Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2.

Acetaminophen (APAP)-induced acute liver injury (ALI) is the principal cause of acute liver failure (ALF) in some countries including the United States and with few available treatments. Isorhamnetin is a bioflavonoid that is found in medicinal plants like Hippophae rhamnoides L. and Ginkgo biloba L. with promising potential to regulate inflammatory responses. In this study, we evaluated the possible effect of isorhamnetin in prevention of APAP-induced ALI and analyzed further the involvement of oxidative stress and inflammation-associated factors. Male C57BL/6 mice were given isorhamnetin (25 or 100 mg/kg b.w., p.o.) three times at 48, 24, and 1 h before APAP administration (300 mg/kg b.w., i.p.). Functional indicators of liver injury were measured as well as analysis of oxidative stress- and inflammation-associated indices and liver histopathology was also conducted. Isorhamnetin at the higher dose of 100 mg/kg significantly lowered serum levels of ALT, ALP, and AST in addition to reduction of ROS, TBARS, IL-6, TNFα, NF-kB, NLRP3, caspase 1, and MPO and significantly prevented reduction of GSH, SOD activity, sirtuin 1, and Nrf2. Additionally, isorhamnetin alleviated pathological changes of the liver tissue and suitably reversed NF-kB and Nrf2 immunoreactivity. These findings show protective effect of isorhamnetin against acetaminophen-induced liver injury through reducing oxidative stress, inflammation, and pyroptosis which is attributed to its regulation of NF-kB, Nrf2, NLRP3, and sirtuin 1.

Assessment the effect of vitamin D supplementation on plasma vitamin D levels, inflammation, and oxidative stress biomarkers based on vitamin D receptor genetic variation in breast cancer survivors: a protocol for clinical trial.

BACKGROUND: Both human genes and environmental exposures, due to complex interplay, play important role in the cancer etiology. Vitamin D is associated with a reduced risk of incidence and mortality of several human cancers. This study will aim to investigate the possible effects of individual polymorphisms in vitamin D receptor (VDR) as well as effects of VDR haplotypes on response to vitamin D supplementation in breast cancer survivors. METHODS: This is an interventional study in which the effects of vitamin D supplementation on plasma vitamin D levels, inflammatory and antioxidant biomarkers and factors associated with cell proliferation, differentiation, damage, and apoptosis will be investigated stratified by variations in VDR genotype. The present study will be conducted on breast cancer survivors referred to the Shohadaye Tajrish hospital and its associated clinics. One hundred ninety-eight breast cancer survivors will receive 4000 IU of vitamin D3 daily for 12 weeks. VDR Fok1, ApaI, TaqI, BsmI, and Cdx-2 genotype will be determined at the end of the study and responses to vitamin D supplements (inflammatory, antioxidant, cell proliferation, differentiation, damage, and apoptosis biomarkers) will be compared between the three subgroups of each VDR polymorphism as well as different VDR haplotype categories. DISCUSSION: Genetic variation is a fundamental factor influencing individuals' divergent responses to diet, nutritional status, metabolic response, and diet-related health disorders. Furthermore, studies of gene and environment interactions will provide a precise and accurate assessments of individuals' dietary requirements by considering both the genetic and environmental aspects simultaneously. The results of the current study, to some extent, will highlight the discrepancies existing in the findings of different studies regarding vitamin D, VDR, and cancer by considering both the genetic and environmental aspects simultaneously. If responses to vitamin D supplementation could be modified by VDR SNPs, determining the distribution of VDR polymorphisms in both breast cancer survivors and healthy populations will provide a new insight into the vitamin D requirements of individuals to prevent cancer and its related mortality based on their genotypes. Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153.

Randomized Study of the Effects of Zinc, Vitamin A, and Magnesium Co-supplementation on Thyroid Function, Oxidative Stress, and hs-CRP in Patients with Hypothyroidism.

Hypothyroidism can occur due to deficiencies in micronutrients such as zinc, magnesium, and vitamin A. The aim of this study was to determine the effects of supplementation with these micronutrients on thyroid function, oxidative stress, and hs-CRP levels in patients with hypothyroidism. In a randomized double-blind, placebo-controlled trial with two parallel groups, 86 hypothyroid patients aged 20-65 were allocated to receive daily supplementation with either: (intervention group, n = 43) one 30 mg zinc gluconate capsule per day, one 250 mg magnesium oxide tablet per day, and one 25,000 IU vitamin A capsule twice/week for 10 weeks or (placebo group, n = 43) placebo capsules and tablets as above for 10 weeks. Neither of the groups changed their diet or physical activity. Thyroid hormones (free and total thyroxine (FT4 and TT4), free tri-iodothyronine (FT3), and thyroid-stimulating hormone (TSH)), oxidative markers (malondialdehyde (MDA) and total antioxidant capacity (TAC)), serum hs-CRP, and anthropometric indices (height and weight) were assessed at the baseline and at the end of the study. In the intervention group, we found a significant increase in serum FT4, decreased anthropometric indices, and lower levels of serum hs-CRP by the end of the 10 week protocol (P < 0.05). In the placebo group, serum TAC was decreased and hs-CRP increased (P < 0.05), with no significant changes in serum TSH, FT3, TT4, and MDA after the intervention. Zinc, vitamin A, and magnesium supplementation may have beneficial effects in patients with hypothyroidism and in diseases associated with hyperthyroidism.

The effect of saffron supplement on clinical outcomes and metabolic profiles in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled clinical trial.

Rheumatoid arthritis (RA) is a systemic autoimmune and inflammatory disease. Our study aimed to determine the effect of saffron supplement on clinical outcomes and metabolic profiles in patients with active RA. In this randomized, double-blind, placebo-controlled trial, 66 women older than 18 years old received 100 mg/day either saffron supplement in the intervention group (n = 33) or matched placebo in the placebo group (n = 33) for a period of 12 weeks. Sixty-one patients (30 in the control and 31 in the saffron group) remained for the final analysis. No adverse effects were reported by the patients. Saffron supplementation significantly decreased the number of tender (-1.38 ± 1.66 vs. 0.10 ± 0.40, p < .001) and swollen (-2.12 ± 2.34 vs. 0.63 ± 2.79, p < .001) joints, pain intensity based on visual analogue scale (-18.36 ± 15.07 vs. -2.33 ± 5.04), p < .001), and disease activity score (DAS28) (-0.75 ± 0.67 vs. 0.26 ± 0.77, p < .001) at the end of intervention between the two groups and in saffron group compared with baseline values. Physician Global Assessment (p = .002) and erythrocyte sedimentation rate were significantly improved after intervention (24.06 ± 12.66 vs. 32.00 ± 14.75, p = 0.028). High-sensitivity C-reactive protein reduced at the end of the intervention in the saffron group compared with baseline values (12.00 ± 7.40 vs. 8.82 ± 7.930, p = .004). Tumor necrosis factor alpha, interferon gamma, and malondialdehyde were decreased, and total antioxidant capacity were increased, but their differences between the two groups were not significant (p > .05). According to the results, saffron supplements could positively and significantly improve clinical outcomes in RA patients.

Effects Of Saffron Supplementation On Inflammation And Metabolic Responses In Type 2 Diabetic Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Type 2 diabetes (T2D) is accompanied by elevated inflammation, oxidative stress, hyperlipidemia and hyperglycemia which all contribute to cardiovascular disease pathogenesis. Saffron as a complementary medicine and source of antioxidants could play a role in alleviating diabetes and its complications. The aim of this study was to determine the effects of saffron supplementation as an adjunct therapy in T2D. PATIENTS AND METHODS: This randomized controlled trial included 80 T2D patients with a mean age of 54.1 years. Participants were randomly assigned into two groups to take either saffron tablets (100 mg/day; n=40) or placebo (n=40) for 12 weeks. Fasting blood samples were obtained at the beginning and after the intervention period to quantify glycemic factors, lipid profile, and biomarkers of inflammation and oxidative stress. Anthropometric indices and dietary intakes were also measured at baseline and at study end. RESULTS: Compared with placebo, saffron supplementation resulted in significant decreases in waist circumference (p<0.001) and malondialdehyde (MDA) (p=0.001). There was no statistically significant difference in other indices, including anthropometric parameters, serum insulin, fasting blood glucose, HbA1c, insulin sensitivity indices, lipid profile, high-sensitivity C-reactive protein, total antioxidant capacity, and tumor necrosis factor-α between the study groups (p>0.05). CONCLUSION: Overall, 12 weeks of saffron supplementation in diabetic patients had beneficial effects on waist circumference and serum MDA levels. However, saffron did not influence other evaluated cardio metabolic risk markers in diabetic patients.

The effect of Cornus mas fruit extract consumption on lipid profile, glycemic indices, and leptin in postmenopausal women- A randomized clinical trial.

Menopause, which occurs following a declined ovarian activity and reduced estrogen levels, can lead to long-term changes in lipid and glycemic profiles and increases the risk of cardiovascular disease and osteoporosis. Cornelian cherry (Cornus mas) is rich in phytochemicals and antioxidants, which appears to be useful in reducing the postmenopausal complications. This interventional, double-blinded, randomized clinical trial carried out on 84 menopaused women aged 45-60 years old. They were randomly divided into two groups. The treatment group received three capsules of 300 mg of Cornus mas extract (CME), and control group received three capsules of 300 mg of starch powder per day for 8 weeks. Then, BMI, waist circumference, glycemic indices, lipid profile, serum apoproteinase, apoprotein B100, fibrinogen, and leptin were measured. The dietary intakes were evaluated using 24-hr dietary recall questionnaire. The consumption of CME in comparison with the control group resulted in a significant reduction in weight, body mass index, waist circumference, LDL to HDL ratio, total cholesterol to HDL ratio, and fibrinogen. There was also a significant increase in HDL and ApoA1 levels in the treatment group. Furthermore, there was a significant decrease in BMI, waist circumference, fasting insulin, and insulin resistance index after 8 weeks of using CME. Summing up the results, it can be concluded that CME can have possible effects on decreasing BMI, waist circumference, and improving some aspects of lipid profile and glycemic indices in postmenopausal women.

The effect of saffron (Crocus sativus L.) supplementation on blood pressure, and renal and liver function in patients with type 2 diabetes mellitus: A double-blinded, randomized clinical trial.

OBJECTIVE: Microalbuminuria and hypertension are the risk factors for diabetic nephropathy, and increased levels of liver enzymes are prevalent among diabetic patients. The aim of this research was to examine the effects of Crocus sativus supplementation on nephropathy indices, liver enzymes, and blood pressure in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This placebo-controlled, randomized clinical trial was performed among 80 T2D patients. Subjects were randomly assigned to either Crocus sativus (n = 40) or placebo (n = 40) groups and treated with C. sativus and or placebo for 12 weeks, respectively. Alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum urea, creatinine, 24-hr urine albumin, systolic blood pressure (SBP), diastolic blood pressure (DBP), physical activity, and dietary intakes were measured and blood samples were taken at baseline and after the 12­week intervention to assess the differences between the two groups. RESULTS: C. sativus supplementation compared with the placebo resulted in a significant reduction of SBP (P<0.005). However, changes in other indices including liver enzymes, serum creatinine, serum urea, and 24-hr urine albumin, and DBP were not significantly different between the two groups (p>0.05). Also, no significant changes in dietary intakes and physical activity were seen between the two groups. CONCLUSION: This report shows that daily supplementation with 100 mg C. sativus powder improved SBP. However, it did not considerably improve DBP, nephropathy indices and liver functions in T2D patients after 12 weeks of administration.

Survey of the effect of doxorubicin and flavonoid extract of white Morus alba leaf on apoptosis induction in a-172 GBM cell line.

In this study, the effect of doxorubicin, flavonoid extract of white Morus alba leaf (MFE) and a combination of doxorubicin and flavonoid extract on Bax and Bcl2 levels and caspase 3 activity of cancer A-172 GBM cell line was investigated. Bax/Bcl2 levels of treated A-172 GBM cell line with flavonoid extract of white mulberry leaf were estimated by ELISA methods. Caspase 3 activity of treated A-172 GBM cells was determined by calorimetric assay. The flow cytometry assessment was used to estimate the apoptosis percent of treated A-172 GBM cells. Treatment of A-172 GBM cells with MFE, doxorubicin and a combination of MFE and doxorubicin caused a significant decrease in Bcl2 level and an increase in Bax level. The apoptosis percent of treated cells were also elevated significantly. Present results suggest that concomitant use of herbal medicine and chemotherapy may be an effective alternative method for the treatment of cancers.

S-allyl cysteine improves clinical and neuropathological features of experimental autoimmune encephalomyelitis in C57BL/6 mice.

Multiple sclerosis (MS) is a deleterious autoimmune and demyelinating disorder of the central nervous system with debilitating sensory and motor complications. There is still no definite cure for it and the main focus for its treatment mostly pivots around subsiding its severity and recurrence. Experimental autoimmune encephalomyelitis (EAE) is an established animal model of MS. S-allyl cysteine (SAC) is the active and main constituent of aged garlic extract with anti-inflammatory and neuroprotective property. This study was conducted to evaluate its possible protective effect in EAE model of MS. SAC was administered p.o. at a dose of 50 mg/kg/day to female C57BL/6 mice immunized with myelin oligodendrocytic glycoprotein (MOG35-55). Results showed that SAC is capable to alleviate clinical signs and severity of the disease and improved lumbar spinal cord tissue level of tumor necrosis factor α (TNFa), interleukin 17 (IL-17), activity-dependent neuroprotector homeobox (ADNP), microtubule-associated proteins 1A/1 B light chain 3A (MAP1LC3A), and matrix metalloproteinase 9 (MMP-9). In addition, SAC attenuated inflammatory cell infiltration, axonal demyelination, and axonal loss in lumbar spinal cord in EAE group, as demonstrated by H & E, Luxol fast blue (LFB), and Bielschowsky silver staining, respectively. Taken together, SAC could mitigate severity of MOG35-55-induced EAE as a valid model of MS via amelioration of pathogenic molecular mechanisms responsible for neuroinflammation and axonal damage.

Effect of contraceptive pill on the selenium and zinc status of healthy subjects.

BACKGROUND: The study was conducted to ascertain the influence of oral contraceptive pill (OCP) uptake on serum zinc and selenium in contraceptive pill users. STUDY DESIGN: The concentration of zinc and selenium was determined by atomic absorption spectrophotometer in 50 healthy women with normal menstrual cycles as a control group and 50 women taking low-dose OCP. RESULTS: The control reference values were 81.61+/-9.44 and 70.35+/-25.57 mcg/dL, which were obtained for zinc and selenium, respectively. Use of OCP resulted in a significant decrease in serum zinc levels (p