Evaluation of Anti-Nociceptive, Anti-Inflammatory, and Anti-Fibrotic effects of noscapine against a rat model of Achilles tendinopathy.

During tendinopathy, prolonged inflammation results in fibrosis and the adherence of tendons to the adjacent tissues, causing discomfort and movement disorders. As a natural compound, noscapine has several anti-inflammatory and anti-fibrotic properties. Therefore, we aimed to investigate the effects of noscapine against a rat model of tendinopathy. We created a surgical rat model of Achilles tendon damage to emulate tendinopathy. Briefly, an incision was made on the Achilles tendon, and it was then sutured using an absorbable surgical thread. Immediately, the injured area was topically treated with the vehicle, noscapine (0.2, 0.6, and 1.8 mg/kg), or dexamethasone (0.1 mg/kg) as a positive control. During the 19-day follow-up period, animals were assessed for weight, behavior, pain, and motor coordination testing. On day 20th, the rats were sacrificed, and the tendon tissue was isolated for macroscopic scoring, microscopic (H&E, Masson's trichrome, Ki67, p53) analyses, and cytokine secretion levels. The levels of macroscopic parameters, including thermal hyperalgesia, mechanical and cold allodynia, deterioration of motor coordination, tendon adhesion score, and microscopic indices, namely histological adhesion, vascular prominence and angiogenesis, and Ki67 and p53 levels, as well as fibrotic and inflammatory biomarkers (IL-6, TNF-α, TGF-ß, VEGF) were significantly increased in the vehicle group compared to the sham group (P < 0.05-0.001 for all cases). In contrast, the administration of noscapine (0.2, 0.6, and 1.8 mg/kg) attenuated the pain, fibrosis, and inflammatory indices in a dose-dependent manner compared to the vehicle group (P < 0.05-0.001). Histological research indicated that noscapine 0.6 and 1.8 mg/kg had the most remarkable healing effects. Interestingly, two higher doses of noscapine had impacts similar to those of the positive control group in both clinical and paraclinical assessments. Taken together, our findings suggested that noscapine could be a promising medicine for treating tendinopathies.

Canine myxoid liposarcoma in Iran: a clinical report.

A 15-year-old male terrier dog with symptoms of lethargy and severe abdominal distension was referred to the polyclinic hospital of the Ferdowsi University of Mashhad, Mashhad, Iran. In addition to numbness and abdominal distension, the dog also had anorexia and severe weakness and some skin masses were observed. Due to the enlarged abdomen, splenomegaly was diagnosed in ultrasonography. Fine needle aspiration was performed on the liver and skin mass and then, neoplastic lesions were reported based on cytology. On the necropsy, two masses were found on the liver and shoulder skin. These masses were well-encapsulated, soft and multi-lobulated. Samples taken from the liver and skin were prepared by Hematoxylin and Eosin staining and then, two different immunohistochemical markers were used to confirm the initial diagnosis. Histopathological examination of these two well-encapsulated, soft and multi-lobulated masses on the liver and skin showed lipid content and liposarcoma was indicated. Immunohistochemical staining using two markers, S100 and MDM2, made a definitive diagnosis and confirmed the diagnosis.

Melatonin ameliorates arsenic-induced cardiotoxicity through the regulation of the Sirt1/Nrf2 pathway in rats.

Chronic arsenic (As) exposure, mainly as a result of drinking contaminated water, is associated with cardiovascular diseases. Mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and autophagy have been suggested as the molecular etiology of As cardiotoxicity. Melatonin (Mel) is a powerful antioxidant. Mel improves diabetic cardiomyopathy, cardiac remodeling, and heart failure. Following pre-treatment with Mel (10, 20, or 30 mg/kg/day i.p.), rats were orally gavaged with As (15 mg/kg/day) for 28 days. Electrocardiographic findings showed that Mel decreased the As-mediated QT interval prolongation. The effects of As on cardiac levels of glutathione (GSH) and malondialdehyde (MDA) were reversed by Mel pretreatment. Mel also modulated the Sirt1 and Nrf2 expressions promoted by As. Mel down-regulated autophagy markers such as Beclin-1 expression and the LC3-II/I ratio. Moreover, the cardiac expression of cleaved-caspase-3 and Bax/Bcl-2 ratio was decreased by Mel pretreatment. Reduced expression of miR-34a and miR-144 by As were reversed by Mel. The histopathological changes of cardiac injury associated with As exposure was moderated by Mel. Mel may improve As-induced cardiac dysfunction through anti-oxidative, anti-apoptotic, and anti-autophagic mechanisms.

Necroptosis triggered by ROS accumulation and Ca2+ overload, partly explains the inflammatory responses and anti-cancer effects associated with 1Hz, 100 mT ELF-MF in vivo.

Whereas the anti-neoplastic activity of extremely low frequency magnetic fields (ELF-EMF) is well-documented in literature, little is known about its underlying anti-cancer mechanisms and induced types of cell death. Here, for the first time, we reported induction of necroptosis, a specific type of programed necrotic cell death, in MC4-L2 breast cancer cell lines following a 2 h/day exposure to a 100 Hz, 1 mT ELF-EMF for five days. For in vivo assessment, inbred BALB/c mice bearing established MC-4L2 tumors were exposed to 100 mT, 1 Hz ELF-EMF 2 h daily for a period of 28-day, following which tumors were dissected and fixed for evaluation of tumor biomarkers expression and types of cell death induced using TUNEL assay, Immunohistochemistry and H&E staining. Peripheral blood samples were also collected for assessing pro-inflammatory cytokine profile following exposure. An exaggerated proinflammatory response evident form enhancement of IFN-γ (4.8 ± 0.24 folds) and TNF-α (3.1 ± 0.19 folds) and number of tumors infiltrating lymphocytes (TILs), specially CD8+ Th cells (~20 folds), proposed occurrence of necroptosis in vivo. Meanwhile, exposure could effectively suppress tumor growth and expression of Ki-67, CD31, VEGFR2 and MMP-9. In vitro studies on ELF-EMF exposed MC-4L2 cells demonstrated a meaningful increase in phosphorylation of RIPK1/RIPK3/MLKL proteins and cleavage of caspase-9/caspase-3, confirming occurrence of both necroptosis and apoptosis. Complementary in vitro studies by treating ELF-EMF exposed MC-4L2 cells with verapamil (a calcium channel inhibitor), N-acetyl cysteine (a ROS scavenger) or calcium chloride confirmed the role of elevated intracellular calcium and ROS levels in ELF-EMF induced necroptosis.

A study on the concentration of heavy metals and histopathological changes in Persian jirds (Mammals; Rodentia), affected by mining activities in an iron ore mine in Iran.

Mining activity constitutes a potential source of heavy metal pollution in the environment. Long-term exposure to heavy metals (e.g., cadmium) has adverse health effects. Rodents frequently serve as bioindicators to monitor the levels of heavy metals in the environment. In the present study, concentrations of 10 heavy metals (Cd, Co, Cr, Cu, Fe, Mo, Ni, Pb, Sb, and Zn) in kidney, liver, and muscle tissue of the Persian jird (Meriones persicus) were evaluated. This is the first study to examine the histopathological changes in Persian jird tissues caused by the bioaccumulation heavy metals. The samples were taken at location that surrounded by Sangan Iron Ore Mine (SIOM) mining activities, in northeastern Iran. The results show that the highest concentrations for the metals were observed in kidney and liver, whereas lowest concentrations were found in muscle of Persian jirds. The concentration of Pb was below the limit of detection. Sex and age were two factors that could explain the different levels of heavy metal bioaccumulation, which affects the concentration of some metals. Adults had significantly higher Cu and Cd levels compared to juveniles. Males bioaccumulated more Zn in their kidneys than females, whereas females bioaccumulated more Fe in their livers. As expected, heavy metals affected various organs of the studied specimens. Hyperemia, hemorrhage, necrosis, and degenerative damage to the epithelial cells of the tubules, the presence of hyaline casts, and in one case, mononuclear leukocyte infiltration, were observed in samples of renal tissue. Hemorrhage and hepatocyte vacuolization were the most common histopathological changes found in samples of hepatic tissue. These effects and the concentrations of heavy metals in the studied specimens indicate the need for monitoring and frequent sampling to evaluate long-term persistent pollutants.

Contractile activity attenuates autophagy suppression and reverses mitochondrial defects in skeletal muscle cells.

Macroautophagy/autophagy is a survival mechanism that facilitates protein turnover in post-mitotic cells in a lysosomal-dependent process. Mitophagy is a selective form of autophagy, which arbitrates the selective recognition and targeting of aberrant mitochondria for degradation. Mitochondrial content in cells is the net balance of mitochondrial catabolism via mitophagy, and organelle biogenesis. Although the latter process has been well described, mitophagy in skeletal muscle is less understood, and it is currently unknown how these two opposing mechanisms converge during contractile activity. Here we show that chronic contractile activity (CCA) in muscle cells induced mitochondrial biogenesis and coordinately enhanced the expression of TFEB (transcription factor EB) and PPARGC1A/PGC-1α, master regulators of lysosome and mitochondrial biogenesis, respectively. CCA also enhanced the expression of PINK1 and the lysosomal protease CTSD (cathepsin D). Autophagy blockade with bafilomycin A1 (BafA) reduced mitochondrial state 3 and 4 respiration, increased ROS production and enhanced the accumulation of MAP1LC3B-II/LC3-II and SQSTM1/p62. CCA ameliorated this mitochondrial dysfunction during defective autophagy, increased PPARGC1A, normalized LC3-II levels and reversed mitochondrially-localized SQSTM1 toward control levels. NAC emulated the LC3-II reductions induced by contractile activity, signifying that a decrease in oxidative stress could represent a mechanism of autophagy normalization brought about by CCA. CCA enhances mitochondrial biogenesis and lysosomal activity, and normalizes autophagy flux during autophagy suppression, partly via ROS-dependent mechanisms. Thus, contractile activity represents a potential therapeutic intervention for diseases in which autophagy is inhibited, such as vacuolar myopathies in skeletal muscle, by establishing a healthy equilibrium of anabolic and catabolic pathways. ABBREVIATIONS: AMPK: AMP-activated protein kinase; BafA: bafilomycin A1; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCA: chronic contractile activity; COX4I1: cytochrome c oxidase subunit 4I1; DMEM: Dulbecco's modified Eagle's medium; GFP: green fluorescent protein; LSD: lysosomal storage diseases; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SOD2: superoxide dismutase 2, mitochondrial; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.

Effect of betaine versus arsenite-induced alterations of testicular oxidative stress and circulating androgenic indices in rats.

The aim of this work was to study the alleviative role of betaine versus arsenite-provoked alterations in testis oxidative status and circulating androgenic indices. Twenty-four adult male rats (204.5 ± 21 g) were divided into four groups, equally. Control group was given basal diet and tap water. Group 2 rats received arsenite (100 mg/L) in drinking water. Rats in group 3 received betaine (2% of the diet) during arsenite exposure. Group 4 received betaine at 2% of the diet during study period (30 days). The results revealed significant decrease in testicular glutathione peroxidase, catalase and glutathione in arsenite-treated animals relative to controls. Significant increase in testicular malondialdehyde was also detected in arsenite-exposed group. Concurrent administration of betaine with arsenite significantly increased glutathione and catalase amounts in comparison with arsenite group. Arsenite exposure resulted in a significant decrease in plasma testosterone and dihydrotestosterone levels over control rats, whereas supplementation of betaine augmented the hormones concentrations to the levels that had no significant difference in comparison with controls. Concentration of all measured oxidative status and hormonal variables in the betaine plus arsenite and betaine groups was not significantly different relative to controls. Taken together, betaine may be proposed as an alleviative agent against arsenite-induced male reprotoxicity.

Combination of Fractional Radiofrequency and Thermo-Contraction Systems for Facial Skin Rejuvenation: A Clinical and Histological Study.

BACKGROUND: Radiofrequency energy systems are popular options in the treatment of skin laxity and wrinkles. Fractional radiofrequency devices (FRFs) have increased the efficacy and safety. The thermo-contraction (TC) system is also a novel technology that can promote a marked lifting effect. OBJECTIVES: This trial was done to assess the safety and efficacy of a combination treatment using the FRF system and TC for facial skin rejuvenation. METHODS: Fifteen female volunteers (mean age, 47.07 ± 8.83 years) received 3 FRF and 6 TC bipolar treatments in 3 weeks. Assessment methods included wrinkle grading by independent investigator using Glogau wrinkle scoring, objective measurement of depth, area, and volume of right nasolabial fold (using the VisioFace CSI software), thickness and echo-density of the dermis (using high-frequency ultrasound), and measurement of the skin biophysical parameters before and 3 months after last treatment. Histological assessment was also performed on 5 volunteer participants. RESULTS: The clinical evaluation showed a significant improvement in Glogau wrinkle scoring after 3 months (P value, 0.041). The area and volume of nasolabial folds were also significantly reduced (P values, 0.026 and 0.031, respectively). Skin ultrasound showed a significant increase in echo-density of the dermis, which was confirmed by histological findings of an increase in dermal collagen content. Adverse reactions were all transient and mild in severity, and subjects were "moderately satisfied" with the treatment (Likert scale, 3.6 out of 5). CONCLUSIONS: The results of this trial showed that a combination therapy by FRF and TC bipolar systems is efficient and safe for facial skin rejuvenation.

Efficacy of Dragon's blood cream on wound healing: A randomized, double-blind, placebo-controlled clinical trial.

The blood-red sap of Dragon's blood has been used in folk medicine for fractures, wounds, inflammation, gastrointestinal disorders, rheumatism, blood circulation dysfunctions, and cancer. Existing in vitro and in vivo bioactivity of this herb on different mechanisms of healing shows strong potential of this sap in wound healing. This clinical trial study was designated to evaluate the wound healing effect of Dragon's blood on human wounds. Sixty patients, between the ages of 14-65 years, who were referred to remove their skin tag, were assigned to this double-blind, placebo-controlled, randomized clinical trial and received either Dragon's blood or a placebo cream. They were visited on the 3rd, 5th, 7th, 10th, 14th, and 20th day of the trial to check the process of healing and to measure the wound's surface. At the end of trial, there was a significant difference in the mean duration of wound healing between the two groups (p = 0.0001). The phenolic compounds and the alkaloid taspine, which exist in Dragon's-blood resin, are probably the main reasons for the wound healing property of this plant. Being natural accessible, safe, and affordable makes Dragon's blood cream, a good choice for addition to the wound healing armamentarium. Further studies on wounds with different causes and among larger populations are suggested to ensure the effectiveness and safety of Dragon's blood.

The topical effect of grape seed extract 2% cream on surgery wound healing.

BACKGROUND: Reducing the wound healing time is crucial in wound as it lowers the chance of infection and decreases complications and cost. Grape seed extract has the ability to release endothelial growth factor and its topical application results in contraction and closure of the skin wound. Furthermore, it possesses antioxidant and antibacterial properties. In several studies it has been proved effective in animals. Therefore, due to low side effects and recognition of herbal medicine, we decided to evaluate the effect of grape seed extract 2% herbal cream on human skin lesions. MATERIALS: This study is a double blind clinical trial conducted on two groups of treatment and placebo. Surgery was performed on skin lesions such as skin tags and moles which were found on the neck, trunk and limbs (except for face). After enrollment and obtaining informed consent from participants, they were randomized into two groups of treatment and placebo. Excision of the lesions was done by surgical scissors. The lesions got restored by secondary intention method. After the first day of treatment, the patients were visited on the 3rd, 7th, 10th, 14th, and 21st day. Grape seed extract cream 2% was produced and coded by the Faculty of Pharmacy, Ahvaz University of Medical Sciences. In order to compare the two groups, T-test was used. For time assessing, analysis of variance with repeated measures was employed. RESULTS: The results showed complete repair of wounds averagely on day 8 for the treatment group and on day 14 for the placebo group, which was clearly significant in terms of statistical difference (p=0.00). CONCLUSION: Proanthocyanidins in grape seed extract trigger the release of vascular endothelial growth factor and its topical application causes wound contraction and closure. Curing skin lesions with grape seed extract caused proliferation areas with protected boundaries in epithelium, increased cell density and increased deposition of connective tissue at the wound site which in general improves cellular structure in wound. In addition, its anti-inflammatory and anti-microbial properties are effective in wound healing.

Large mass arising from the tongue as an initially and sole manifestation of Kaposi sarcoma.

We report a 30- year-old Iranian woman presenting with a red to yellowish, well demarcated, painless exophytic and lobulated mass originating from the right hand side of the tongue. An excisional biopsy was obtained and it was diagnosed histopathologically as Kaposi's sarcoma by detecting atypical spindle cells with rare mitoses delineating blood-filled vascular slits.

One-year survey of cutaneous lesions in 1000 consecutive Iranian newborns.

Our objective was to study skin disorders in neonates within the first 48 hours of life in Ahvaz, Iran. One thousand consecutive neonates were examined in a descriptional prospective cohort study for 1 year (2002-03). The rate of skin disorders and their relationship to age of gestation and sex were calculated and analyzed using the computerized program SPSS version 10 and chi-squared test (chi2). Our findings were Mongolian spots (71.3%), Epstein pearls (70.2%), sebaceous hyperplasia (43.7%), salmon patch (26.2%), hypertrichosis (25.7%), erythema toxicum (11.1%), milia (7.5%), desquamation (1.9%), hemangioma (1.3%), and miliaria (1.3%). The most frequent skin disorders were Mongolian spots, Epstein pearls, and sebaceous hyperplasia. Differences between our study findings and those of others may be based on racial differences and study method.