Calcium Dobesilate Ameliorates Cisplatin-induced Hepatotoxicity by Inhibiting Liver Oxidative Stress in Mice.

Background: Cisplatin has potent antitumor properties. It has several toxic side effects, such as hepatotoxicity. It is thought that hepatotoxicity induced by cisplatin is caused by oxidative stress. Objectives: It has shown that calcium dobesilate (CD) has potent antioxidant properties. The present study aimed to assess CD protective effects on cisplatin-induced hepatotoxicity in mice. Methods: In this study, 28 mice were selected randomly and were divided into four groups, including control, cisplatin (20 mg/kg, i.p., only on the first day of the experiment), Cisplatin+CD 50 (50 mg/kg CD, orally), and Cisplatin+CD 100 (cisplatin with 100 mg/kg CD, orally). A 4-day oral gavage of CD was applied to the treated groups. The mice were sacrificed on the 5th day, and serum glutamic pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), malondialdehyde (MDA) and reactive oxygen species (ROS) levels, superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzyme activity levels in liver tissue were evaluated. Histopathological evaluation was assessed using hematoxylin and eosin-stained liver tissue sections. Results: The results indicated that there was a significant increase in GSPT, SGOT, ALP, and MDA and also a significant reduction in the liver activity of SOD and GPx in cisplatin-treated animals. Treatment with CD (100 mg/kg) remarkably attenuated the GSPT, SGOT, ALP, MDA, and ROS levels. Moreover, CD (100 mg/kg) elevated the SOD and GPx activity in the liver tissue of cisplatin-treated mice. Conclusions: The findings showed that CD has a protective effect against cisplatin-induced hepatotoxicity, at least by improving the antioxidant parameters.

Distinct signatures on d-galactose-induced aging and preventive/protective potency of two low-dose vitamin D supplementation regimens on working memory, muscular damage, cardiac and cerebral oxidative stress, and SIRT1 and calstabin2 downregulation.

Chronic administration of d-galactose (d-gal) in rodents reproduces the overproduction of reactive oxygen species of physiological aging. The present research shows for the first time distinct signatures on d-gal-induced aging (500 mg/kg, 6 weeks) and the preventive and protective potential of two vitamin D (50 IU) supplementation regimens (pre-induction and simultaneous, respectively) in two vital organs (heart and brain). d-gal-induced notorious alterations in working memory, a strong increase in brain malondialdehyde (MDA) oxidative levels, and strong downregulation of sirtuin 1 (SIRT1) in the heart and hippocampus and of calstabin2 in the heart. Cardiac and brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic antioxidant capacities were damaged, brain calstabin2 was downregulated, and neuropathology was observed. Heart damage also included a moderate increase in MDA levels, serologic lactate dehydrogenase (LDH), total creatine kinase (CK) activities, and histopathological alterations. The used dose of vitamin D was enough to prevent cognitive impairment, avoid muscular damage, hamper cardiac and cerebral oxidative stress, and SIRT1 and calstabin2 downregulation. Most importantly, the potencies of the two preventive schedules depended on the tissue and level of study. The pre-induction schedule prevented d-gal-induced aging by 1 order of magnitude higher than simultaneous administration in all the variables studied except for SIRT1, whose strong downregulation induced by d-gal was equally prevented by both schedules. The benefits of vitamin D for oxidative stress were stronger in the brain than in the heart. Brain MDA levels were more sensitive to damage, while SOD and GPx antioxidant enzymatic activities were in the heart. In this order, the magnitude of SOD, MDA, and GPx oxidative stress markers was sensitive to prevention. In summary, the results unveiled distinct aging induction, preventive signatures, and sensitivity of markers depending on different levels of study and tissues, which are relevant from a mechanistic view and in the design of targeted interventions.

Dietary antioxidants and liver enzymes in Rafsanjan, a Region in Southeast Iran.

Oxidative stress has been considered the main contributor to liver injury. Dietary antioxidants would be expected to improve liver function. The hepatoprotective effects of antioxidants are controversial. In the present study, the associations of some dietary antioxidants and the levels of serum liver enzymes were examined. This cross-sectional study was conducted using the Rafsanjan Cohort Study (RCS) data as a population-based prospective cohort which is a part of the Prospective Epidemiological Research Studies in IrAN (PERSIAN). A total of 9942 participants aged 35-70 years old were included in this study. Among this population, 4631 (46.59%) were male, and 5311 (53.42%) were female. Dietary intakes were collected by a validated food frequency questionnaire (FFQ) with 128 items. Aspartate transaminase (AST), Alanine transaminase (ALT), γ-glutamyl transferase (GGT), and Alkaline phosphatase (ALP) were measured by a biotecnica analyzer. Dichotomous logistics regression models were used to investigate the association between the elevated liver enzymes and intake of dietary antioxidants using crude and adjusted models. In the adjusted model, in subjects with higher consumption of Se, Vit A, Vit E, ß-carotene, α-carotene, and ß-cryptoxanthin, the odds ratios of elevated ALP were decreased compared to the reference group (ORs 0.79 (0.64-0.96), 0.80 (0.66-0.98), 0.73 (0.60-0.89), 0.79 (0.64-0.96), 0.78 (0.64-0.95), 0.80 (0.66-0.98), and 0.79 (0.64-0.98), respectively). Subjects with higher consumption of Se, Vit A, Vit E, and provitamin A carotenoids (ß-carotene, α-carotene, ß-cryptoxanthin) showed decreased odds of elevated ALP. These findings support the hypothesis that Se, Vit A, Vit E, and provitamin A carotenoids may be associated with improvements in ALP and act as suppressors against the development of liver injury.

Apelin receptor antagonist boosts dendritic cell vaccine efficacy in controlling angiogenic, metastatic and apoptotic-related factors in 4T1 breast tumor-bearing mice.

Apelin/APJ axis plays a critical role in cancer progression, thus its targeting inhibits tumor growth. However, blocking of Apelin/APJ axis in combination with immunotherapeutic approaches may be more effective. This study aimed to investigate the effects of APJ antagonist ML221 in combination with a DC vaccine on angiogenic, metastatic and apoptotic-related factors in a breast cancer (BC) model. Four groups of female BALB/c mice with 4T1-induced BC were treated with PBS, APJ antagonist ML221, DC vaccine, and "ML221 + DC vaccine". After completion of the treatment, the mice were sacrificed and the serum levels of IL-9 and IL-35 as well as the mRNA expression of angiogenesis (including VEGF, FGF-2, and TGF-ß), metastasis (including MMP-2, MMP-9, CXCR4) and apoptosis-related markers (Bcl-2, Bax, Caspase-3) in tumor tissues were determined using ELISA and real-time PCR, respectively. Angiogenesis was also evaluated by co-immunostaining of tumor tissues with CD31 and DAPI. Primary tumor metastasis to the liver was analyzed using hematoxylin-eosin staining. The efficiency of combination therapy with "ML221 + DC vaccine" was remarkably higher than single therapies in preventing liver metastasis compared to the control group. In comparison with the control group, combination therapy could significantly reduce the expression of MMP-2, MMP-9, CXCR4, VEGF, FGF-2, and TGF-ß in tumor tissues (P < 0.05). It also decreased the serum level of IL-9 and IL-35 compared with the control group (P < 0.0001). Moreover, vascular density and vessel diameter were significantly reduced in the combination therapy group compared with the control group (P < 0.0001). Overall, our findings demonstrate that combination therapy using a blocker of the apelin/APJ axis and DC vaccine can be considered a promising therapeutic program in cancers.

Cohort-based analysis of paternal opioid use in relation to offspring's BMI and plasma lipid profile.

A growing body of evidence suggests that opioid use may affect consumer's offspring by second-hand passive smoke exposure, as well as by transgenerational impacts mediated by genetic and epigenetic alterations of paternal gametes. In human studies, these effects are limited to investigating the neural, behavioral and cognitive characteristics of offspring. Only animal studies have investigated the metabolic parameters influenced by passive opium smoke exposure. Here, we conducted population-based analyses aimed to estimate the association of paternal opioid consumption, started before or after child birth, with BMI status and plasma lipid profile of young adult offspring. The present study includes 840 parents-offspring trios (offspring aged 15-35, parents aged 35-70) who participated in the prospective Rafsanjan Cohort Study (RCS)-a city in the south-east of Iran-as one of the district areas of the PERSIAN cohort (Prospective Epidemiological Research Studies in IrAN). All procedures for interviews, anthropometric measurements and physical examinations, biological sample collection and laboratory tests for blood biochemical parameters were conducted according to the PERSIAN cohort protocol, and in the well-established RCS setting. Crude and adjusted multiple logistic regression analysis were conducted to assess the relationship of paternal regular opioid use with offspring's BMI status, and plasma lipid factors. The prevalence of fathers who use opioids regularly among the studied trios was 42.8% (360/840). Our regression analyses demonstrated that paternal opioid use started pre-fatherhood is associated with 76% higher adjusted odds ratio (OR) of overweight/obesity in young offspring (adjusted OR 1.76 (95% CI 1.15-2.71)), adjusting for sex, age, parental BMIs, paternal smoking status and socioeconomic status index (WSI). This relationship persisted when fathers who used opioid by routes other than inhaling (oral) were excluded from logistic analysis (adjusted OR 1.73 (95% CI 1.12-2.68)). Interestingly, sex stratified analysis displayed a 201% increased odds ratio of overweight/obesity in sons of fathers who use opioid regularly, started after child birth (Adjusted OR 3.01 (95% CI 1.68-5.39), while no significant association was found in daughters (adjusted OR 0.74 (95% CI 0.35-1.54)). Additionally, increasing exposure-response relationships were observed between odds ratios of overweight/obesity and the number of years of paternal opioid use after birth (p-trend = 0.0008). Paternal regular opioid use started pre-fatherhood was associated with 54% lowered risk of underweight [adjusted OR 0.46 (95% CI 0.24-0.86)]. Finally, paternal opioid consumption started either before or after child birth did not show a significant association with the high level of the three parameters of plasma lipid factors (triglyceride, cholesterol and HDL-cholesterol) in offspring. Our results suggest that the environmental impacts of paternal regular opioid use may be sufficient to make an effect on male offspring metabolism independent of genetic and epigenetic impact on gametes.

Smoking, alcohol and opioids effect on coronary microcirculation: an update overview.

Smoking, heavy alcohol drinking and drug abuse are detrimental lifestyle factors leading to loss of million years of healthy life annually. One of the major health complications caused by these substances is the development of cardiovascular diseases (CVD), which accounts for a significant proportion of substance-induced death. Smoking and excessive alcohol consumption are related to the higher risk of acute myocardial infarction. Similarly, opioid addiction, as one of the most commonly used substances worldwide, is associated with cardiac events such as ischemia and myocardial infarction (MI). As supported by many studies, coronary artery disease (CAD) is considered as a major cause for substance-induced cardiac events. Nonetheless, over the last three decades, a growing body of evidence indicates that a significant proportion of substance-induced cardiac ischemia or MI cases, do not manifest any signs of CAD. In the absence of CAD, the coronary microvascular dysfunction is believed to be the main underlying reason for CVD. To date, comprehensive literature reviews have been published on the clinicopathology of CAD caused by smoking and opioids, as well as macrovascular pathological features of the alcoholic cardiomyopathy. However, to the best of our knowledge there is no review article about the impact of these substances on the coronary microvascular network. Therefore, the present review will focus on the current understanding of the pathophysiological alterations in the coronary microcirculation triggered by smoking, alcohol and opioids.

Nursing strikes among infants and its affecting factors in Rafsanjan city.

The infant's refusal to breastfeed can be a stressful and concerning matter for a mother. This study aimed to investigate the frequency and factors leading to nursing strikes in Rafsanjan city. This descriptive study was performed on infants who had been referred to the pediatrician's office with a complaint of a nursing strike. The research sample included 70 infants, and all the required data, including the causes of the nursing strike and the demographic information of the mother and the infant, were collected using a checklist. The Statistical Package for the Social Sciences (SPSS) software version 20 was used to analyze the data. The percentage was used to express qualitative indices, and the mean and standard deviation were used to express quantitative indices. The results showed that the most common factors contributing to the infants' breast refusal were playfulness and distraction (50%) and recent vaccinations in the last 12 days (48.6%). Besides, the most common maternal factors affecting breast refusal were level of education (67.1%), recent acute stress (41.4%), and inadequate milk production (35.7%). The results of the present study showed that playfulness and distraction of the baby, recent vaccination, use of a pacifier, level of education and recent stress of the mother, breastfeeding program, and insufficient milk production are the most common reasons for nursing strikes.

The profile of Rafsanjan Cohort Study.

Owning the largest human-made jungle of pistachio, the second largest copper mine, and being located on the trade route of opium transit, distinguish Rafsanjan from many other cities in Iran. The environmental exposures and lifestyle factors associated with these characteristics of Rafsanjan, have raised concern about possible health outcomes for individuals living in and around this city. Thus, local health authorities initiated the Rafsanjan Cohort Study (RCS), as part of the prospective epidemiological research studies in IrAN (PERSIAN). RCS is a population-based prospective cohort of men and women aged 35-70 years, launched in August 2015. Individuals from diverse socioeconomic levels and lifestyles were recruited from four urban and suburban areas of Rafsanjan (participation rate 67.42%). Questionnaire-based interviews regarding demographics, dietary and environmental exposures, medical and occupational history, as well as anthropometric measurements were completed for all participants. Additionally, bio-specimens (blood, urine, hair, and nail) were collected, and dental and eye examinations were performed. The enrollment phase ended in December 2017, and a 15-year follow-up is planned. A total of 9990 individuals were enrolled in RCS (53.41% females). About 26% of men are pistachio farmers. The baseline prevalence of major non-communicable disease (NCD) risk factors such as cigarette smoking, alcohol consumption and opium use were 25.45%, 10.02%, and 23.81%, respectively. The mean ± SD of other common risk factors are as follows: body mass index (27.83 ± 4.89 mm Hg), systolic blood pressure (107.18 ± 17.56 mm Hg) diastolic blood pressure (71.13 ± 10.83), fasting blood sugar (113.27 ± 39.11 mg/dL) and plasma cholesterol (198.78 ± 41.89 mg/dL). These results indicate a concerning prevalence of NCD risk factors in Rafsanjan city, warranting further detailed investigations, particularly regarding the association of NDC with agricultural/industrial pollutants and drug abuse.

Calcium dobesilate prevents cisplatin-induced nephrotoxicity by modulating oxidative and histopathological changes in mice.

Cisplatin is one of the synthetic cancer medicines with nephrotoxicity being one of its major side effects. Past research shows that calcium dobesilate (CaD), as a vascular protective agent in diabetic retinopathy, has antioxidant properties. Thus, this study aims to evaluate the protective effects of CaD in cisplatin-induced nephrotoxicity in mice. A many as 28 mice, in the present experimental research, were randomly distributed into four groups, including control, cisplatin (the intraperitoneal administration of 20 mg/kg cisplatin only on the first day of the experiment), cisplatin + CaD 50 (cisplatin with the oral administration of 50 mg/kg CaD), and cisplatin + CaD 100 (cisplatin with the oral administration of 100 mg/kg CaD). The treated groups received CaD by oral gavage for 4 constitutive days. On the fifth day, the mice were sacrificed, and some biochemical (serum levels of Cr and BUN, renal tissue levels of MDA, and renal activities of SOD and GPx) and pathological parameters were evaluated. Based on the results, there was a significant decrease in the renal SOD and GPx activities; in contrast, there was a significant increase in the BUN, Cr, and renal MDA levels following administering cisplatin. However, the CaD treatment (100 mg/kg) significantly attenuated these alterations. In addition, the kidney's histological examination of kidneys confirmed the nephroprotective effects of CaD. The findings proved the protective impact of CaD on cisplatin-induced nephrotoxicity by an improvement in the oxidative stress factors.

Sumatriptan ameliorates renal injury induced by cisplatin in mice.

OBJECTIVES: Cisplatin (Cis) is an anticancer compound, which is used for the treatment of various cancers. Sumatriptan (Suma) is a selective agonist of 5-hydroxytryptamine 1B/1D (5HT1B/1D) receptor, which is prescribed for the management of migraine. It is well-established that Suma has anti-inflammatory and antioxidant properties. We have explored the protective effects of Suma in the mitigation of Cis-induced nephrotoxicity. MATERIALS AND METHODS: The mice received a single IP injection of Cis (20 mg/kg) on the first day of the experiment. Suma treatment (0.1 and 0.3 mg/kg/day, IP) was started on day 1 and continued for 3 consecutive days. RESULTS: Creatinine (Cr), blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were elevated and glutathione peroxidase (GPx) as well as superoxide dismutase (SOD) activities were decreased in Cis-treated mice. Suma (more potently 0.3 mg/kg) reduced Cr, BUN and MDA levels and increased SOD and GPx levels. Suma also reduced the acute renal injury (tubular degeneration, tubular cells vacuolation, tubular necrosis and cast), which corresponded to kidney damage in Cis-treated mice. CONCLUSION: These findings demonstrate that Suma mitigates Cis-induced renal injury by inhibition of oxidative stress and enhancing the antioxidant enzymes activities.

Treatment with troxerutin protects against cisplatin-induced kidney injury in mice.

BACKGROUND: Cisplatin (CP) is a synthetic and anticancer drug, and one of the major side effects of CP is nephrotoxicity. This study was done to evaluate the renoprotective effects of troxerutin (Tro) in nephrotoxicity induced by CP in male mice. METHODS: In this experimental study, 28 male mice were divided randomly into four groups. Mice were treated with CP (20 mg/kg, i.p.) then Tro (75 and 150 mg/kg/day, po) was administered for three consecutive days. Blood samples were collected to determine serum creatinine (Cr) and blood urea nitrogen (BUN) levels. The kidney tissues were used for histological examination and biochemical assays. Malondialdehyde (MDA) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were assessed in renal tissue. RESULTS: Results showed a significant increase in the Cr, BUN and MDA levels and a significant decrease in the renal SOD and GPx activity by CP administration. Treatment with Tro for three consecutive days attenuated these changes. Also, the renoprotective effect of the Tro was confirmed by the histological examination of the kidneys. CONCLUSIONS: Our results demonstrated that Tro has protective effects against CP-induced nephrotoxicity through improving the biochemical indices and the oxidative stress parameters.

Toll-like receptor 4 and breast cancer: an updated systematic review.

Toll-like receptors (TLRs) may play dual roles in human cancers. TLR4 is a key molecule which may participate in both friend and foe roles against breast cancer. This review article collected recent data regarding the mechanisms used by TLR4 in the eradication of breast cancer cells and induction of the tumor cells, and discussed the mechanisms involved in the various functions of TLR4. The literature searches revealed that TLR4 is a key molecule that participates in breast cancer cell eradication or induction of breast cancer development and also transformation of the normal cells. TLR4 eradicates breast cancer cells via recognition of their DAMPs and then induces immune responses. Over-expression of TLR4 and also alterations in its signaling, including association of some intrinsic pathways such as TGF-ß signaling and TP53, are the crucial factors to alter TLR4 functions against breast cancer.

Human papillomavirus genotypes in Iranian patients with cervical cancer.

The aim of this study was to determine the frequency of HPV genotypes isolated from cervical intra-epithelial neoplasia grade III and invasive carcinomas of Iranian patients. A total of 94 cases were selected in five years from 2003 to 2007. After nucleic acid purification, real-time PCR was performed by means of GP5+/GP6+ primers. Subsequently, PCR products were sequenced, on the basis of which a phylogenetic tree was constructed. Negative samples and twelve randomly selected positive samples were also typed by reverse hybridization to increase the sensitivity and to confirm the results. Of 94 evaluated samples, 7 were negative for internal control gene and were excluded from the study. The overall genotyping results of phylogenetic analysis and hybridization methods were as follows: HPV 16: 75% (65/87); HPV 18: 3% (2/87); HPV 31: 1% (1/87); HPV 45: 1% (1/87). High frequency of HPV 16 and low frequency of HPV 18 were found in this study. Information about HPV genotype distribution is important in cervical cancer screening and prevention.

Significance of deep section in small gastric biopsies.

AIM OF STUDY: Chronic gastritis is defined as the presence of chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia. This condition constitutes a background for dysplasia and thereby carcinoma. Detection of exact histopathology of inflammatory process is necessary in biopsy specimen. We designed the current study to determine the value of taking more sections in small gastric biopsies for better histopathologic evaluation. MATERIALS AND METHODS: Gastric biopsy specimen of children who suffered from gastrointestinal (GI) symptoms was sent in 10% formalin to our laboratory. After routine processing, three slides with several sections on them were taken from the specimen: t0 he first was named the superficial section, the second was stained by Giemsa and the third was named deep section (further sections after this slide will diminish in size). The slides were not taken exactly consecutively but several sections were discarded between them. The purpose of this study is to compare the superficial and deep sections for detection of inflammatory processes. RESULTS: In 1062 specimens the results of superficial section and deep section were the same (87.1%) and in 158 specimens the results were different. In 88 (7.2%) specimens deep section was diagnostic. The difference was seen usually as normal tissue in superficial sections but presence of lymphoid follicle in deep sections. The difference between superficial and deep sections was statistically significant. Although obtaining more sections will put an economic burden on the laboratory, we propose that in small gastric biopsies, it is helpful in better evaluation of histopathological changes.