Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

Effect of sumac powder on clinical symptoms, hyperandrogenism, inflammation, blood glucose, lipid profiles in women with polycystic ovary syndrome: A double-blind randomized clinical trial.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders associated with a high risk of diabetes, atherosclerosis, and cardiovascular disease. The purpose of this study was to determine the effect of sumac powder on clinical symptoms and laboratory parameters in women with PCOS. The double-blind randomized controlled clinical trial was conducted on 88 women with PCOS randomly assigned to the intervention and control groups. The intervention group received three capsules each containing 1 g of sumac powder for 12 weeks. All data and serum levels of sex hormone, hs-CRP, glucose, and lipid profiles were measured at the baseline and at the end of the study. Data were analyzed using SPSS version 25 software. The ANCOVA test results showed that hs-CRP level was significantly reduced in the intervention group (p = .008). Blood glucose and lipid profiles in the intervention group were significantly reduced compared to the placebo group (p < .05). Insulin sensitivity and HDL levels were increased significantly in the Sumac group after the intervention (p < .05). Sumac powder can reduce the inflammatory effects, and glycemic status and lipid profile of polycystic ovaries in affected women, but has no significant effect on anthropometric parameters and sex hormones.

Catalase application in cancer therapy: Simultaneous focusing on hypoxia attenuation and macrophage reprogramming.

The tumor microenvironment (TME), as an immunosuppressive milieu, has a critical role in tumor progression and increases resistance to the conventional treatments. Among the abundant immunosuppressive cells in the TME, tumor-associated macrophages (TAMs) could be a promising target for reprogramming and potentiating the local anti-tumor response. On the other hand, hypoxia is a major barrier in treating solid tumors, which aggravates the situation and alleviates the anti-tumor immune responses. Moreover, catalase and catalase-mimicking compounds can efficiently participate in the TAMs polarization and hypoxia attenuation in the TME. In this review, we will introduce a practical and novel approach which can simultaneously reduce hypoxia and polarize TAMs in the TME. Furthermore, catalase therapeutic effects in combination with cancer therapy methods will be fully discussed. This work aims to inspire readers to explore new avenues for designing and development of next-generation catalase-based formulations for cancer therapy.

Rolipram and pentoxifylline combination ameliorates experimental diabetic neuropathy through inhibition of oxidative stress and inflammatory pathways in the dorsal root ganglion neurons.

Diabetic neuropathy (DN) is the most challenging microvascular complication of diabetes and there is no suitable treatment for it, so the development of new agents to relieve DN is urgently needed. Since oxidative stress and inflammation play an essential role in the development of DN, clearance of these factors are good strategies for the treatment of this disease. According to key role of cyclic adenosine monophosphate (cAMP) in the regulation of oxidative stress and inflammatory pathways, it seems that phosphodiesterase inhibitors (PDEIs) can be as novel drug targets for improving DN through enhancement of cAMP level. The aim of this study was to evaluate the effects of rolipram, a selective PDE4 inhibitor, and pentoxifylline, a general PDE inhibitor on experimental model of DN and also to determine the possible mechanisms involved in the effectiveness of these agents. We investigated the effects of rolipram (1 mg/kg) and pentoxifylline (100 mg/kg) and also combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for five weeks in rats that became diabetic by STZ (55 mg/kg, i.p.). After treatments, motor function was evaluated by open-field test, then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Next, oxidative stress biomarkers and inflammatory factors were assessed by biochemical and ELISA methods, and RT-PCR analysis in DRG neurons. Rolipram and/or pentoxifylline treatment significantly attenuated DN - induced motor function deficiency by modulating distance moved and velocity. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, as well as suppressed DN - induced oxidative stress which was associated with decrease in LPO and ROS and increase in TAC, total thiol, CAT and SOD in DRG neurons. On the other hand, the level of inflammatory factors (TNF-α, NF-kB and COX2) significantly decreased following rolipram and/or pentoxifylline administration. The maximum effectiveness was with rolipram and/or pentoxifylline combination on mentioned factors. These findings provide novel experimental evidence for further clinical investigations on rolipram and pentoxifylline combination for the treatment of DN.

Anti-convulsive Effect of Thiamine and Melatonin Combination in Mice: Involvement of Oxidative Stress.

BACKGROUND: Epilepsy, the second most frequent neurological disease, is a chronic disorder with a high lifetime prevalence. Therefore, various studies are needed to find new effective therapeutic agents to treat seizures or prevent their complications. In this study, we investigated the effects of thiamine, melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice. METHODS: Male mice were randomly divided into six groups, including control, seizure control, diazepam, melatonin, thiamine and melatonin, and thiamine combination groups. Drugs were given orally in drinking water for 14 days. On the 15th day, the seizure was induced (except the control group) by intraperitoneal injection of PTZ. In all groups, the time between the injection and the start of the seizure (latency), and also the length of the seizure attack (duration), were measured in a 30-minute period. After measuring the latency and duration in all groups, mice were killed by CO2 Box and their brains were dissected to be analyzed for malondialdehyde (MDA) level as a marker of oxidative stress. RESULTS: The seizure duration was significantly lower in the groups of melatonin, thiamine and thiamine and melatonin combination compared to the seizure control group. The latency times in these groups were significantly greater than in the seizure control group. Moreover, MDA concentrations were lower in these groups compared to the seizure control group. CONCLUSION: Thiamine, melatonin and their combination can decrease the duration time of seizure and increase the latency period, which may result from inhibition of oxidative stress in the brain.

Effects of coenzyme Q10 on health-related quality of life, clinical disease activity and blood pressure in patients with mild to moderate ulcerative colitis: a randomized clinical trial.

Background: Ulcerative colitis (UC) is specified by a chronic mucosal inflammation that has a deleterious impact on the quality of life (QoL). Coenzyme Q10 (CoQ10) appears to influence disease activity by its obvious properties. Therefore, the current research intends to assess the impacts of CoQ10 on QoL, disease activity, and blood pressure in UC patients. Methods: This clinical trial performed on men and women with UC in 2017 who were attended the gastrointestinal center of Hazrat Rasool Akram Hospital and private clinic. Eighty-eight UC patients were randomly allocated to receive either CoQ10 (200 mg/day) or placebo for 8 weeks. The anthropometric parameters, blood pressure, inflammatory bowel disease questionnaire-32 (IBDQ-32) score, and the Simple Clinical Colitis Activity Index (SCCAI) score were measured pre and post-intervention. P-value <0.05 was considered to be statistically significant. All statistical analysis was done using SPSS software version 24. Results: Eighty-six UC patients (44 males) with a mean age of 39.29 (10.19) years completed the trial. The results of between- and within-group analysis revealed that the SCCAI score (p<0.001 and p<0.001, respectively), diastolic blood pressure (p=0.025 and p=0.001, respectively), and systolic blood pressure (p=0.001 and p<0.001, respectively) decremented significantly; while, the mean IBDQ-32 (p<0.001 and p=0.001, respectively) increased substantially in the CoQ10 group; whereas there was no significant difference in anthropometric indices in both groups. Conclusion: Findings suggest that CoQ10 can be used as a potential intervention for diminishing the disease severity and blood pressure and may improve QoL and UC patients. IRCT number: IRCT20090822002365N17.

SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: beneficial effects of melatonin.

Coronaviruses (CoVs) are a group of single stranded RNA viruses, of which some of them such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are associated with deadly worldwide human diseases. Coronavirus disease-2019 (COVID-19), a condition caused by SARS-CoV-2, results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with high mortality in the elderly and in people with underlying comorbidities. Results from several studies suggest that CoVs localize in mitochondria and interact with mitochondrial protein translocation machinery to target their encoded products to mitochondria. Coronaviruses encode a number of proteins; this process is essential for viral replication through inhibiting degradation of viral proteins and host misfolded proteins including those in mitochondria. These viruses seem to maintain their replication by altering mitochondrial dynamics and targeting mitochondrial-associated antiviral signaling (MAVS), allowing them to evade host innate immunity. Coronaviruses infections such as COVID-19 are more severe in aging patients. Since endogenous melatonin levels are often dramatically reduced in the aged and because it is a potent anti-inflammatory agent, melatonin has been proposed to be useful in CoVs infections by altering proteasomal and mitochondrial activities. Melatonin inhibits mitochondrial fission due to its antioxidant and inhibitory effects on cytosolic calcium overload. The collective data suggests that melatonin may mediate mitochondrial adaptations through regulating both mitochondrial dynamics and biogenesis. We propose that melatonin may inhibit SARS-CoV-2-induced cell damage by regulating mitochondrial physiology.

A randomized controlled trial on the coloprotective effect of coenzyme Q10 on immune-inflammatory cytokines, oxidative status, antimicrobial peptides, and microRNA-146a expression in patients with mild-to-moderate ulcerative colitis.

PURPOSE: Coenzyme Q10 (CoQ10), having potent antioxidant and anti-inflammatory pharmacological properties, has recently been shown to be a safe and promising agent in maintaining remission of ulcerative colitis (UC). This trial was, therefore, designed to determine CoQ10 efficacy on inflammation and antioxidant status, antimicrobial peptides, and microRNA-146a expression in UC patients. METHODS: In this randomized double-blind controlled trial, 88 mild-to-moderate UC patients were randomly allocated to receive CoQ10 (200 mg/day) or placebo (rice flour) for 2 months. At the baseline and at an 8-week follow-up, serum levels of Nrf2, cathelicidin LL-37, ß-defensin 2, IL-10, IL-17, NF-κB p65 activity in peripheral blood mononuclear cells (PBMCs), simple clinical colitis activity index questionnaire (SCCAIQ), and quality of life (IBDQ-32 score), as well as an expression rate of microRNA-146a were measured. RESULTS: A significant reduction was detected in the serum IL-17 level, activity of NF-κB p65 in PBMCs, and also SCCAI score in the CoQ10 group compared to the placebo group, whereas IL-10 serum concentrations and IBDQ-32 score of the CoQ10 group considerably increased versus the control group; the changes of these variables were also significantly different within and between groups at the end of the study. Furthermore, CoQ10 remarkably increased serum levels of cathelicidin LL-37. A significant change in serum cathelicidin LL-37 levels was also observed between the two groups. No statistical difference, however, was seen between the two groups in terms of the serum levels of Nrf2 and ß-defensin 2 and the relative expression of microRNA-146a. CONCLUSIONS: Our results indicate that CoQ10 supplementation, along with drug therapy, appears to be an efficient reducer of inflammation in patients with mild-to-moderate UC at a remission phase. TRIAL REGISTRATION: The research has also been registered at the Iranian Registry of Clinical Trials (IRCT): IRCT20090822002365N17.

Thermosensitive magnetic nanoparticles exposed to alternating magnetic field and heat-mediated chemotherapy for an effective dual therapy in rat glioma model.

The goal of this study was to develop a new method based on Oncothermia with concomitant use of the temozolomide (TMZ)-loaded magnetic nanoparticles conjugated with folic acid (TMZ/MNPs-FA) and alternative magnetic field (AMF) and evaluate its efficacy in the treatment of C6 glioma in rats. TMZ/MNPs-FA were prepared and evaluated for their size, surface charge, magnetic saturation, hemolysis and in vitro AMF-triggered release. The glioma rat models were treated with free TMZ, MNPs-FA and TMZ/MNPs-FA in the presence or absence of AMF (43 °C). The results confirmed that a combinatorial therapy consisting of AFM hyperthermia and thermosensitive TMZ/MNPs-FA could significantly suppress tumor growth, increase survival rate and promote apoptosis (P < 0.0001). Therefore, this treatment strategy may be a powerful modality for treatment of cancer, as the thermal and mechanical effects of magnetic nanoparticles exposed to AMF can increase the therapeutic efficacy of conventional chemotherapy.

Enhancement radiation-induced apoptosis in C6 glioma tumor-bearing rats via pH-responsive magnetic graphene oxide nanocarrier.

5-iodo-2-deoxyuridine (IUdR) has been demonstrated to induce an appreciable radiosensitizing effect on glioblastoma patients, but due to the short circulation half-life times and failure to pass through the blood-brain barrier (BBB), its clinical use is limited. Accordingly, in this study, we used magnetic graphene oxide (NGO/SPIONs) nanoparticles coated with PLGA polymer as a dynamic nanocarrier for IUdR and, evaluated its sensitizing enhancement ratio in combination with a single dose X-ray at clinically megavoltage energies for treatment of C6 glioma rats. Nanoparticles were characterized using Zetasizer and TEM microscopy, and in vitro biocompatibility of nanoparticles was assessed with MTT assay. IUdR/MNPs were intravenously administered under a magnetic field (1.3 T) on day 13 after the implantation of C6 cells. After a day following the injection, rats exposed with radiation (8 Gy). ICP-OES analysis data indicated an effective magnetic targeting, leading to remarkably improved penetration through the BBB. In vivo release analysis with HPLC indicated sustained release of IUdR and, prolonged the lifespan in plasma (P < .01). In addition, our findings revealed a synergistic effect for IUdR/MNPs coupled with radiation, which significantly inhibited the tumor expansion (>100%), prolonged the survival time (>100%) and suppressed the anti-apoptotic response of glioma rats by increasing Bax/Bcl-2 ratio (2.13-fold) in compared with the radiation-only. In conclusion, besides high accumulation in targeted tumor sites, the newly developed IUdR/MNPs, also exhibited the ability of IUdR/MNPs to significantly enhance radiosensitizing effect, improve therapeutic efficacy and increase toxicity for glioma-bearing rats.

Ellagic Acid Prevents Oxidative Stress, Inflammation, and Histopathological Alterations in Acrylamide-Induced Hepatotoxicity in Wistar Rats.

The present study was designed to investigate the changes in rat liver tissue after administration of acrylamide (ACR) and ellagic acid (EA). The latter compound was applied for its strong antioxidant and anti-inflammatory properties. In the present study, 35 male Wistar rats were randomly divided into five equal groups. These groups were normal saline (NS), ACR (20 mg/kg), ACR + EA (10 and 30 mg/kg EA), and EA (30 mg/kg). At the end of the experiment, the rats were decapitated. Biochemical and histopathological studies were conducted on liver and serum samples. ACR administration significantly decreased hepatic GSH level, SOD, GPx, and CAT activity when compared to the NS group. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), nitric oxide (NO), protein carbonyl (PC), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1ß) levels increased as a result of ACR administration. Administration of EA (more potently at a dose of 30 mg/kg) resulted in a significant reversal of biochemical, inflammatory, and hepatic markers in ACR-intoxicated rats. These biochemical and inflammatory disturbances were supported by histopathological observations of the liver. Our results indicate that EA might be useful for the treatment of the hepatotoxicity induced by ACR via ameliorative effects on biochemical, oxidative stress, and inflammatory indices.

Cerium and Yttrium Oxide Nanoparticles and Nano-selenium Produce Protective Effects Against H2O2-induced Oxidative Stress in Pancreatic Beta Cells by Modulating Mitochondrial Dysfunction.

BACKGROUND: Type 1 diabetes mellitus is characterized by the destruction of insulin- producing Beta cells in the pancreas. Researchers hope that islet transplantation will help to patients with insulin-dependent diabetes mellitus (IDDM). Oxidative stress is the most important challenge that beta cells face to it after isolation, and mitochondrial dysfunction is a crucial mediator in beta cells death. Hence, therapeutic approaches can shift to antioxidants through the application of nanoparticles such as cerium and yttrium oxide nanoparticles (Cer and Ytt Ox NPs) and nano-selenium (Nan Se). OBJECTIVE: This study evaluates the effects of Cer and Ytt Ox NPs and Nan Se on H2O2- induced oxidative stress in pancreatic beta cells with focus on mitochondrial dysfunction pathway. METHODS: CRI-D2 beta-cell line were pretreated with Cer Ox NPs (200 µM) + Ytt Ox NPs (0.5 µg/mL) for 3 days and/or Nan Se (0.01 µM) for 1 day. Then markers of oxidative stress, mitochondrial dysfunction, insulin and glucagon secretion were measured. RESULTS: We reported a decrease in H2O2-induced reactive oxygen species (ROS) level and glucagon secretion, and an increase in H2O2-reduced ATP/ADP ratio, MMP, as well as UCP2 protein expression, and insulin secretion by pretreatment of CRI-D2 cells with Cer and Ytt Ox NPs and/or Nan Se. CONCLUSION: We found maximum protective effect with Cer and Ytt Ox NPs on CRI-D2 beta-cell line exposed by H2O2 for keeping beta cells alive until transplant whereas combination of Cer and Ytt Ox NPs and Nan Se had very little protective effect in this condition.

Phosphodiesterase 4 and 7 inhibitors produce protective effects against high glucose-induced neurotoxicity in PC12 cells via modulation of the oxidative stress, apoptosis and inflammation pathways.

Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50-60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways. Phosphodiesterase 4 and 7 (PDE 4 and 7) regulate oxidative damage, neurodegenaration, and inflammatory responses through modulation of cyclic adenosine monophosphate (cAMP) level, and thus can be as important drug targets for regulating DN. The aim of this study was to evaluate the protective effects of inhibitors of PDE 4 and 7, named rolipram and BRL5048, on HG-induced neurotoxicity in PC12 cells as an in vitro cellular model for DN and determine the possible mechanisms for theirs effects. We report that the PC12 cells pre-treatment with rolipram (2 µM) and/or BRL5048 (0.2 µM) for 60 min and then exposing the cells to HG (4.5 g/L for 72 h) or normal glucose (NG) (1 g/L for 72 h) condition show: (1) significant attenuation in ROS, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, MMP and ATP levels. All these data together led us to propose PDE 4 and 7 inhibitors, and specifically, rolipram and BRL5048, as potential drugs candidate to be further studied for the prevention and treatment of DN.

Sildenafil protective effects on high glucose-induced neurotoxicity in PC12 cells: the role of oxidative stress, apoptosis, and inflammation pathways in an in vitro cellular model for diabetic neuropathy.

Objectives Diabetic neuropathy (DN) induces lifetime disability and there is currently no effective therapy to treat or to minimize patients suffering, so it is thereby imperative to develop therapeutic strategies for this disease. Since oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial mechanisms in development and progression of DN, it is important to explore tools by which one can reduce factors related to these pathways. Herein, the understandings of the sildenafil neuroprotective effect through increase of cGMP level and the mediation of oxidative stress, apoptosis, and inflammation pathways on neurotoxicity induced by high glucose (HG) in PC12 cells as an in vitro cellular model for DN were investigated. Methods We reported that the PC12 cells pre-treatment with sildenafil (0.008 µM) for 60 min and then exposing the cells to HG (25 mM for 72 h) or normal glucose (NG) (5 mM for 72 h) condition, show: Results (1) significant attenuation in reactive oxygen species, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, mitochondrial membrane potential, and ATP levels. Conclusion All these data together led us to propose neuroprotective effect of sildenafil is probably through its antioxidant, antiapoptotic, and anti-inflammatory activities. Of course, further studies are required to explain the underlying mechanism of the sildenafil effects.

Genetic polymorphisms in FAS (CD95) and FAS ligand (CD178) promoters and risk of tobacco-related oral carcinoma: gene-gene interactions in high-risk Indians.

We assessed the association of functional single nucleotide polymorphisms (SNP) in FAS -1377, -670 and FAS ligand (FASL) -844 promoters in 139 oral cancer patients and 126 normal subjects by PCR-RFLP. In logistic regression analysis FAS -1377 GA genotype appeared to marginally increase the risk while FASL -844 TC genotype appeared as low risk factor. The combined genotypes FAS -1377 GA or AA and FASL -844 TT (p <0.03), and FAS -670 AG or GG and FASL -844 TT (p <0.007) appeared to double the risk. FAS and FASL gene-gene and gene-environment interactions seems to modulate susceptibility/resistance to tobacco-related oral cancer in Indians.