Rutin-loaded chitosan nanoparticles alleviated Freund's adjuvant induced rheumatoid arthritis via modulating oxidative stress and inflammatory parameters in Wistar rats.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, primarily affecting the joints and with stromal tissue dysregulation causing chronic inflammation and joint destruction. Rutin is a natural flavonoid with potential therapeutic properties in chronic destructive conditions including rheumatoid diseases. In this study, the protective effects of rutin nanoformulation in an animal model of rheumatoid arthritis caused by Freund's complete adjuvant (FCA) were investigated. Sixty male rats were randomly divided into ten groups including normal, negative control, prednisolone 10 mg/kg (positive control), 3 doses of rutin (15, 30, 45mg/kg), rutin nanoparticles (15, 30, 45 mg/kg), and nanoparticle without rutin, for 28 days. Different behavioral parameters including the open field test, acetone drop test, hot plate test, Von Frey test, and inclined plane test were evaluated. Serum levels of glutathione (GSH), catalase, and nitric oxide as well as histopathological analyses were measured in different groups. Also, matrix metalloproteinase (MMP)-2 and MMP-9 activity were appraised by gelatin zymography. The injection of FCA prolonged the rats' immobility duration in comparison to the control group. Rheumatoid arthritis induction also increased nitric oxide and decreased GSH and catalase levels, while these effects were reversed in the groups that received nanoparticles containing rutin and prednisolone. Rutin nanoparticles suppressed MMP-9 and activated MMP-2. Also, this rutin drug delivery system plays a significant role in the improvement of histopathological symptoms. Considering the improvement of behavioral and tissue symptoms and the modulation of the level of inflammatory cytokines, nanoparticles containing rutin can be proposed as a suitable approach in the management of patients with rheumatoid arthritis.

Retinoic acid loaded with chitosan nanoparticles improves spermatogenesis in scrotal hyperthermia in mice.

OBJECTIVE: High temperatures can trigger cellular oxidative stress and disrupt spermatogenesis, potentially leading to male infertility. We investigated the effects of retinoic acid (RA), chitosan nanoparticles (CHNPs), and retinoic acid loaded with chitosan nanoparticles (RACHNPs) on spermatogenesis in mice induced by scrotal hyperthermia (Hyp). METHODS: Thirty mice (weighing 25 to 30 g) were divided into five experimental groups of six mice each. The groups were as follows: control, Hyp induced by a water bath (43 °C for 30 minutes/day for 5 weeks), Hyp+RA (2 mg/kg/day), Hyp+CHNPs (2 mg/kg/72 hours), and Hyp+RACHNPs (4 mg/kg/72 hours). The mice were treated for 35 days. After the experimental treatments, the animals were euthanized. Sperm samples were collected for analysis of sperm parameters, and blood serum was isolated for testosterone measurement. Testis samples were also collected for histopathology assessment, reactive oxygen species (ROS) evaluation, and RNA extraction, which was done to compare the expression levels of the bax, bcl2, p53, Fas, and FasL genes among groups. Additionally, immunohistochemical staining was performed. RESULTS: Treatment with RACHNPs significantly increased stereological parameters such as testicular volume, seminiferous tubule length, and testicular cell count. Additionally, it increased testosterone concentration and improved sperm parameters. We observed significant decreases in ROS production and caspase-3 immunostaining in the RACHNP group. Moreover, the expression levels of bax, p53, Fas, and FasL significantly decreased in the groups treated with RACHNPs and RA. CONCLUSION: RACHNPs can be considered a potent antioxidative and antiapoptotic agent for therapeutic strategies in reproductive and regenerative medicine.

Falcaria vulgaris L. hydroalcoholic extract protects against harmful effects of mercuric chloride on the rat kidney.

Objective: Mercuric chloride (Merc; HgCl2) is toxic to humans and animals and contributes to environmental pollution, which usually results in nerve and systemic harm to different organs. Falcaria vulgaris (FV) is a medicinal plant rich in antioxidants. This research aimed to assess the FV hydroalcoholic extract effects on kidney toxicity induced by Merc. Materials and Methods: Forty-eight male rats were divided into eight groups: the control group: received saline; the Merc group: received 0.5 ml/day of 0.5 ppm aqueous Merc; FV1, 2, and 3 groups: received 50, 100, 150 mg/kg FV, respectively; and Merc + FV1, 2, and 3 groups: received Merc and FV at three doses. The administration period was 14-days. Subsequently, kidneys and sera were cumulated from each group for the analysis. Samples were analyzed via hematoxylin-eosin staining and biochemical tests. Results: The rats that received Merc displayed significant decrement in the kidney index, the diameter of renal corpuscles, total antioxidant capacity levels, superoxide dismutase activity (all, p<0.01), and 150 mg/kg FV mitigated these outcomes (all, p<0.05). Urea, creatinine, nitric oxide, and the level of apoptosis revealed a significant increment in the kidney of the rats that received Merc (all, p<0.01), and 150 mg/kg FV decreased these results. Furthermore, FV ameliorated histological changes induced by Merc (all, p<0.05). Conclusion: The FV hydroalcoholic extract protects the kidneys against Merc-induced nephrotoxicity. Antioxidant and anti-apoptotic FV hydroalcoholic extract properties were involved in this healing effect.

Nobiletin in Cancer Therapy; Mechanisms and Therapy Perspectives.

Cancer has remained to be one of the major challenges in medicine and regarded as the second leading cause of death worldwide. Different types of cancer may resist anti-cancer drugs following certain mutations such as those in tumor suppressor genes, exhaustion of the immune system, and overexpression of drug resistance mediators, which increase the required concentration of anticancer drugs so as to overcome drug resistance. Moreover, treatment with a high dose of such drugs is highly associated with severe normal tissue toxicity. Administration of low-toxic agents has long been an intriguing idea to enhance tumor suppression. Naturally occurring agents e.g., herb-derived molecules have shown a dual effect on normal and malignant cells. On the one hand, these agents may induce cell death in malignant cells, while on the other hand reduce normal cell toxicity. Nobiletin, one of the well-known polymethoxyflavones (PMFs), has reportedly shown various beneficial effects on the suppression of cancer and the protection of normal cells against different toxic agents. Our review aims to explain the main mechanisms underlying nobiletin as an inhibitor of cancer. We have reviewed the mechanisms of cancer cell death caused by nobiletin, such as stimulation of reactive oxygen species (ROS), modulation of immune evasion mechanisms, targeting tumor suppressor genes, and modulation of epigenetic modulators, among others; the inhibitory mechanisms of nobiletin affecting tumor resistance properties such as modulation of hypoxia, multidrug resistance, angiogenesis, epithelial-mesenchymal transition (EMT) have been fully investigated. Also, the inhibition of anti-apoptotic and invasive mechanisms induced by nobiletin will later be discussed. In the end, protective mechanisms of nobiletin on normal cells/tissue, clinical trial results, and future perspectives are reviewed.

Analysis of injuries and deaths from road traffic accidents in Iran: bivariate regression approach.

BACKGROUNDS: This study aims to estimate and compare the parameters of some univariate and bivariate count models to identify the factors affecting the number of mortality and the number of injured in road accidents. METHODS: The accident data used in this study are related to Kermanshah province in march2020 to march2021. Accidents areas were divided into 125 areas based on density characteristics. In a one-year period, 3090 accidents happened on the suburban roads of Kermanshah province, which resulted in 398 deaths and 4805 injuries. Accident information, including longitude and latitude of accident location, type of accident (fatal and injury), number of deaths, number of injuries, accident type, the reason of the accident, and the kind of accident were all included as population-level variables in the regression models. We investigated four frequently used bivariate count regression models for accident data in the literature. RESULTS: In bivariate analysis, except for the DNM model, there is a reasonable decrease in the AIC measures of the saturated model compared to the reduced model for the other three models. For the injury models, MSE is lowest, respectively for DIBP (137.87), BNB (289.46), BP (412.36) and DNM (3640.89) models. These results are also established for death models. But, in univariate analysis, only injury models almost present reasonable results. CONCLUSIONS: Our findings show that the IDBP model is better suitable for evaluating accident datasets than other models. Motorcycle accidents, pedestrian accidents, left turn deviance, and dangerous speeding were all significant variables in the IDBP death model, and these parameters were linked to accident mortality.

Repeatedly heated palm olein disrupts male reproductive system of rat: A histological and biochemical study.

The aim of this study was to investigate the effect of heated and unheated palm olein in different doses on the male reproductive system of rats. Forty male rats were randomly classified into five groups (n = 8) including Control, Low palm, High palm, Heated low palm and Heated high palm. The palm olein was administrated orally for 6 months. Histological and biochemical parameters of the male reproductive system were measured. There was a significant reduction in sexual hormones, serum levels of superoxide dismutase, high-density lipoprotein, testis weight and sperm parameters in the high dose and heated palm olein groups compared to the other group (p < 0.05). The levels of malondialdehyde, apoptosis rate, proteins levels (TNF-α, IL-1ß, IL-6), low-density lipoprotein, cholesterol, triglyceride and the weight of the rats were significantly higher in the high dose and heated palm olein groups than the others (p < 0.05). High dose and heated palm olein treatment could damage the male rat's reproductive indices that were related to increased inflammatory markers, decreased sex hormone levels, and negative effects on testicular tissue and sperm parameters.

Protective effect of gallic acid on nicotine-induced testicular toxicity in mice.

BACKGROUND AND PURPOSE: Nicotine is an alkaloid found in many nutrients and tobacco that can cause infertility in men. Gallic acid is a powerful antioxidant that possesses antimutagenic and anticancer activities. This study aimed to determine the potential protective effect of gallic acid against nicotine-induced testicular toxicity in male mice. EXPERIMENTAL APPROACH: In this in vivo study, forty-eight mice were equally divided into eight groups intraperitoneally receiving normal saline (control), nicotine (0.6 mg/kg), gallic acid (5, 10, and 15 mg/kg), and gallic acid (5, 10, and 15 mg/kg) plus nicotine. Nicotine was injected intraperitoneally for 14 days and gallic acid was administered concomitantly with nicotine and continued for 7 days later. Then, body and testicular weights, the sperm parameters (viability, number, motility, and morphology of sperm), and testicular histology were evaluated. Also, serum levels of nitric oxide, total antioxidant, superoxide dismutase, malondialdehyde, and testosterone were measured. FINDINGS/RESULTS: The results showed that the administration of nicotine significantly reduced testis and body weight, sperm count, viability, normal morphology and motility, seminiferous tubules diameter, testosterone levels, serum levels of total antioxidants, and superoxide dismutase compared to the control group (P < 0.05). It also significantly increased the level of nitric oxide and malondialdehyde (P < 0.05). Increasing the dose of gallic acid along with nicotine significantly increased body weight, sperm count, viability, normal morphology and motility, the diameter of seminiferous, testosterone concentration, total antioxidant levels (P < 0.05). This combination also significantly decreased malondialdehyde and nitric oxide levels compared to the nicotine-receiving group (P < 0.05). CONCLUSION AND IMPLICATIONS: Gallic acid had a protective effect on nicotine-induced testicular toxicity in mice. It can neutralize the harmful effect of nicotine on male fertility in smokers.

Chemical characterization and antioxidant, cytotoxic, antibacterial, and antifungal properties of ethanolic extract of Allium Saralicum R.M. Fritsch leaves rich in linolenic acid, methyl ester.

The purpose of the recent research was to assess the chemical characterization and antioxidant, cytotoxic, antibacterial, and antifungal effects of Allium Saralicum R.M. Fritsch leaves. After identification of the plant, its ethanolic extract was obtained using Soxhlet extractor without leaving any chemicals in it. Gas chromatography-mass spectrometry (GC/MS) was performed to detect the percentage, retention index, and time of A. Saralicum compounds. Agar diffusion tests were applied to determine the antibacterial and antifungal characteristics. In agar disk diffusion test, dimethyl sulfoxide (DMSO) was used as negative control, while antibacterial (Difloxacin, Chloramphenicol, Streptomycin, Gentamicin, Oxytetracycline, Ampicillin, and Amikacin) and antifungal (Fluconazole, Itraconazole, Miconazole, Amphotericin B, and Nystatin) antibiotics were used as positive controls. Macro broth tube test was run to determine Minimum Inhibitory Concentration (MIC). The findings indicated that linolenic acid, methyl ester was the most frequent constituent found in A. Saralicum. Indeed, A. Saralicum showed higher antibacterial and antifungal properties than all standard antibiotics (p ≤ .01). Also, A. Saralicum prevented the growth of all bacteria and fungi at 15-125 mg/mL concentrations and destroyed them at 15-250 mg/mL concentrations (p ≤ .01). DPPH free radical scavenging test was carried out to examine the antioxidant effect, which indicated similar antioxidant activity with butylated hydroxy toluene (BHT) as a positive control. The synthesized ethanolic extract had great cell viability dose-dependently and demonstrated this method was nontoxic for synthesizing A. Saralicum. In conclusion, the findings showed the useful antioxidant, non-cytotoxic, antibacterial, and antifungal effects of A. Saralicum ethanolic extract.

Persistent median artery in the carpal tunnel and anastomosis with superficial palmar arch.

Persistent median artery (PMA) in present cadaver originated from the brachial artery and anastomosed with the superficial palmar arch (SPA). As the PMA may be the cause of carpal tunnel syndrome and SPA is the main source of arterial supply, knowledge of which are important for the hand surgical interventions.

Role of phosphodiesterase inhibitor Ibudilast in morphine-induced hippocampal injury.

BACKGROUND: Opioid drugs are used in the treatment of acute post-surgical pain and chronic pain, such as those associated with cancer. Opioid used is associated with complications such as analgesic tolerance, dependence and opioid abuse. The molecular mechanisms of unwanted opioid responses are varied but recent advances have highlighted elevations in pro-inflammatory cytokines and pro-inflammatory glial following chronic administration of morphine. In this study we investigated the neurodegenerative effects of morphine through its effects on Toll-Like Receptor 4 (TLR4) in the male rat hippocampus and evaluated the level of Interleukin-1 beta (IL-1ß). Then we compared the difference between inhibitory effects on mu opioid receptors (by ß-Funaltrexamine, ß-FNA) and TLR4 (by Ibudilast). Subsequently, we assessed the amount of IL-1ß and the number of granular cells in male rat hippocampus. METHODS: Adult male rats (n=24) were treated with sucrose, morphine, Ibudilast (7.5 mg/kg) and ß-FNA (20 mg/kg) for 30 days. Their brains were isolated and hemisected with one hippocampus for granular cell and the other used for IL-1 ß immunoblotting. RESULTS: Data showed that Ibudilast suppresses IL-1 ß expression significantly more than ß-FNA. The granular cell count displayed significant differences. CONCLUSIONS: Our results suggested that Ibudilast can be used for controlling and treatment of morphine-induced CNS inflammations or traumatic conditions.