Targeted Anticancer Drug Delivery Using Chitosan, Carbon Quantum Dots, and Aptamers to Deliver Ganoderic Acid and 5-Fluorouracil.

Breast cancer is a malignancy that affects mostly females and is among the most lethal types of cancer. The ligand-functionalized nanoparticles used in the nano-drug delivery system offer enormous potential for cancer treatments. This work devised a promising approach to increase drug loading efficacy and produce sustained release of 5-fluorouracil (5-FU) and Ganoderic acid (GA) as model drugs for breast cancer. Chitosan, aptamer, and carbon quantum dot (CS/Apt/COQ) hydrogels were initially synthesized as a pH-sensitive and biocompatible delivery system. Then, CS/Apt/COQ NPs loaded with 5-FU-GA were made using the W/O/W emulsification method. FT-IR, XRD, DLS, zeta potentiometer, and SEM were used to analyze NP's chemical structure, particle size, and shape. Cell viability was measured using MTT assays in vitro using the MCF-7 cell lines. Real-time PCR measured cell apoptotic gene expression. XRD and FT-IR investigations validated nanocarrier production and revealed their crystalline structure and molecular interactions. DLS showed that nanocarriers include NPs with an average size of 250.6 nm and PDI of 0.057. SEM showed their spherical form, and zeta potential studies showed an average surface charge of +37.8 mV. pH 5.4 had a highly effective and prolonged drug release profile, releasing virtually all 5-FU and GA in 48 h. Entrapment efficiency percentages for 5-FU and GA were 84.7±5.2 and 80.2 %±2.3, respectively. The 5-FU-GA-CS-CQD-Apt group induced the highest cell death, with just 57.9 % of the MCF-7 cells surviving following treatment. 5-FU and GA in CS-CQD-Apt enhanced apoptotic induction by flow cytometry. 5-FU-GA-CS-CQD-Apt also elevated Caspase 9 and downregulated Bcl2. Accordingly, the produced NPs may serve as pH-sensitive nano vehicles for the controlled release of 5-FU and GA in treating breast cancer.

Effect of Rosa damascena Extract on Rat Model Alzheimer's Disease: A Histopathological, Behavioral, Enzyme Activities, and Oxidative Stress Study.

The purpose of the current study is to investigate the effect of aquatic Rosa damascena extract against the oxidative damage induced by aluminum chloride intoxication in Alzheimer's model of Wister rats. Rats were divided randomly into seven groups (n = 10). Control group received no treatment, sham group received distilled water orally, aluminum group (AL) was administered AlCl3 (100 mg/kg) orally, extract 1 and 2 groups were treated with only aqueous R. damascena extract (DRE) (500 and 1000 mg/kg), and treatment 1 and 2 groups received aqueous R. damascena extract (500 and 1000 mg/kg) and AlCl3 (100 mg/kg) orally. The brain tissues were sampled for histopathological examination, and biochemical analysis was conducted for estimating the enzyme activities of acetylcholinesterase and catalase (CAT), the levels of GSH and MDA, and ferric reducing antioxidant power. According to the results of behavioral tests, AL administration showed a reduction in spatial memory and remarkably increased the time needed for reaching the invisible platform. The administration of Al-induced oxidative stress and an increase of the enzyme activity of AChE. Al administration increased AChE level from 1.176 ± 0.173 to 3.62 ± 0.348, which was a significant rise. However, treating with the extract at the dose of 1000 mg/kg downregulated it to 1.56 ± 0.303. Administration of the R. damascene extract caused an increased level of catalase and glutathione levels in treatment groups, attenuated MDA level, and regulated AChE activity. Our results illustrate that administration of R. damascene extract has a protective effect against the oxidative damage induced by AlCl3 intoxication in Alzheimer's model.

Changes in hormones, Leukocyte Telomere Length (LTL), and p16INK4a expression in SM-exposed individuals in favor of the cellular senescence.

Sulfur mustard (SM) is a chemical warfare agent with well-known severe toxic effects and may cause long-term debilitating injuries. We aimed to evaluate aging and longevity in Iranian SM-exposed survivors using some endocrine and molecular biomarkers for the first time. Dehydroepiandrosterone (DHEA), prolactin (PRL), cortisol, testosterone, and luteinizing hormone (LH) were measured in 289 male SM-veterans and 66 age-matched males using the ELISA method. Leukocyte Telomere Length (LTL) measurement and p16INK4a expression were measured in the peripheral blood leukocytes of 55 males who were exposed to SM. We found a significantly lower serum DHEAS level and higher serum PRL level in SM-exposed groups (without any related to the severity of lung injuries) compared to healthy controls, but no significant difference in serum levels of cortisol, testosterone, and LH. The molar ratio of DHEAS/cortisol was significantly higher in controls compared to the SM-exposed individuals especially those with severe lung damage. Some biological parameters of allostatic load score such as DHEAS and DHEAS/cortisol ratio significantly decreased long-term after the SM exposure. Additionally, we found that LTL was shorter in SM-exposed veterans rather than unexposed controls while p16INK4a gene expression significantly increased in these groups. It seems that DHEAS, DHEAS/cortisol ratio, LTL, and p16INK4a gene expression have changed significantly in favor of cellular senescence in SM-exposed patients. Therefore, it seems that SM exposure increases biological age compared to chronological age in SM-exposed survivors.

The inhibitory effect of PLGA-encapsulated berberine on hepatotoxicity and α-smooth muscle actin (α-SMA) gene expression.

BACKGROUND: Liver injury results in excessive extracellular matrix (ECM) deposition in the liver, which is mainly produced by hepatic stellate cells (HSC). Alpha-smooth muscle actin (α-SMA) and liver enzymes are the two hallmarks of liver injury. Previously, it has been confirmed that berberine (BBR) attenuates liver injury. This study aimed to investigate the protective effect of Poly Lactic-co-Glycolic Acid (PLGA) encapsulated BBR against liver injury. METHODS: Nanoprecipitation, encapsulation, and physio-chemical characterization of BBR-PLGA nanoparticles (BBR-PLGA-NP) have been done. The protective effects of BBR-PLGA-NPs and BBR against carbon tetrachloride (CCl4)-treated Wistar rats were investigated. The serum levels of alanine aminotransferase and aspartate transaminase were measured, and the expression level of α-SMA was quantified by qRT-PCR. To evaluate the liver changes, morphological and histological staining was done. RESULTS: BBR-PLGA-NPs markedly reduced serum ALT and AST in rats treated with CCl4. Although the expression level of α-SMA was downregulated in the CCl4-injected rats that were treated with BBR, α-SMA expression in this group was still remarkably higher than the control group. α-SMA mRNA was significantly under-expressed (p < 0.05) by BBR-PLGA-NPs and the hepatic histology revealed BBR-PLGA-NPs made further improvements than free BBR. CONCLUSION: The use of nanoparticle to encapsulate BBR is a worthy approach to enhance the curative effect of BBR against liver injuries, which donate a safe and effective drug delivery strategy to treat liver injuries.

Association of MUC1 5640G>A and PSCA 5057C>T polymorphisms with the risk of gastric cancer in Northern Iran.

BACKGROUND: Gastric cancer is one of the four most common cancer that causing death worldwide. Genome-Wide Association Studies (GWAS) have shown that genetic diversities MUC1 (Mucin 1) and PSCA (Prostate Stem Cell Antigen) genes are involved in gastric cancer. The aim of this study was avaluating the association of rs4072037G > A polymorphism in MUC1 and rs2294008 C > T in PSCA gene with risk of gastric cancer in northern Iran. METHODS: DNA was extracted from 99 formalin fixed paraffin-embedded (FFPE) tissue samples of gastric cancer and 96 peripheral blood samples from healthy individuals (sex matched) as controls. Two desired polymorphisms, 5640G > A and 5057C > T for MUC1 and PSCA genes were genotyped using PCR-RFLP method. RESULTS: The G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR = 0.507, 95% CI: 0.322-0.799, p = 0.003). A significant decreased risk of gastric cancer was observed in people with either AG vs. AA, AG + AA vs. GG and AA+GG vs. AG genotypes of MUC1 polymorphism (OR = 4.296, 95% CI: 1.190-15.517, p = 0.026), (OR = 3.726, 95% CI: 2.033-6.830, p = 0.0001) and (OR = 0.223, 95% CI: 0.120-0.413, p = 0.0001) respectively. Finally, there was no significant association between the PSCA 5057C > T polymorphism and risk of gastric cancer in all genetic models. CONCLUSION: Results indicated that the MUC1 5640G > A polymorphism may have protective effect for gastric cancer in the Northern Iran population and could be considered as a potential molecular marker in gastric cancer.

Biochemical, Toxicological, and Histopathological outcome in rat brain following treatment with NiO and NiO nanoparticles.

Nickel oxide nanoparticle (NiO NPs) has been widely used in various fields such as catalysts, radiotherapy, and nanomedicine. The aim of this study was to compare the effects of nickel oxide (NiO) and NiO NPs on oxidative stress biomarkers and histopathological changes in brain tissue of rats. In this study, 49 male rats were randomly divided into one control group and 6 experimental groups (n = 7). The control group received normal saline and the treatment groups received NiO and NiO NPs at doses of 10, 25, and 50 mg/kg intraperitoneally for 8 days. After 8 days, animal was sacrificed, brain excised, homogenized, centrifuged, and then supernatant was collected for antioxidant assays. The results showed that activity of GST in NiO NPs groups with doses of 10, 25, and 50 mg/kg (79.42 ± 4.24, p = 0.035; 78.77 ± 8.49, p = 0.041; 81.38 ± 12.39, p = 0.042 to 47.26 ± 7.17) and catalase in NiO NPs groups with concentrations of 25 and 50 mg/kg (69.95 ± 8.65 to 39.75 ± 5.11, p = 0.02) and (68.80 ± 4.18 to 39.75 ± 5.11 p = 0.027) were significantly increased compared with the control, respectively. Total antioxidant capacity in NiONPs group with doses of 50 mg/kg was significantly decreased (345.00 ± 23.62, p = 0.015 to 496.66 ± 25.77) compared with control. The GSH level in all doses NiO and NiONPs was significantly decreased compared with the control (p = 0.002). MDA level in NiONPs and NiO groups with doses of 50 mg/kg was significantly increased (13.03 ± 1.29, p = < 0.01; 15.61 ± 1.08, p = < 0.001 to 7.32 ± 0.51) compared with the control, respectively. Our results revealed a range of histopathological changes, including necrosis, hyperemia, gliosis, and spongy changes in brain tissue. Thus, increasing level of MDA, GST, and CAT enzymes and decreasing GSH and TAC and also histopathological changes confirmed NiONPs and NiO toxicity.

Protective Effect of Rosa damascena Against Aluminum Chloride-Induced Oxidative Stress.

Aluminum is considered an essential element endowed with toxicity potentials in human and animal. Thus, intoxication with aluminum can lead to oxidative stress, which is associated with oxidative damage to various macromolecules. Moreover, antioxidants from natural sources can play an important role in human health. Accordingly, the purpose of this study was to investigate the protective effect of Rosa damascena extract against aluminum-induced oxidative stress. In this study, 60 male rats were randomly divided into six groups and then they were given daily aluminum chloride and Rosa damascena extract. After 8 weeks of treatment, the levels of total antioxidant and malondialdehyde, as well as antioxidant enzymes including catalase, glutathione S-transferase, and myeloperoxidase, were measured in all experimental groups in this study. A significant increase was found in the total antioxidant level in the rats treated with aluminum, Rosa damascena extract, and aluminum plus Rosa damascena extract compared with those in the control group. Also, malondialdehyde levels were not significantly different in all the studied groups. Glutathione S-transferase activity levels in rats receiving the Rosa damascena extract as well as rats taking aluminum with Rosa damascena extract increased significantly compared with the ones in the control group. Catalase activity in the aluminum-treated group also increased significantly compared with the rates in the control group (31.34 ± 4.50 U/gHb vs. 14.04 ± 6.17 U/gHb, p = 0.014). Furthermore, myeloperoxidase activity in the aluminum-treated group increased significantly compared with the control group (49.47 ± 5.12 U/L vs. 25.28 ± 2.18 U/L, p < 0.001). The Rosa damascena extract could improve antioxidant capacity and reduce oxidative conditions in rats receiving aluminum chloride as evidenced by assays of the ferric reducing ability of plasma and activity of antioxidant enzymes. According to the findings of this study, it can be concluded that the Rosa damascena extract with its high antioxidant content is able to exert a protective effect against aluminum-induced oxidative stress.

Comprehensive analysis of oxidative stress markers and antioxidants status in preeclampsia.

Preeclampsia is a hypertensive disorder in pregnant women, which can be the leading cause of maternal and neonatal death or premature birth. Although the cause of preeclampsia is still not clear, local or systemic oxidative stress may explain the pathological features associated with this complication. However, it is not clear whether oxidative stress is the cause or the result of preeclampsia. For this purpose, the present meta-analysis was intended to evaluate the oxidant and antioxidant status in women with preeclampsia. Relevant studies were identified after a preliminary investigation of research articles published up to September 2017. In the overall analysis, including 2953 cases and 3621 controls, a statistically significant reduction in total antioxidant capacity, nitric oxide, superoxide dismutase, glutathione, vitamin E and C was observed in preeclampsia women. On the other hand, a statistically significant increase in malondialdehyde, protein carbonyl, total peroxide, glutathione peroxidase, catalase and uric acid were observed in preeclampsia women. The increased products of oxidative stress, which were found in the present meta-analysis might be an underlying mechanism for endothelial dysfunction in preeclampsia. This meta-analysis provides a scientific support that primary reduction of antioxidant capacity and increased levels of oxidative stress products may induce a condition in which the pathways responsible for blood pressure homeostasis are disrupted. In conclusion, it is hypothesized when oxidative stress is established, a protective response is induced by increasing some antioxidants. Further studies are warranted to investigate the role of dietary supplementation and genetic variation in women with different ethnicity.

Evidence of oxidative stress after continuous exposure to Wi-Fi radiation in rat model.

Exposure to electromagnetic radiation (EMR) is rapidly increasing in everyday environment, consequently conferring potential health effects. Oxidative stress is emerging as a mechanism implicated in pathophysiology and progression of various diseases. To our knowledge, no report has been made on the status of antioxidant redox systems after continuous exposure to radiofrequency radiation emitted from a Wi-Fi access point in animal model so far. Therefore, we aimed to continuously subject rats in the experimental group to radiofrequency (RF) radiation emitted from a commercially available Wi-Fi device. Male Wister rats were exposed to 2.45 GHz RF radiation emitted from a Wi-Fi for 24 h/day for 10 consecutive weeks. In order to assess the change in antioxidant redox system of plasma after continuous exposure to a Wi-Fi device, the total antioxidant capacity of plasma, level of thiobarbituric acid reactive substances, concentration of reduced glutathione (GSH), and activity of different enzymatic antioxidants, e.g., superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GSH-Px], and glutathione S-transferase [GST], were measured. In the Wi-Fi exposed group, a significant decrease was detected in total antioxidant capacity of plasma and the activities of several antioxidant enzymes, including CAT, GSH-Px, and SOD (P < 0.05). Meanwhile, the GST activity was significantly increased in this group (P < 0.05). However, no significant changes were found in GSH and TBARS levels following exposure to RF radiation. According to the results, oxidative defense system in rats exposed to Wi-Fi signal was significantly affected compared to the control group. Further studies are needed to better understand the possible biological mechanisms of EMR emitted from Wi-Fi device and relevant outcomes.

Altered levels of GST activity, Vit C, TPX and Cu in individuals with long-term sulfur mustard-induced lung complications.

CONTEXT: Sulfur mustard (SM) as a cytotoxic and blistering agent can alkylate a variety of cellular components, causing the incidence of ongoing oxidative stress. OBJECTIVE: The present study was conducted to assess oxidative stress index (OSI) in SM-exposed veterans with long-term pulmonary complications. METHODS: Participants consisted of 289 SM-exposed individuals with pulmonary complications (classified into three groups: mild, moderate and severe) and 66 healthy individuals as the control group. Enzymatic and non-enzymatic antioxidant and also trace elements were measured in the study groups. Moreover, some of oxidative stress indicators consist of malondialdehyde (MDA), protein carbonyl (CO), total antioxidant (TA) and total peroxide (TPX) were measured and then OSI was calculated. RESULTS: Glutathione-S-transferase (GST) activity and vitamin C (Vit C) were significantly decreased in SM-exposed patients as compared with controls. Besides, Cu level and Cu/Zn ratio in SM-exposed veterans showed a significant correlation with the severity of the diseases. Serum TPX was significantly increased in SM-exposed individuals, as a result of which the OSI was slightly higher in them than controls. This can be considered as an indicative for oxidative stress in SM-exposed patients. CONCLUSION: This study suggests a particular role for TPX, Cu, Vit C and GST in SM-induced pulmonary complications. Therefore, a special attention should be paid to these factors in designing therapeutic protocols, which can reduce the progression risk of the disease.

Catechol-O-methyltransferase Gene Polymorphism (Val158Met) and Development of Pre-eclampsia.

OBJECTIVES: Catechol-O-methyltransferase (COMT) is a key enzyme in degradation pathways of estrogens and catecholamines. The present meta-analysis was done to elucidate the association of COMT Val158Met polymorphism with pre-eclampsia among pregnant women. METHODS: A literature search was conducted in electronic databases including PubMed, Scopus, Elsevier, Springer and Google Scholar to find eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals were calculated under dominant, recessive, co-dominant, and allelic models. RESULTS: This meta-analysis included 6 eligible studies consisting 2596 cases and 4223 controls. The ORs for the COMT G472A polymorphism and pre-eclampsia were indicative of positive association under several genetic models. The results indicated that COMT Val158Met polymorphism was significantly associated with the increased risk of pre-eclampsia in recessive model (AA vs. AG + GG: OR = 1.522 [95% CI: 1.089-2.127]; p = 0.014), co-dominant model (AA vs. GG: OR = 1.605 [95% CI: 1.102-2.336]; p = 0.014), and allelic model (A vs. T: OR = 1.200 [95% CI: 1.021-1.402]; p = 0.021). CONCLUSIONS: In summary, COMT Val158Met polymorphism is positively associated with the increased risk of pre-eclampsia among pregnant women, especially the homozygous carriers. It could be of value to investigate its association with pre-eclampsia in combination with additional risk factors. However, very large studies with different ethnic population are required to accurately demonstrate the role of this candidate gene in development of pre-eclampsia.

Association of glutathione S-transferase polymorphisms with the severity of mustard lung.

Introduction: Glutathione S-transferase (GST) is one of the major detoxifiers in alveoli. Polymorphism in GST genes can influence the ability of individuals to suppress oxidative stress and inflammation. The present study was aimed to explore the hypothesis that the genetic polymorphisms of GST T1, M1 and P1 are associated with the severity of the mustard lung in the sulfur mustard-exposed individuals. Methods: Blood samples were taken from 185 sulfur mustard-exposed and 57 unexposed subjects. According to the stage of the mustard lung, sulfur mustard-exposed patients were categorized in the mild/moderate and severe/very severe groups. A multiplex PCR method was conducted to identify GSTM1 and GSTT1 null genotypes. To determine the polymorphisms of GSTP1 in exon 5 (Ile105Val) and exon 6 (Ala114Val), RFLP-PCR method was performed. Results: The frequency of GSTM1 homozygous deletion was significantly higher in the severe/very severe patients compared with the mild/moderate subjects (66.3% vs. 48%, P = 0.013). The GSTM1 null genotype was associated with the severity of mustard lung (adjusted odds ratio [OR], 2.257; 95% CI, 1.219-4.180). There was no significant association between GSTT1 and GSTP1 polymorphisms with the severity of the mustard lung. Conclusion: The different distribution of GSTM1 null genotype in severe/very severe and mild/moderate groups indicated that the severity of the mustard lung might be associated with the genetic polymorphism(s).

Effects of paraoxonase 1 activity and gene polymorphisms on long-term pulmonary complications of sulfur mustard-exposed veterans.

Sulfur mustard (SM) is an alkylating agent with prolonged adverse effects. The antioxidant paraoxonase 1 (PON1), an endogenous free radical scavenger, plays a protective role against oxidative stress. The possible roles of oxidative stress in the pathogenesis of SM, together with the antioxidant activity of PON1, are enough to warrant the analysis of PON1 polymorphisms and allelic variants in incapacitated veterans. PON1 55 L/M and 192 Q/R polymorphisms were assayed in 289 male veterans with severe pulmonary conditions, who were exposed to SM 20-25 years ago, and 66 gender-, age- and ethnic-matched healthy controls. As we showed previously the PON1 activity decreased significantly in veterans. However, PON1 55 L/M and 192 Q/R genotype distributions were not significantly different between the veterans and the controls. R and L allele carriers have also significantly higher basal and salt-stimulated PON1 activity than Q and M allele carriers. Paraoxonase and arylesterase activities in individuals with the QQ+(MM or LM) genotype were significantly lower than those with the (RR or QR)+LL genotype. Furthermore, basal and salt-stimulated paraoxonase activity in veterans with the (RR or QR)+LL genotype was significantly lower than that in the controls. A positive correlation has been determined between serum PON1 activity and pulmonary function test in QR/LL genotypes. Some of the veterans with RR+QR genotypes have also shown a novel missense change of Asn227Ser in exon 6 of the enzyme. This substitution is close to the binding domain of PON1 and so modifies enzyme activity.

Serum albumin and paraoxonase activity in Iranian veterans 20 years after sulfur mustard exposure.

Sulfur mustard, a chemical warfare agent, has short- and long-term effects on various organs including respiratory system. Its late toxic effects on biological macromolecules among exposed veterans have not been well studied. We performed a study to determine paraoxonase-1 (PON1) activity and phenotype distribution as well as its correlation with albumin level in 289 male veterans with severe pulmonary complications who had exposure to sulfur mustard 20 years ago and in 66 age and ethnic matched healthy male subjects as controls. Serum albumin levels were lower in the veterans compared to controls (P < 0.001). Mean basal PON1 activity was 91.61 ± 44.80 U/mL in the veteran group versus 110.27 ± 50.23 U/mL in controls (P = 0.005). Arylesterase activity was not significantly different between the two groups. Paraoxonase to arylesterase activity ratio was significantly lower in the veterans as compared to controls (P = 0.005), mainly indicative of decreased PON1 activity rather the enzyme level. Significant reduction was found in serum albumin and PON1 activity with disease severity. Moreover, decreased high active BB (high activity) phenotype and increased intermediate active AB (moderate activity) phenotype were found in the veterans. This condition may lead to long-term accumulation of reactive oxygen metabolites resulting in a pro-oxidation milieu, which in turn can lead to increased peroxide levels and decreased antioxidant PON1 activity. In conclusion, lower serum PON1 activity and albumin might contribute to morbidity and occurrence of other complications such as atherosclerosis and rapid aging in the veterans suffering from late toxic effects of sulfur mustard.