Antioxidant therapy for chronic hepatitis C after failure of interferon:Results of phase Ⅱ randomized,double-blind placebo controlled clinical trial

AIM： TO assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus （HCV） infection.METHODS： One hundred chronic HCV infection patients failed in interferon treatment were enrolled and randomly assigned to receive combined intravenous and oral antioxidants or placebo, or oral treatment alone, Primary end points were liver enzymes, HCV-RNA levels and histology.RESULTS： Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52% of patients who received antioxidant therapy vs 20% of patients who received placebo （P = 0.05）. Histology activity index （HAI） score at the end of treatment was reduced in 48% of patients who received antioxidant therapy vs 26% of patients who received placebo （P = 0.21）. HCV-RNA levels decreased by l-log or more in 28% of patients who received antioxidant therapy vs 12% who received placebo （P = NS）. In part 11 of the trial, oral administration of antioxidants was not associated with significant alterations in any of the end points.CONCLUSION： Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon. Combined antiviral and antioxidant therapy may be beneficial for these patients.

Long-term outcome of patients with chronic pancreatitis treated with micronutrient antioxidant therapy

BACKGROUND： Micronutrient antioxidant therapy did not relieve pain in a European randomized trial of patients with chronic pancreatitis without malnutrition. However, intervention was undertaken only for 6 months leaving unanswered the question of whether long-term antioxidant therapy may modulate chronic pancreatitis. The aim of this study is to assess the outcome of long-term use of micronutrient antioxidant therapy in patients with chronic pancreatitis.METHODS： This is a single center clinical cohort report of patients with chronic pancreatitis prescribed micronutrient antioxidant therapy and followed for up to 10 years. Data were collected on demographic detail, clinic pain assessment, insulin requirements, interventions and outcome.RESULTS： A group of 30 patients with a diagnosis of chronic pancreatitis constitute the study population. Median age at time of diagnosis was 40 years（range 14-66）; 19（63%） were male and the median duration of symptoms was 2 years（range 0-18）. Alcohol was the dominant cause in 22（73%） patients and 16（53%） patients were Cambridge stage 1. Twenty-four（80%） patients had pain at presentation. During antioxidant treatment of 4 years（range 1-10）, pain decreased but the proportion with abdominal pain compared to those who were pain-free remained constant（P=0.16; two-way ANOVA with Bonferroni correction）. There was a significant increase in requirement for insulin（P=0.028） with time together with use of both endoscopic and surgical interventions.CONCLUSIONS： This is the first study to report long-term disease-specific outcome in patients with chronic pancreatitis prescribed micronutrient antioxidant therapy. There appears to be no effect of intervention on outcome.

Antioxidants,inflammation and cardiovascular disease

Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.

Antioxidant and immunomodulatory effects of Viusid in patients with chronic hepatitis C

AIM:To investigate the efficacy of Viusid,a nutritional supplement,as an antioxidant and an immunomodulator in patients with chronic hepatitis C.METHODS:Sixty patients with chronic hepatitis C who were non-responders to standard antiviral treatment were randomly assigned to receive Viusid(3 sachets daily,n=30) or placebo(n=30) for 24 wk.The primary outcome was the change in serum malondialdehyde and 4-hydroxyalkenals(lipid peroxidation products).Secondary outcomes were changes in serum tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ) and interleukin-10(IL-10).RESULTS:Statistically significant reductions in serum 4-hydroxyalkenals and malondialdehyde levels were observed in both groups in comparison with pretreatment values,but the patients who received Viusid showed a more marked reduction as compared with the control group(P=0.001).TNF-α levels significantly increased from 6.9 to 16.2 pg/mL(P< 0.01) in the patients who received placebo in comparison with almost unchanged levels,from 6.6 to 7.1 pg/mL(P=0.26),in the patients treated with Viusid(P=0.001).In addition,IL-10 levels were markedly increased in the patients treated with Viusid(from 2.6 to 8.3 pg/mL,P=0.04) in contrast to the patients assigned to placebo(from 2.8 to 4.1 pg/mL,P=0.09)(P=0.01).Likewise,the administration of Viusid markedly increased mean IFN-γ levels from 1.92 to 2.89 pg/mL(P< 0.001) in comparison with a reduction in mean levels from 1.80 to 1.68 pg/mL(P=0.70) in the placebo group(P< 0.0001).Viusid administration was well tolerated.CONCLUSION:Our results indicate that treatment with Viusid leads to a notable improvement of oxidative stress and immunological parameters in patients with chronic hepatitis C.

Insights on antioxidant therapeutic strategies in type 2 diabetes mellitus:A narrative review of randomized control trials

BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Imbalance in generation and elimination of free radicals generate oxidative stress which modulates glucose metabolism and insulin regulation,resulting in the occurrence and progression of diabetes and associated complications.Antioxidant supplements in T2DM can be seen as a potential preventive and effective therapeutic strategy.AIM To compare randomized controlled trials(RCTs)in which antioxidants have been shown to have a therapeutic effect in T2DM patients.METHODS We systematically searched the electronic database PubMed by keywords.RCTs evaluating the effect of antioxidant therapy on glycaemic control as well as oxidant and antioxidant status as primary outcomes were included.The outcomes considered were:A reduction in blood glucose;changes in oxidative stress and antioxidant markers.Full-length papers of the shortlisted articles were assessed for the eligibility criteria and 17 RCTs were included.RESULTS The administration of fixed-dose antioxidants significantly reduces fasting blood sugar and glycated hemoglobin and is associated with decreased malondialdehyde,advanced oxidation protein products,and increased total antioxidant capacity.CONCLUSION Antioxidant supplements can be a beneficial approach for the treatment of T2DM.

The research status of Asprosin and its application prospect in the protection of myocardial injury

Asprosin is a newly discovered protein hormone that promotes appetite,regulates glucose homeostasis,increases insulin resistance and has potential myocardial protection.Myocardium is vulnerable to oxidative stress injury caused by factors such as high glucose,anti-tumor drugs,ischemia reperfusion and so on,and currently there is a lack of effective preventive measures.It has been reported in the literature that Asprosin has a unique protective effect on myocardium,but the protective mechanism of Asprosin is not clear.In this paper,the general situation and functions of Asprosin,as well as the protective mechanism of Asprosin on myocardium were reviewed,in order to provide reference for the application of Asprosin in the treatment of cardio-related diseases.

Research progress on the antioxidant therapy for gastric cancer

Gastric cancer is one of common malignant tumors from a global perspective, and its morbidity ranks the forth and also the second largest cause of cancer-related death worldwide. Many factors can cause gastric cancer, including helicobacter pylori infection, chronic inflammation, genetic factors et al. Among all of these, helicobacter pylori infection can significantly increase the production of reactive oxygen species（ROS） and reactive nitrogen species（RNS） in human stomach, which can cause the oxidative stress. Oxidative stress plays an important role in the pathogenesis of gastro-intestinal diseases such as mucosal damage, gastro-intestinal ulcers and cancer. Modern therapeutic treatments such as surgery and chemotherapy have undesired side effects, so the antioxidant therapy gains more and more attentions. Antioxidant therapy system comprises of various antioxidants（SOD, catalase, glutathione peroxidase and carnosine） and Chinese herbal medicine, which is mainly focused on the chemoprevention. Natural products and their derivatives, such as tea polyphenol, resveratrol and vitamins, have some potential benefits on their chemoprevention. Besides, much work has been done to understand the role of dietary factors playing in the prevention of gastrointestinal cancers. In this review based on some valuable studies, we aim to make some brief summaries about risk factors, pathogenic mechanism of oxidative stress and antioxidants therapy in gastric cancer.

Oxidative stress and diabetes:antioxidative strategies

Diabetes mellitus is one of the major public health problems worldwide.Considerable recent evidence suggests that the cellular reduction-oxidation(redox)imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in p-cell dysfunction and insulin resistance.Reactive oxide species(ROS)can also directly oxidize certain proteins(defined as redox modification)involved in the diabetes process.There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility,storage instability and nonselectivity of antioxidants.Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS.We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus.Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.

An ROS-Responsive Antioxidative Macromolecular Prodrug of Caffeate for Uveitis Treatment

Uveitis is a sophisticated syndrome showing a high relevance with reactive oxygen species(ROS).Herein,an ROS-responsive PEGylated polypeptide based macromolecular prodrug of herbaceous antioxidant ethyl caffeate(EC)is designed via phenylboronic esters with improved solubility for the alleviation of uveitis.The antioxidative 4-hydroxybenzyl alcohol(HBA)and EC can be released from the macromolecular EC prodrug under the stimulation of ROS,which can effectively protect cells against oxidative stress-induced injury in an ROS-depletion way.The antioxidative and protective effects of the macromolecular EC prodrug in vivo are further verified in a uveitis mouse model.Overall,this work not only provides a handy method to synthesize a phenylboronic ester-bearing EC prodrug which is highly sensitive to pathological ROS,but also depicts a promising future to apply macromolecular antioxidative prodrugs in the treatment of uveitis as well as other ROS-related diseases.

An update on the role of medical treatment including antioxidant therapy in varicocele

Varicocele-associated male infertility has classically been managed using surgery or assisted reproductive techniques. With increasing evidence of oxidative stress as a pathophysiological factor in varicocele-associated infertility, medical therapy especially antioxidants might become a treatment option with lower risks. We reviewed the existing literature on the role of various medical agents in the management of male infertility attributed to varicoceles. Medical therapy is typically evaluated in three different situations such as （a） comparison of two drugs or one drug with placebo, （b） comparison of drugs versus surgery, and （c） comparison of drugs as adjuvant therapy with surgery versus drug therapy alone. Due to heterogeneity of data and lack of well-conducted studies, there is insufficient data to recommend routine use of medical therapy for men with varicocele-associated infertility and surgery remains the treatment of choice. Pregnancy and live birth rates are usually not reported in most studies and mere improvement in sperm parameters or antioxidant capacity is insufficient to support its routine use. Antioxidant therapy is a potential option due to its theoretical benefit, data from preclinical studies, and lack of major side effects. Adjuvant therapy with antioxidants after surgical repair of varicocele may improve the outcome and is a potential area for further research.

Single-atom nanozymes:From bench to bedside

Single-atom nanozymes(SANs)are the new emerging catalytic nanomaterials with enzyme-mimetic activities,which have many extraordinary merits,such as low-cost preparation,maximum atom utilization,ideal catalytic activity,and optimized selectivity.With these advantages,SANs have received extensive research attention in the fields of chemistry,energy conversion,and environmental purification.Recently,a growing number of studies have shown the great promise of SANs in biological applications.In this article,we present the most recent developments of SANs in anti-infective treatment,cancer diagnosis and therapy,biosensing,and antioxidative therapy.This text is expected to better guide the readers to understand the current state and future clinical possibilities of SANs in medical applications.

Reactive oxygen species-based nanomaterials for the treatment of myocardial ischemia reperfusion injuries

Interventional coronary reperfusion strategies are widely adopted to treat acute myocardial infarction,but morbidity and mortality of acute myocardial infarction are still high.Reperfusion injuries are inevitable due to the generation of reactive oxygen species(ROS)and apoptosis of cardiac muscle cells.However,many antioxidant and anti-inflammatory drugs are largely limited by pharmacokinetics and route of administration,such as short half-life,low stability,low bioavailability,and side effects for treatment myocardial ischemia reperfusion injury.Therefore,it is necessary to develop effective drugs and technologies to address this issue.Fortunately,nanotherapies have demonstrated great opportunities for treating myocardial ischemia reperfusion injury.Compared with traditional drugs,nanodrugs can effectively increase the therapeutic effect and reduces side effects by improving pharmacokinetic and pharmacodynamic properties due to nanodrugs’size,shape,and material characteristics.In this review,the biology of ROS and molecular mechanisms of myocardial ischemia reperfusion injury are discussed.Furthermore,we summarized the applications of ROS-based nanoparticles,highlighting the latest achievements of nanotechnology researches for the treatment of myocardial ischemia reperfusion injury.

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney

Currently,there are no clinical drugs available to treat acute kidney injury(AKI).Given the high prevalence and high mortality rate of AKI,the development of drugs to effectively treat AKI is a huge unmet medical need and a research hotspot.Although existing evidence fully demonstrates that reactive oxygen and nitrogen species(RONS)burst at the AKI site is a major contributor to AKI progression,the heterogeneity,complexity,and unique physiological structure of the kidney make most antioxidant and anti-inflammatory small molecule drugs ineffective because of the lack of kidney targeting and side effects.Recently,nanodrugs with intrinsic kidney targeting through the control of size,shape,and surface properties have opened exciting prospects for the treatment of AKI.Many antioxidant nanodrugs have emerged to address the limitations of current AKI treatments.In this review,we systematically summarized for the first time about the emerging nanodrugs that exploit the pathological and physiological features of the kidney to overcome the limitations of traditional small-molecule drugs to achieve high AKI efficacy.First,we analyzed the pathological structural characteristics of AKI and the main pathological mechanism of AKI:hypoxia,harmful substance accumulation-induced RONS burst at the renal site despite the multifactorial initiation and heterogeneity of AKI.Subsequently,we introduced the strategies used to improve renal targeting and reviewed advances of nanodrugs for AKI:nano-RONS-sacrificial agents,antioxidant nanozymes,and nanocarriers for antioxidants and anti-inflammatory drugs.These nanodrugs have demonstrated excellent therapeutic effects,such as greatly reducing oxidative stress damage,restoring renal function,and low side effects.Finally,we discussed the challenges and future directions for translating nanodrugs into clinical AKI treatment.