Astaxanthin prevents nephrotoxicity through Nrf2/HO-1 pathway.

Renal toxicity is one of the side effects of methotrexate (MTX). Therefore, this study explored the use of astaxanthin (AST), as a natural carotenoid, against MTX-induced nephrotoxicity emphasizing the changes in oxidative stress and the expression of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1). During the 10 days of the experiment, male Wistar rats in different groups received MTX (10 mg/kg) on days 6, 8, and 10 and three doses of AST (25, 50, and 75 mg/kg) during the entire course. Renal failure caused by MTX was observed in significant histopathological changes and a significant increase in serum levels of creatinine, urea, and uric acid (p < 0.05). Oxidative change induced by MTX injection was also observed by remarkably increasing the tissue level of malondialdehyde (MDA) and decreasing the activity of superoxide dismutase (SOD) and catalase (p < 0.001). AST decreases the adverse effects of MTX by upregulating the expression of Nrf2/HO-1 genes (p < 0.01) and decreasing the tissue level of MDA (p < 0.01). Also, AST significantly reduced the amount of creatinine, urea, and uric acid in the serum and improved the activity of SOD and catalase in the kidney tissue (p < 0.05). Thus, AST may protect the kidney against oxidative stress caused by MTX.

Impact of polyphenols on heart failure and cardiac hypertrophy: clinical effects and molecular mechanisms.

Polyphenols are abundant in regular diets and possess antioxidant, anti-inflammatory, anti-cancer, neuroprotective, and cardioprotective effects. Regarding the inadequacy of the current treatments in preventing cardiac remodeling following cardiovascular diseases, attention has been focused on improving cardiac function with potential alternatives such as polyphenols. The following online databases were searched for relevant orginial published from 2000 to 2023: EMBASE, MEDLINE, and Web of Science databases. The search strategy aimed to assess the effects of polyphenols on heart failure and keywords were "heart failure" and "polyphenols" and "cardiac hypertrophy" and "molecular mechanisms". Our results indicated polyphenols are repeatedly indicated to regulate various heart failure-related vital molecules and signaling pathways, such as inactivating fibrotic and hypertrophic factors, preventing mitochondrial dysfunction and free radical production, the underlying causes of apoptosis, and also improving lipid profile and cellular metabolism. In the current study, we aimed to review the most recent literature and investigations on the underlying mechanism of actions of different polyphenols subclasses in cardiac hypertrophy and heart failure to provide deep insight into novel mechanistic treatments and direct future studies in this context. Moreover, due to polyphenols' low bioavailability from conventional oral and intravenous administration routes, in this study, we have also investigated the currently accessible nano-drug delivery methods to optimize the treatment outcomes by providing sufficient drug delivery, targeted therapy, and less off-target effects, as desired by precision medicine standards.

Melatonin targeting non-coding RNAs in cancer: Focus on mechanisms and potential therapeutic targets.

Despite, melatonin is mainly known as a regulatory factor for circadian rhythm, its notable role in other fundamental biological processes, such as redox homeostasis and programmed cell death, has been found. In this line, a growing body of evidence indicated that melatonin could apply an inhibitory effect on the tumorigenic processes. Hence, melatonin might be considered an efficient adjuvant agent for cancer treatment. Besides, the physiological and pathological functions of non-coding RNAs (ncRNAs) in various disease, particularly cancers, have been expanded over the past two decades. It is well-established that ncRNAs can modulate the gene expression at various levels. Thereby, ncRNAs can regulate the numerous biological processes, including cell proliferation, cell metabolism, apoptosis, and cell cycle. Recently, targeting the ncRNAs expression provides a novel insight in the therapeutic approaches for cancer treatment. Moreover, accumulating investigations have revealed that melatonin could impact the expression of different ncRNAs in a multiple disorders, including cancer. Therefore, in the precent study, we discuss the potential roles of melatonin in modulating the expression of ncRNAs and the related molecular pathways in different types of cancer. Also, we highlighted its importance in therapeutic application and translational medicine in cancer treatment.

Melatonin and 5-fluorouracil combination chemotherapy: opportunities and efficacy in cancer therapy.

Combined chemotherapy is a treatment method based on the simultaneous use of two or more therapeutic agents; it is frequently necessary to produce a more effective treatment for cancer patients. Such combined treatments often improve the outcomes over that of the monotherapy approach, as the drugs synergistically target critical cell signaling pathways or work independently at different oncostatic sites. A better prognosis has been reported in patients treated with combination therapy than in patients treated with single drug chemotherapy. In recent decades, 5-fluorouracil (5-FU) has become one of the most widely used chemotherapy agents in cancer treatment. This medication, which is soluble in water, is used as the first line of anti-neoplastic agent in the treatment of several cancer types including breast, head and neck, stomach and colon cancer. Within the last three decades, many studies have investigated melatonin as an anti-cancer agent; this molecule exhibits various functions in controlling the behavior of cancer cells, such as inhibiting cell growth, inducing apoptosis, and inhibiting invasion. The aim of this review is to comprehensively evaluate the role of melatonin as a complementary agent with 5-FU-based chemotherapy for cancers. Additionally, we identify the potential common signaling pathways by which melatonin and 5-FU interact to enhance the efficacy of the combined therapy. Video abstract.

Targeting Glioma Cells with Nutraceuticals: Therapeutic Effects Based on Molecular Mechanisms, New Evidence and Perspectives.

Gliomas are the most common malignant cancers of the brain that have unregulated proliferation and are known as highly invasive tumors. Hence, their relapse rate is high, and the prognosis is low. Despite remarkable advances in neuroimaging, neurosurgery, and radiation therapy, they, especially glioblastoma, are highly resistant to treatments, including radiotherapy, surgery, and temozolomide chemotherapy. The average survival rate for patients with malignant glioma is still less than two years. Accordingly, the search for new treatment options has recently become an urgent need. Today, a number of nutraceuticals have been considered because of their special role in inhibiting the angiogenic process, metastasis, and apoptosis, resulting in the inhibition of tumor growth, including glioma. Nutraceuticals can disrupt cancer cells by affecting different pathways. In fact, these compounds can reduce the growth of cancer cells, inhibit their proliferation and angiogenesis, as well as induce apoptosis in these cells and play an important role in various stages of treatment. One of the key targets of nutraceuticals may be to regulate cellular signaling pathways, such as PI3K/Akt/mTORC1, JAK/STAT, and GSK-3, or to exert their effects through other mechanisms, such as cytokine receptors and inflammatory pathways, reactive oxygen species, and miRNAs. This review refers to the results of recent studies and target molecules as well as signaling pathways affected by some nutraceuticals in glioma cells. These studies indicated that clinical trials are imminent and new approaches can be beneficial for patients.

Possible Mechanisms and Molecular Signaling of Incretins against the Development of Type 2 Diabetes Mellitus.

The increasing number of cases of diabetes mellitus (DM) and related diseases has become a global health concern. In this context, controlling blood glucose levels is critical to prevent and/or slow down the development of diabetes-related complications. Incretins, as gutderived hormones that trigger the post-meal secretion of insulin, are a well-known family of blood glucose modulators. Currently, incretin medications, including glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are extensively used to treat patients with type 2 diabetes mellitus (T2D). Several experimental and clinical studies illustrate that these metabolic hormones exert their antidiabetic effects through multiple molecular mechanisms. Accordingly, the current review aims to investigate key mechanisms and signaling pathways, such as the cAMP/PKA, Nrf2, PI3K/Akt, and AMPK pathways, associated with the antidiabetic effects of incretins. It also summarizes the outcomes of a group of clinical trials evaluating the incretins' antidiabetic potential in diabetic patients.

A CB2 Receptor Agonist Reduces the Production of Inflammatory Mediators and Improves Locomotor Activity in Experimental Autoimmune Encephalomyelitis.

Background: Cannabinoids (CBs) have been found to regulate the immune system, affect innate and adaptive immune responses, and reduce inflammatory reactions. This study assessed the therapeutic effects of GW-405833 synthetic CB2 agonist on inflammatory factors as well as locomotor activity in experimental autoimmune encephalomyelitis (EAE). Methods: In this experimental study, 48 adult male C57BL/6 mice were randomly and equally assigned to eight groups. By injecting 250 mg of MOG35-55 peptide, EAE was induced. Every other day for 17 days after EAE onset, EAE-afflicted mice in groups 1-3 received an intraperitoneal injection of GW-405833 at a dose of 3, 10, and 30 mg/kg, respectively. Clinical status and locomotor activity, measured using the beam walking assay, were assessed every other day during the first 17 days after EAE onset. Mice were euthanized in day 17th of treatment and the serum levels of the IL-1ß, IL-12, CRP, and TNF-α proinflammatory cytokines as well as IL-4 and TGF-ß anti-inflammatory cytokines were measured by ELISA method. Results: Clinical manifestations of EAE in groups 2 and 3 were significantly milder than group 4 and locomotor activity in groups 1-3 was significantly better than group 4 in days 5-17 (p< 0.05). GW-405833 also significantly decreased the levels of IL-12, TNF-α, and CRP and significantly increased the levels of IL-4 and TGF-ß but had no significant effects on the level of IL-1ß. GW-405833 was not associated with significant side effects. Conclusion: The CB2 receptor agonist GW-405833, improves clinical conditions and reduces inflammation in mice with EAE.

Therapeutic Potential of Resveratrol in Diabetic Nephropathy According to Molecular Signaling.

BACKGROUND: Diabetic nephropathy (DN), as a severe complication of diabetes mellitus (DM), is a crucial menace for human health and survival and remarkably elevates the healthcare systems' costs. Therefore, it is worth noting to identify novel preventive and therapeutic strategies to alleviate the disease conditions. Resveratrol, as a well-defined anti-diabetic/ antioxidant agent has capabilities to counteract diabetic complications. It has been predicted that resveratrol will be a fantastic natural polyphenol for diabetes therapy in the next few years. OBJECTIVE: Accordingly, the current review aims to depict the role of resveratrol in the regulation of different signaling pathways that are involved in the reactive oxygen species (ROS) production, inflammatory processes, autophagy, and mitochondrial dysfunction, as critical contributors to DN pathophysiology. RESULTS: The pathogenesis of DN can be multifactorial; hyperglycemia is one of the prominent risk factors of DN development that is closely related to oxidative stress. Resveratrol, as a well-defined polyphenol, has various biological and medicinal properties, including anti-diabetic, anti-inflammatory, and anti-oxidative effects. CONCLUSION: Resveratrol prevents kidney damages that are caused by oxidative stress, enhances antioxidant capacity, and attenuates the inflammatory and fibrotic responses. For this reason, resveratrol is considered an interesting target in DN research due to its therapeutic possibilities during diabetic disorders and renal protection.

Anti-osteoarthritis potential of peppermint and rosemary essential oils in a nanoemulsion form: behavioral, biochemical, and histopathological evidence.

BACKGROUND: This study aimed to evaluate the effect of nanoemulsion containing peppermint and rosemary essential oils in rats with osteoarthritis (OA). METHODS: In this experimental study, we prepared a nanoemulsion containing peppermint and rosemary essential oils by spontaneous emulsification and evaluated the nanoemulsion's dermal irritation and toxicity. Investigating the analgesic effect of the nanoemulsion, we randomly assigned 36 male rats to 6 groups: Control (saline injection into the knee), osteoarthritis (intra-articular injection of 2 mg monosodium iodoacetate), and four groups of OA treated with nanoemulsion gel, nanoemulsion solution, rosemary and peppermint essential oil gel, or diclofenac sodium. Treatments were administered topically at a dose of 1 ml daily. Using behavioral tests, we assessed pain on days 1, 4, 7, and 14 after injection. Finally, we did the histopathological and biochemical evaluation of rats' knee joints. RESULTS: There were no irritation signs on the animals' skin after receiving the nanoemulsion and no changes in the hematological and biochemical parameters of rats' blood compared to the control group. Receiving nanoemulsion decreased the mechanical (P < 0.001) and thermal allodynia (P < 0.05), thermal hyperalgesia (P < 0.05), and ambulatory-evoked pain in comparison with the OA group. Also, the nanoemulsion receiving rats showed an increase in SOD and GPx activity and a decrease in MDA level. Histopathology of synovial tissues confirmed the results of behavioral and biochemical tests. CONCLUSION: The nanoemulsion containing essential oils of peppermint and rosemary reduces osteoarthritis pain via increasing antioxidant capacity and improving the histopathological features of the rats' knee joint.

Deep skin wound healing potential of lavender essential oil and licorice extract in a nanoemulsion form: Biochemical, histopathological and gene expression evidences.

Cutaneous wound healing is one of the public health interests. This study aimed to investigate the effects of nanoemulsion cream containing lavender essential oil and licorice extract on the healing of deep skin wound in a rat model. Eighty-five male Wistar rats were randomly divided into five groups including untreated defects as negative control and defects treated with vehicle ointment, lavender essential oil and licorice extract in emulsion and nanoemulsion forms, and phenytoin 1% as the positive control with an excisional wound on the dorsal neck of each rat. On days 2, 7 and 14 oxidative stress factors were evaluated in wound tissue homogenates. The expression of transforming growth factor-ß (TGF-ß), and type I and type III collagen genes were evaluated. Also, wound tissue samples were processed for Hematoxylin & Eosin and Masson-Trichrome staining. Nanoemulsion reduced the wound area more than other groups significantly. Real-time PCR data demonstrated that nanoemulsion and phenytoin groups have shown the best result in increasing TGF-ß1, Type I and type III collagen genes expression compared to the other groups. Reduction in lipid peroxidation level and increasing in SOD and GPx activity was also significant in the nanoemulsion and phenytoin groups. The formation of granular tissue likewise the appearance of collagen in nanoemulsion and phenytoin groups were faster than the other groups. Nanoemulsion cream containing lavender essential oil and licorice extract exhibited a promising wound healing potential towards the excisional wound model in rats.

To estimate effective antiamyloidogenic property of melatonin and fisetin and their actions to destabilize amyloid fibrils.

Aggregating of amylin as pancreatic deposition is connected with pancreas degeneration in type 2 diabetes mellitus. Suppression of the amylin accumulation and so instability of the pre-formed pancreatic ß-amyloid, may be attractive curative goal for mediation of diabetes mellitus. Fluorimetric assay by Thioflavin-T was utilized for investigating the properties of melatonin and fisetin on the generation and instability of ß-amyloid near to physiological conditions. The results showed that after 168 hours incubation by shaker incubator in 37oC, melatonin at 10µM and 40 µM repressed amylin amyloid formation by 20.1% and 27.5% respectively (p<0.05) and the similar values of fisetin inhibited the formation of ß-sheet structure by 16.5% and 23.2% respectively (p<0.05).The obtained data also confirmed that amyloidal sheet opening was induced by melatonin and fisetin significantly (p<0.05). It may be concluded that islet amyloid cytotoxicity to ß-cells may be reduced by melatonin and fisetin, and they should be important constituents of new drugs for diabetes mellitus treatment.

Effects of Synbiotic Food Consumption on Serum Minerals, Liver Enzymes, and Blood Pressure in Patients with Type 2 Diabetes: A Double-blind Randomized Cross-over Controlled Clinical Trial.

BACKGROUND: This research was to examine the effects of synbiotic intake on minerals, liver enzymes, and blood pressure in patients with type 2 diabetes (T2D). METHODS: This randomized, cross-over clinical trial was performed among 62 diabetic patients. Persons were randomly assigned to intake either a synbiotic (n = 62) or a control food (n = 62) for 6 weeks. A 3-week washout period was applied following which persons were crossed over to the alternate intervention arm for an additional 6 weeks. The synbiotic was consisted of Lactobacillus sporogenes (1 × 107 CFU), 0.04 g inulin (HPX) as prebiotic. Persons were asked to consume the synbiotic and control foods 27 g a day. Blood pressure was measured, and blood samples were taken at baseline and after 6-week intervention to assess calcium, magnesium, iron, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. RESULTS: The consumption of a synbiotic food, compared to the control food, resulted in a significant rise of calcium (0.66 vs. -0.14 mg/dL, P = 0.03) and iron (5.06 vs. -9.98 mg/dL, P = 0.03). The decrease of total bilirubin (0.08 vs. -0.04 mg/dL; P = 0.009) was also seen in the synbiotic group compared with the control group. CONCLUSIONS: Overall, synbiotic in T2D patients had beneficial effects on calcium, iron, and total bilirubin concentrations.

The effects of omega-3 fatty acids and vitamin E co-supplementation on clinical and metabolic status in patients with Parkinson's disease: A randomized, double-blind, placebo-controlled trial.

The current research was performed to evaluate the effects of omega-3 fatty acids and vitamin E co-supplementation on clinical signs and metabolic status in people with Parkinson's disease (PD). This randomized double-blind placebo-controlled clinical trial was conducted in 60 patients with PD. Participants were randomly assigned into two groups to receive either 1000 mg omega-3 fatty acids from flaxseed oil plus 400 IU vitamin E supplements (n = 30) or placebo (n = 30) for 12 weeks. Unified Parkinson's disease rating stage (UPDRS) were recorded at baseline and the after 3-month intervention. After 12 weeks' intervention, compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation led to a significant improve in UPDRS (-3.3 ± 10.0 vs. +4.4 ± 14.9, P = 0.02). Furthermore, co-supplementation decreased high-sensitivity C-reactive protein (hs-CRP) (-0.3 ± 0.6 vs. +0.3 ± 0.3 µg/mL, P < 0.001), and increased total antioxidant capacity (TAC) (+65.2 ± 68.7 vs. +16 ± 52.4 µmol/L, P = 0.003) and glutathione (GSH) concentrations (+41.4 ± 80.6 vs. -19.6 ± 55.9 µmol/L, P = 0.001) compared with the placebo. Additionally, co-supplementation meaningfully decreased insulin (-2.1 ± 4.9 vs. +1.4 ± 6.2 µIU/mL, P = 0.01), homeostasis model of assessment-estimated insulin resistance (-0.7 ± 1.8 vs.+0.3 ± 1.6, P = 0.02) and Beta cell function (-5.9 ± 13.9 vs. +5.7 ± 25.5, P = 0.03), and increased quantitative insulin sensitivity check index (+0.009 ± 0.02 vs. -0.006 ± 0.03, P = 0.03) compared with the placebo. Overall, our study demonstrated that omega-3 fatty acids and vitamin E co-supplementation in people with PD had favorable effects on UPDRS, hs-CRP, TAC, GSH and markers of insulin metabolism.

Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease.

AIM: To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. METHODS: Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. RESULTS: Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [ß = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [ß = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [ß = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [ß = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. CONCLUSION: Certain adipokines may determine the severity of NAFLD histology accurately.

Prediction of Nonalcoholic Fatty Liver Disease Via a Novel Panel of Serum Adipokines.

Considering limitations of liver biopsy for diagnosis of nonalcoholic liver disease (NAFLD), biomarkers' panels were proposed. The aims of this study were to establish models based on serum adipokines for discriminating NAFLD from healthy individuals and nonalcoholic steatohepatitis (NASH) from simple steatosis.This case-control study was conducted in patients with persistent elevated serum aminotransferase levels and fatty liver on ultrasound. Individuals with evidence of alcohol consumption, hepatotoxic medication, viral hepatitis, and known liver disease were excluded. Liver biopsy was performed in the remaining patients to distinguish NAFLD/NASH. Histologic findings were interpreted using "nonalcoholic fatty liver activity score." Control group consisted of healthy volunteers with normal physical examination, liver function tests, and liver ultrasound. Binary logistic regression analysis was applied to ascertain the effects of independent variables on the likelihood that participants have NAFLD/NASH.Decreased serum adiponectin and elevated serum visfatin, IL-6, TNF-a were associated with an increased likelihood of exhibiting NAFLD. NAFLD discriminant score was developed as the following: [(-0.298 × adiponectin) + (0.022 × TNF-a) + (1.021 × Log visfatin) + (0.709 × Log IL-6) + 1.154]. In NAFLD discriminant score, 86.4% of original grouped cases were correctly classified. Discriminant score threshold value of (-0.29) yielded a sensitivity and specificity of 91% and 83% respectively, for discriminating NAFLD from healthy controls. Decreased serum adiponectin and elevated serum visfatin, IL-8, TNF-a were correlated with an increased probability of NASH. NASH discriminant score was proposed as the following: [(-0.091 × adiponectin) + (0.044 × TNF-a) + (1.017 × Log visfatin) + (0.028 × Log IL-8) - 1.787] In NASH model, 84% of original cases were correctly classified. Discriminant score threshold value of (-0.22) yielded a sensitivity and specificity of 90% and 66% respectively, for separating NASH from simple steatosis.New discriminant scores were introduced for differentiating NAFLD/NASH patients with a high accuracy. If verified by future studies, application of suggested models for screening of NAFLD/NASH seems reasonable.

Comparative in vitro study of the intestinal absorption of titanium and iron in rats.

Rat Everted Gut Sac (EGS) model was employed to study the intestinal uptake of titanium and iron. Incubation of freshly prepared rat EGS in Earle's medium pH = 7.4 containing titanium showed that the absorption of titanium as well as iron was a dose dependent process. Ascorbic acid enhanced the absorption of both metal ions, while NaF (1 mM) as an inhibitor of glycolytic energy supply, decreased their absorption. The Na+-K+ ATPase inhibitor, ouabain (1 mM) reduced intestinal absorption of Titanium. This suggests that titanium uptake is an active transport process as is iron uptake. Iron absorption was reduced approximate by 17% when titanium was presented to incubation medium EGS whereas, the absorption of titanium was decreased by 35% when iron was added to the reaction mixture.