of NMR, GC‐MS and gas chromatography‐tandem mass spectrometry (GC‐MS/MS) data confirmed the finding of a new ‘designer’ steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α‐chloro‐17α‐methyl‐5α‐androstan‐17β‐ol using equine and human S9 liver fractions were performed. For equine, GC‐MS/MS analysis identified the diagnostic 3α‐chloro‐17α‐methyl‐5α‐androstane‐16α,17β‐diol metabolite. For human, the 17α‐methyl‐5α‐androstane‐3α,17β‐diol metabolite was found. Results from these studies were used to verify the ability of GC‐MS/MS precursor‐ion scanning techniques to support untargeted detection strategies for designer steroids in anti‐doping analyses. Copyright © 2015 John Wiley & Sons, Ltd.     

Microwave‐accelerated synthesis of psychoactive deuterated N,N‐dialkylated‐[α,α,β,β‐d4]‐tryptamines

A large number of N,N‐dialkylated tryptamines are known to induce psychoactive effects in humans. This has resulted in their increased attention within clinical and forensic communities. Deuterated tryptamines are ideal for use as internal standards during MS bioanalysis or of use in biochemical NMR studies. The present study reports on a microwave‐enhanced synthesis of 22 N,N‐dialkylated‐[α,α,β,β‐d4]‐tryptamines via the reduction with lithium aluminium deuteride of glyoxalylamide precursors obtained by the procedure of Speeter and Anthony. Syntheses were carried out using a single‐mode system under elevated pressure conditions where anhydrous tetrahydrofuran was used as the solvent at 150°C. Good yields were obtained within 5 min. Copyright © 2008 John Wiley & Sons, Ltd.     

Facile synthesis of Nα‐protected‐l‐α,γ‐diaminobutyric acids mediated by polymer‐supported hypervalent iodine reagent in water

Abstract: Hofmann rearrangement of N^α‐Boc‐l ‐Gln‐OH mediated by a polymer‐supported hypervalent iodine reagent poly[(4‐diacetoxyiodo)styrene] (PSDIB) in water afforded N^α‐Boc‐l ‐α,γ‐diaminobutyric acid (Boc‐Dab‐OH, 1 ) in 87% yield. N^α‐Z‐derivative (Z‐Dab‐OH, 2 ) was prepared with PSDIB in 83% yield. Since the reaction of N^α‐Fmoc‐Gln‐OH by this procedure did not proceed because of the insolubility of Fmoc‐Gln‐OH in aqueous media, we synthesized Fmoc‐Dab(Boc)‐OH ( 5 ) from 2 in 54% yield. Polymyxin B heptapeptide (PMBH) which contains four Dab residues was successfully synthesized in a solution‐phase synthesis.     

Effects of Dietary β‐Cyclodextrin in Hypercholesterolaemic Rats

Abstract: β‐Cyclodextrin is a compound that forms inclusion complexes with a variety of molecules, specially bile acids and sterols. This study examines the effects of β‐cyclodextrin on cholesterol and bile acid metabolism in hypercholesterolaemic rats. Male Wistar rats were divided into 4 groups that received during 7 weeks: control diet, 2% cholesterol diet (A), A+2.5% β‐cyclodextrin (B) and A+5% β‐cyclodextrin (C). The cholesterol‐rich diet induced hepatomegaly and fatty liver and significantly reduced cholesterol, bile acid and phospholipid secretion. Addition of β‐cyclodextrin normalised biliary lipid secretion. Moreover, when compared to A, β‐cyclodextrin significantly lowered plasma phospholipid concentration (B: ?21%; C: ?29%) and the liver free/total cholesterol molar ratio (B: ?40%; C: ?38%), increased bile acid faecal output (B: +17%; C: +62%) and enhanced cholesterol 7α‐hydroxylase activity (B:+50%; C: +100%) and mRNA levels (B: +14%; C: +29%). 5% β‐cyclodextrin also reduced plasma triglycerides concentration (?38%). However, ALT and AST activities were significantly increased (B: +140% and +280%; C: +72% and +135%) and there was a high incidence of cell necrosis with portal inflammatory cell infiltration. Addition of β‐cyclodextrin to a cholesterol‐rich diet results in a triglyceride‐lowering action, enhancement of bile acid synthesis and excretion, and normalization of biliary lipid secretion, but produces a marked hepatotoxic effect.     

α1‐ and α2‐Adrenoceptor hyporesponsiveness in isolated bisected vas deferens of bile duct‐ligated rats

1 It has been suggested that cholestasis accompanied with changes in autonomic balance and hyporesponsiveness in muscarinic and adrenergic receptors of some organs, e.g. cardiovascular system. Increased plasma levels of epinephrine and norepinephrine has been shown during cholestasis suggesting augmented activity of sympathetic nervous system. In this study we evaluate both α₁ and α₂ responsiveness in isolated rat vas deferens, as a tissue with rich adrenergic innervations. 2 Epididymal and prostatic halves of vas deferens responsiveness have been studied to phenylephrine and clonidine respectively in three groups of un‐operated, sham‐operated (sham), and bile duct‐ligated (BDL) rats. 3 Our results indicate that in vas deferens of BDL animals, the concentration‐response curve of both phenylephrine and clonidine shifted to rightward compared to control group, while the position of concentration‐response curve of sham group did not change significantly (P > 0.05). EC₅₀ of phenylephrine and IC₅₀ of clonidine were increased showing a decreased responsiveness of tissue to phenylephrine (P < 0.05) and clonidine (P < 0.001) in BDL rats. 4 In this study, both subtype of α‐adrenoceptors (α₁ and α₂) has been studied in cholestatic rat vas deference. Our results showed that cholestasis induce hyporesponsiveness to phenylephrine and clonidine. These results are consistent with previous reports, suggesting the hyporesponsiveness of α₁‐adrenoceptors in pulmonary artery and papillary muscle and mesenteric beds. Our conclusion is that the cholestasis induces hyporesponsiveness to phenylephrine and clonidine in epididymal (α₁‐adrenoceptors) and prostatic (α₂‐adrenoceptors) halves of rat vas deferens respectively. Although the logical explanation to this hyporesponsiveness is the down regulation but it has been suggested that it is not because of down regulation.     

黄肝煎液对胆汁淤积性肝损伤大鼠的保护作用及急性毒性研究

目的：观察医院制剂黄肝煎液对胆汁淤积性肝损伤的保护作用及急性毒性。方法：将72只SD大鼠随机分为正常对照组、模型组、阳性对照组和黄肝煎液低、中、高剂量组,每组12只,均连续灌胃给予相应药物14天,每天2次。除正常对照组外,其它各组均于给药第12天灌胃给予α-萘异硫氰酸酯（ANIT）建立胆汁淤积性肝损伤大鼠模型。采用全自动生化分析仪检测大鼠血清肝功能指标丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、羟脯氨酸（Hyp）,血清黄疸指数总胆汁酸（TBA）及总胆红素（TBIL）水平;测定各组大鼠胆汁流量并计算肝脏指数;采用HE染色检测肝组织病理变化。急性毒性试验研究中,40只KM小鼠随机分为对照组和黄肝煎液组,黄肝煎液组以最大给药剂量灌胃给予黄肝煎液,对照组灌胃给予等量生理盐水。观察给药后14 d内小鼠的急性毒性反应,并测定血清ALT、AST、ALP、肌酐（CRE）、尿素氮（BUN）、白蛋白（ALB）水平,计算脏器指数,评价黄肝煎液的急性毒性。结果：与模型组比较,黄肝煎液能够显著降低大鼠血清肝功能指标（ALT、AST、ALP和Hyp）及黄疸指数（TBIL和TBA）,明显减小肝脏系数,增加胆汁流量,差异具有统计学意义（P < 0.01）,肝组织病理学改变显著改善。急性毒性试验中,以最大给药浓度1.63 g·mL-1,最大给药体积40 mL·kg-1灌胃小鼠,24 h内给予黄肝煎液3次,最大日给药量为195.6 g·kg-1（相当于临床成人日用剂量的80倍）时,除部分小鼠体质量降低、稀便软便外,其余小鼠均未出现死亡和明显的急性毒性反应。结论：黄肝煎液对ANIT诱导的大鼠胆汁淤积性肝损伤具有一定的保护作用,且无明显急性毒性反应。     

Growth Kinetics of Enzyme-Altered Liver Foci in Rats Treated with Phenobarbital or α-Hexachlorocyclohexane

A quantitative method based upon a stochastic model for the appearance of initiated cells and their clonal growth was used to estimate cell birth and death rates in enzyme-altered liver foci (EAF). γ-Glutamyltranspeptidase (γ-GT)-positive foci were initiated in livers of female SPF Wistar rats by a single application of N-nitrosomorpholine. Serial terminations during and after stop of promoter treatment with either phenobarbital (PB) or α-hexachlorocyclohexane (α-HCH) provided information on the growth and regression of the EAF. Simultaneous labeling index (LI) measurements were obtained via single injections with [³H]thymidine. No significant increases of the LI were observed with PB or α-HCH treatment. Since both agents are strong liver promoters we conclude that the growth of γ-GT-positive foci is mainly due to a decrease in the rate of apoptosis. Indeed, our analysis supports this conclusion but determines that the abrogation of homeostatic control during promoter treatment is subtle. The ratio of cell death and cell birth rate is found to be decreased only slightly during promoter treatment and slightly increased after stop of promotion. For the mathematical analysis, two distinct focal growth scenarios were employed: (i) volume growth, i.e., all cells within individual foci cycle actively with the same rate, and (ii) surface growth where only cells on the surface of foci cycle actively while interior cells are resting. The model based upon scenario (ii) provides a better fit to the data and is more consistent with the experimental observations indicating heterogeneity of cell division rates within individual foci.     

Peroxisome proliferator‐activated receptor‐γ coactivator‐1α in muscle links metabolism to inflammation

1. In higher eukaryotes, metabolism and immunity are tightly coupled. However, whereas in evolutionary terms a compromised immune response due to undernourishment has been the predominant problem, the inflammatory response to obesity and other lifestyle‐associated diseases has increased in relevance in Western societies in the past 100 years. 2. Traditionally, fat tissue has been considered as the major source of pro‐inflammatory secreted factors in these pathologies. However, in recent years the contribution of other tissues to disease‐causing chronic inflammation has been increasingly appreciated. 3. Peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) is one of the key regulatory factors in active skeletal muscle. Aberrant expression of PGC‐1α in inactive muscle fibres could be linked to a sedentary lifestyle, persistent systemic inflammation and a higher risk for many chronic diseases. Accordingly, modulation of PGC‐1α activity in skeletal muscle may have a broad range of therapeutic effects. Here, recent advances in the understanding of the role of muscle PGC‐1α in health and disease are reviewed.     

Synthesis,crystal structure and molecular conformation of Nα‐Boc‐l‐leucyl‐(Z)‐β‐(3‐pyridyl)‐α,β‐ dehydroalanyl‐l‐leucine methyl ester*

Abstract: A protected tridehydropeptide containing (Z)‐β‐(3‐pyridyl)‐α,β‐dehydroalanine (Δ^Z3Pal) residue, Boc‐Leu‐Δ^Z3Pal‐Leu‐OMe ( 1 ), was synthesized via Erlenmeyer azlactone method. X‐ray crystallographic analysis revealed that the peptide 1 adopts an extended conformation, which is similar to that of a Δ^ZPhe analog, Boc‐Leu‐Δ^ZPhe‐Leu‐OMe ( 2 ).     

Specific Role of α2A‐ and α2B‐, but not α2C‐, Adrenoceptor Subtypes in the Inhibition of the Vasopressor Sympathetic Out‐flow in Diabetic Pithed Rats

Several lines of evidence have shown an association of diabetes with a catecholamines' aberrant homeostasis involving a drastic change in the expression of adrenoceptors. This homeostatic alteration includes, among other things, atypical actions of α₂‐adrenoceptor agonists within central and peripheral α₂‐adrenoceptors (e.g. profound antinociceptive effects in diabetic subjects). Hence, this study investigated the pharmacological profile of the α₂‐adrenoceptor subtypes that inhibit the vasopressor sympathetic out‐flow in streptozotocin‐pre‐treated (diabetic) pithed rats. For this purpose, B‐HT 933 (up to 30 μg/kg min) was used as a selective α₂‐adrenoceptor agonist and rauwolscine as a non‐selective α_2A/2B/2C‐adrenoceptor antagonist; in addition, BRL 44408, imiloxan and JP‐1302 were used as subtype‐selective α_2A‐, α_2B‐ and α_2C‐adrenoceptor antagonists, respectively (all given i.v.). I.v. continuous infusions of B‐HT 933 inhibited the vasopressor responses induced by electrical sympathetic stimulation without affecting those by i.v. bolus injections of noradrenaline in both normoglycaemic and diabetic rats. Interestingly, the ED₅₀ for B‐HT 933 in diabetic rats (25 μg/kg min) was almost 1‐log unit greater than that in normoglycaemic rats (3 μg/kg.min). Moreover, the sympatho‐inhibition induced by 10 μg/kg min B‐HT 933 in diabetic rats was (i) abolished by 300 μg/kg rauwolscine or 100 and 300 μg/kg BRL 44408; (ii) partially blocked by 1000 μg/kg imiloxan; and (iii) unchanged by 1000 μg/kg JP‐1302. Our findings, taken together, suggest that B‐HT 933 has a less potent inhibitory effect on the sympathetic vasopressor responses in diabetic (compared to normoglycaemic) rats and that can probably be ascribed to a down‐regulation of α_2C‐adrenoceptors.     

Semiquinone fraction isolated from Bacillus sp. INM‐1 protects hepatic tissues against γ‐radiation induced toxicity

Present study was focused on evaluation of a semiquinone glucoside derivative (SQGD) isolated from radioresistant bacterium Bacillus sp. INM‐1 for its ability against γ radiation induced oxidative stress in irradiated mice. Animals were divided into four group, i.e., (i) untreated control mice; (ii) SQGD treated (50 mg/kg b. wt. i.p.) mice; (iii) irradiated (10 Gy) mice; and (iv) irradiated mice which were pre‐treated (?2 h) with SQGD (50 mg/kg b. wt. i.p.). Following treatment, liver homogenates of the treated mice were subjected to endogenous antioxidant enzymes estimation. Result indicated that SQGD pre‐treatment, significantly (P < 0.05) induced superoxide dismutase (SOD) (19.84 ± 2.18% at 72 h), catalase (CAT) (26.47 ± 3.11% at 12 h), glutathione (33.81 ± 1.99% at 24 h), and glutathione‐S‐transferase (24.40 ± 2.65% at 6 h) activities in the liver of mice as compared with untreated control. Significant (P < 0.05) induction in SOD (50.04 ± 5.59% at 12 h), CAT (62.22 ± 7.50 at 72 h), glutathione (42.92 ± 2.28% at 24 h), and glutathione‐S‐transferase (46.65 ± 3.25 at 12 h) was observed in irradiated mice which were pre‐treated with SQGD compared with only irradiated mice. Further, significant induction in ABTS⁺ radicals (directly proportional to decrease mM Trolox equivalent) was observed in liver homogenate of H₂O₂ treated mice which were found to be significantly inhibited in H₂O₂ treated mice pre‐treated with SQGD. Thus, it can be concluded that SQGD treatment neutralizes oxidative stress caused by irradiation not only by enhancing endogenous antioxidant enzymes but also by improving total antioxidant status of cellular system and thus cumulative effect of the phenomenon may contributes to radioprotection. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1471–1478, 2014.     

Ambroxol Inhibits Peroxynitrite‐Induced Damage of α1‐Antiproteinase and Free Radical Production in Activated Phagocytic Cells

Abstract: The present study examined the effect of ambroxol on toxic action of peroxynitrite and the respiratory burst in activated phagocytic cells. Ambroxol decreased the inactivation or destruction of α₁‐antiproteinase induced by peroxynitrite (ONOO^?) or hypochlorous acid (HOCl), which was similar to penicillamine and glutathione and was greater than diclofenac sodium and naproxen sodium. Ambroxol significantly decreased ONOO^?–mediated tyrosine nitration and iron plus EDTA‐mediated degradation of 2‐deoxy‐D‐ribose. Ambroxol significantly attenuated the production of superoxide, hydrogen peroxide, HOCl, and nitric oxide in fMLP– or IL‐1‐activated phagocytic cells, while the inhibitory effects of antiinflammatory and thiol compounds were only observed in HOCl production. Ambroxol and antiinflammatory drugs did not show a cytotoxic effect on macrophages. The results suggest that ambroxol protects tissue components against oxidative damage by an action different from antiinflammatory drugs. Ambroxol may interfere with oxidative damage of α₁‐antiproteinase through a scavenging action on ONOO^? and HOCl and inhibition of the respiratory burst of phagocytic cells.