The effect of topical 0.5% humic acid gel on male rats with skin ulcer.

Background: Humic derivatives have antibacterial and anti-inflammatory properties. Aim: This study aimed to assess the experimental wound-healing effect of 0.5% humic acid gel. Materials and Methods: A full-thickness skin wound was created on the dorsal side of 24 Sprague Dawley male rats (220-250 g). The animals were then randomly divided into the control, sham, and experimental groups. Skin wounds were bandaged daily using sterile gauze dipped in normal saline, carboxymethylcellulose, and 0.5% humic acid for 21 days. The wound-healing rate was evaluated grossly and histologically at various time intervals post-injury. Results: Wound-healing percentage was significantly higher in the gel treatment group at all time points (P < 0.05). The mean number of inflammatory cells was significantly lower in the humic acid gel group than in the other groups (P < 0.001). Moreover, the number of new vascular cells and fibroblasts were significantly increased in the humic acid gel compared to the control (P < 0.001). Conclusion: These data confirmed that 0.5% humic acid gel accelerates wound healing, probably by anti-inflammatory effects, as well as by promoting vascular and fibroblast proliferation. Therefore, the humic acid gel may be used to improve wound care.

The effect of combining humic and fulvic acids poultice on wound healing in male rats.

Background: Finding new compounds to accelerate wound healing is critical today. Humic substances or fulvic acid each have anti-inflammatory properties. Aims and Objectives: The purpose of this study is to determine the effects of poultice 0.5% containing humic and fulvic acids on wound healing in male rats. Materials and Methods: An animal model was arranged by making a full-thickness skin wound was created in each rat. Animals were randomly divided into control, sham, and treatment groups. To investigate the effect of humic and fulvic acids combining poultice, the wound area and histological analyses of the number of inflammatory cells, fibroblasts, and angiogenesis were evaluated for 21 days. Results: The animals in the treated group showed higher wound healing percentage, angiogenesis, and fibroblast distribution compared with the control (P < 0.001). Moreover, the topical administration of humic and fulvic acids 0.5% poultice decreased the mean number of inflammatory cells significantly than the other groups (P < 0.001). Conclusion: The topical administration of a poultice containing humic and fulvic acid accelerated wound healing by increasing angiogenesis and fibroblast and reducing inflammatory cell distribution in a rat model.

Computational analysis of the functional and structural impact of the most deleterious missense mutations in the human Protein C.

Protein C (PC) is a vitamin K-dependent factor that plays a crucial role in controlling anticoagulant processes and acts as a cytoprotective agent to promote cell survival. Several mutations in human PC are associated with decreased protein production or altered protein structure, resulting in PC deficiency. In this study, we conducted a comprehensive analysis of nonsynonymous single nucleotide polymorphisms in human PC to prioritize and confirm the most high-risk mutations predicted to cause disease. Of the 340 missense mutations obtained from the NCBI database, only 26 were classified as high-risk mutations using various bioinformatic tools. Among these, we identified that 12 mutations reduced the stability of protein, and thereby had the greatest potential to disturb protein structure and function. Molecular dynamics simulations revealed moderate alterations in the structural stability, flexibility, and secondary structural organization of the serine protease domain of human PC for five missense mutations (L305R, W342C, G403R, V420E, and W444C) when compared to the native structure that could maybe influence its interaction with other molecules. Protein-protein interaction analyses demonstrated that the occurrence of these five mutations can affect the regular interaction between PC and activated factor V. Therefore, our findings assume that these mutants can be used in the identification and development of therapeutics for diseases associated with PC dysfunction, although assessment the effect of these mutations need to be proofed in in-vitro.

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.

BACKGROUND: Cytochrome P450 4F2 (CYP4F2) enzyme is a member of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules such as arachidonic acid, tocopherols, and vitamin K. Several reports have demonstrated that the missense variant CYP4F2*3 (V433M) causes decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M in CYP4F2 at the atomic level has not yet been completely elucidated. METHODS AND RESULTS: In the current study, we evaluated the effect of the V433M substitution on CYP4F2 using 14 different bioinformatics tools. Further molecular dynamics (MD) simulations were performed to assess the impact of the V433M mutation on the CYP4F2 protein structure, stability, and dynamics. In addition, molecular docking was used to illustrate the effect of V433M on its interaction with vitamin K1. Based on our results, the CYP4F2*3 variant was a damaging amino acid substitution with a destabilizing nature. The simulation results showed that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means that it tends to change the overall structural conformation and flexibility of CYP4F2. The docking results showed that the CYP4F2*3 variant decreased the binding affinity between vitamin K1 and CYP4F2, which reduced the activity of CYP4F2*3 compared to native CYP4F2. CONCLUSIONS: This study determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and provided new information for understanding the structure-function relationship of CYP4F2 and other CYP4 enzymes. These findings will aid in the development of effective drugs and treatment options.

Evaluation of a warfarin dosing algorithm including CYP2C9, VKORC1, and CYP4F2 polymorphisms and non-genetic determinants for the Iranian population.

BACKGROUND: The response to warfarin, as an oral anticoagulant agent, varies widely among patients from different ethnic groups. In this study, we tried to ascertain and determine the relationship between non-genetic factors and genetic polymorphisms with warfarin therapy; we then proposed a new warfarin dosing prediction algorithm for the estimation of drug sensitivity and resistance in the Iranian population. METHODS: Overall, 200 warfarin-treated patients with stable doses were recruited, the demographic and clinical characteristics were documented, and genotyping was done using a sequencing assay. RESULTS: The outcomes of our investigation showed that the genetic polymorphisms of VKORC1(-1639 G > A), CYP2C9*3, CYP2C9*2, amiodarone use, and increasing age were found to be related to a significantly lower mean daily warfarin dose. In contrast, the CYP4F2*3 variant and increased body surface area were linked with an increased dose of warfarin in the Iranians. Our descriptive model could describe 56.5% of the variability in response to warfarin. This population-specific dosing model performed slightly better than other previously published warfarin algorithms for our patient's series. Furthermore, our findings provided the suggestion that incorporating the CYP4F2*3 variant into the dosing algorithm could result in a more precise calculation of warfarin dose requirements in the Iranian population. CONCLUSIONS: We proposed and validated a population-specific dosing algorithm based on genetic and non-genetic determinants for Iranian patients and evaluated its performance. Accordingly, by using this newly developed algorithm, prescribers could make more informed decisions regarding the treatment of Iranian patients with warfarin.

KRAS, NRAS, BRAF, and PIK3CA mutation rates, clinicopathological association, and their prognostic value in Iranian colorectal cancer patients.

AIM: Mutations in KRAS, NRAS, BRAF, and PIK3CA genes are critical factors in clinical evaluation of colorectal cancer (CRC) development and progression. In Iran, however, the data regarding genetic profile of CRC patients is limited except for KRAS exon2 and BRAF V600F mutations. This study aimed to investigate the mutational spectrum and prognostic effects of these genes and explore the relationship between these mutations and clinicopathological features of CRC. METHOD: To achieve these objectives, mutations in KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), and BRAF (exon 15) was determined using PCR and pyrosequencing in a total of 151 patients with colorectal cancer. RESULTS: KRAS, BRAF, NRAS, and PIK3CA mutations were identified in 41%, 5.96%, 3.97%, and 13.24% of the cases, respectively. There were some significant correlations between clinicopathological features and KRAS, PIK3CA, BRAF, and NRAS mutations. Mutations in KRAS and PIK3CA were shown to be independent risk factors for poor survival of the patients at stage I-IV (p < 0.0001 and p = 0.001, respectively). No significant impact on prognosis was observed in patients with BRAF mutations. CONCLUSION: Our study revealed the prevalence of CRC biomarkers mutations in Iranian patients and emphasized the role of KRAS and PIK3CA on shorter overall survival rates in this population.

A Young Iranian Woman with Pure Primary Ovarian Neuroendocrine Tumor: A Case Report.

Pure ovarian neuroendocrine tumors are very rare. Herein, we present a young Iranian woman with a pure primary ovarian neuroendocrine tumor. A 26-year-old female presented with chronic abdominal pain and progressive constipation and was referred to the emergency room. Imaging findings confirmed a mass in the right adnexa. Following the resectional surgery of the ovarian mass, histopathological and immunohistochemistry results disclosed a mixed type of primary ovarian neuroendocrine tumor. The patient did not experience tumor recurrence afterward. Due to the rarity and low prevalence of primary pure ovarian neuroendocrine tumors, the histopathologic diagnosis should be confirmed by an immunohistochemistry study.

Evaluation of Healing Effects of Poultice Containing 0.5% Fulvic Acid on Male White-Male Rats with Skin Ulcer.

Background: Chronic and acute skin wounds are an important health concern because they are very frequent during human life and affect millions of people worldwide. Shortening the wound healing process reduces treatment costs and hospitalization. Therefore, researchers have been looking for new treatment approaches to shorten the wound healing process. Aims and Objectives: The aim of this study was to evaluate the wound healing properties of poultice containing 0.5% fulvic acid. Materials and Methods: In this experimental study, a full-thickness skin wound was created on the dorsal side of 24 male rats. The animals were then randomly assigned to control, sham, and experiment groups. The skin defects were daily bandaged by using sterile gauze dipped in normal saline, carboxymethylcellulose, and 0.5% fulvic acid for 21 days, respectively. The wound healing rate was evaluated grossly and histologically at various time intervals post injury. Both descriptive and statistical analysis methods were applied (P < 0.05). Results: The wound healing percentage was significantly higher in the poultice treatment group at all time intervals (P < 0.001). The wound was completely closed in this group compared with other groups at the end of week 4 post treatment. The mean numbers of inflammatory cells were statistically lower, and fibroblasts and vessels were higher in the poultice group than in the other groups at various time intervals post injury (P < 0.001). Conclusion: Fulvic acid (0.5%) could be used as an effective therapeutic approach to improve the wound healing process because of its unique anti-inflammatory and neovascularization properties at the skin wound site.

Clinicopathological Significance of PTEN Expression and Its Prognostic Effect in Colorectal Adenocarcinoma Patients.

Background & Objective: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located at chromosome 10. PTEN is a regulator of the PI3K/AKT signaling pathway that inhibits cell proliferation and promotes apoptosis. PTEN loss of function occurs in a spectrum of cancers, including colorectal adenocarcinoma. This study aimed to investigate the probable correlation of negative PTEN expression with clinicopathological features and colorectal adenocarcinoma (CRC) patients' survival. Methods: In this cross-sectional study using Immunohistochemistry stainingPTEN expression status on 151 CRC tissues was evaluated. Then the results of IHC staining was compared to those of clinicopathological features. The relationship between PTEN and KRAS mutation status was also investigated. Results: Of 151 CRC samples, 89 (58.9%) were negative for PTEN expression. Loss of PTEN expression was associated with KRAS mutation (P<0.0001), lymph node metastasis (P=0.002), and advanced tumor stage (P=0.016), whereas no significant association was found with other clinicopathological features. Multivariate analysis indicated that tumor site and KRAS mutation were independent prognostic CRC patients (P<0.05). The Kaplan-Meier analysis indicated a correlation between loss of PTEN expression and overall survival of patients with colorectal adenocarcinoma (P= 0.01). Conclusion: The current study suggests that decreasing PTEN expression or its negative expression may be associated with a higher stage and poor prognosis. Combined analysis of mutated KRAS and PTEN expression could be a good predictor of disease prognosis as well as its clinical outcomes.

Evaluation of expression level and methylation profile of CXX1 gene in breast cancer tissue blocks.

AIMS: The hypermethylation of CpG islands in the promoter of tumor-suppressor genes (TSGs) leads to silencing the transcription of tumor suppressors, which lead to the development of cancer. The hypermethylation of CXX1 and CDH1 genes, as TSGs, plays an essential role in the development of various types of cancer, i.e., colorectal and gastric cancer. This study aims at evaluating the expression level of CXX1 and CDH1 genes and the methylation status of CXX1 CpG island's promoter in breast cancer (BC). MATERIALS AND METHODS: In this study, the expression level of the CXX1 and CDH1 genes and the promoter methylation status of the CXX1 gene were evaluated in 30 paraffin-embedded tissue blocks of malignant BC and 18 benign breast lesions, using quantitative reverse transcription-PCR and methylation-specific (MS)-PCR assays, respectively. RESULTS: The CXX1 gene was downregulated in the malignant tissues due to the hypermethylation of the CpG islands in the promoter, compared to the control group (P = 0.031). The downregulation of CDH1 gene expression was observed in the patient group compared to control, but this reduction was not statistically significant. The results show that the risk of BC is increased with aging (P < 0.001). Furthermore, the benign breast lesions (controls) had more mobility in comparison with the malignant breast tumors (P < 0.001). In the malignant samples, the size of the mass was larger than control's mass samples (P = 0.006). CONCLUSIONS: In the pathophysiological state of BC, the aberrant DNA hypermethylation in CpG island of CXX1 promoter is responsible for the reduction of its expression level in BC patients.

An Iranian man with increased thigh mass due to a hydatid cyst.

Background: Hydatid cyst is a zoonotic infection caused by Echinococcosis granulosus. Primary single-intramuscular hydatid disease is rare, even in endemic regions of the world. Here we report the case of exceptional thigh mass due to a hydatid cyst in an Iranian man. Case presentation: An 86-year-old man, initially presented to Velayat teaching hospital surgery clinic in May 2017 with a single right-thigh mass, but physical examinations of other organs were unremarkable. Based on sonographic findings, the differential diagnosis was hydatid cyst. He underwent surgical resection of the cyst. Histopathological results confirmed the diagnosis. There was no evidence of recurrence of the lesion during the 23-month follow-up. Conclusion: Increase thigh mass due to a hydatid cyst is a rare event. In endemic regions with the presence of hydatid cysts, especially physicians of surgical clinics have to consider differential diagnosis of hydatid cysts in unusual locations in case of such a lesion.

The Effect of Oral Consumption of Propolis Alone and in Combination With Silver Nanoparticles on Wound Healing in Male Wistar Rats.

Research to identify and develop compounds that facilitate wound healing is important, especially for hard-to-heal chronic wounds. PURPOSE: This study was conducted to investigate the effects of orally administered propolis (a resinous substance found in beehives), alone and in combination with silver nanoparticles (SNPs), on the wound healing process in male rats. METHODS: Forty (40) male Wistar rats were randomly divided into 4 groups of 10 each: 1 control group received no treatment, and 3 study groups received a daily dose of 1) propolis (100 mg/kg), 2) propolis + 30 ppm SNPs, or 3) propolis + 60 ppm SNPs. Healing rate was determined by wound surface area reduction on days 4, 6, 8, and 10 post-surgery. On day 12 after wound creation, histological changes of wound healing, including number of new vessels, inflammatory cells (neutrophils, eosinophils, and mast cells) and fibroblasts were counted based on morphology using a 400x objective lens, and collagen deposition density was determined using hematoxylin and eosin and trichrome staining, respectively. The histological scores were based on a 0 to 4 scale from lowest to highest amount of improving tissue status and were analyzed using one-way analysis of variance, Tukey test, Kruskal-Wallis test, t test, and Mann-Whitney U test to examine differences among the groups. Significance was set at P <.05. RESULTS: The rate of wound healing was significantly different between the control and the treated groups on days 4, 6, 8, and 10 (percent change was not assessed on day 12) post-surgery, especially in the propolis + 30 ppm SNPs group compared to the control group. This difference was more significant on days 6 (wound healing percentage [WHP]: 75% and 45%) and 8 (WHP: 88% and 65% ) post-surgery (P <.001). Mean neutrophil count on day 12 was highest in the control (34.8 ± 2.97) and lowest in the propolis + 30 ppm SNPs group (16.55 ± 2.12). The number of eosinophils on day 12 was considerably higher in the control group (1.05 ± 4) compared to those in the propolis group (3 ± 0.70), propolis + 30 ppm SNPs group (60/0 ± 1/1), and propolis + 60 ppm SNPs group (0.5 ± 0.52) (P <.001). Mean propolis + 30 ppm SNPs scores for epithelialization and granulation tissue formation were 3 and 4, respectively; in the propolis + 60 ppm SNPs, scores were 2 and 3, respectively; in the propolis alone group scores were 2 and 3, respectively (statistical significance not computed for semiquantitative values). The highest fibroblast count was in the propolis + 30 ppm SNPs group (114.44 ± 3.90) compared to control group (73.2 ± 2.8); P <.001). The difference in collagen fiber density scores was also significant: 1.2 ± 0.42 in the control and 3.66 ± 0.50 in the propolis + 30 ppm SNPs group; (P <.001). The mean of collagen fiber density in the propolis + 60 ppm SNPs group was 2.63 ± 0.51. CONCLUSION: Oral propolis alone and in combination with 30 ppm SNPs appears to provide anti-inflammatory effects and increase fibroblast proliferation and collagen deposition in experimental wounds, which may explain the observed differences in healing. Propolis + 60 ppm SNPs appears to have a cytotoxic effect. Research confirming these results and that examines toxicity levels in animals and humans is needed.

Comparison of Diagnostic Methods in Detection of Squamous Cell Abnormalities in Iranian Women with Abnormal Pap's Smear Test and Associated Demographic and Issues.

BACKGROUND & OBJECTIVE: Premalignant lesions of cervix have increased dramatically in recent years. Early diagnosis and management of abnormalities have an effective role in preventing the invasion of the disease and also in timely treatment. This study aimed to compare diagnostic methods in the detection of squamous cell abnormalities with abnormal Pap smear test. METHODS: This cross-sectional study was performed on 1000 women with abnormal Pap smears in 2007-2018. Sampling was performed with simple method. All samples were subjected to an immediate assessment of colposcopy and histopathology if suspected. The checklist included demographic information as well as symptoms, cytopathology, colposcopy and histopathology findings. Data analysis was performed using descriptive and statistical analysis (P<0.05). RESULTS: A significant relationship between histopathology and Pap smear findings was found (P=0.009), also there was a significant correlation between histopathology and colposcopy findings (P=0.001). However, there was no significant relationship between clinical symptoms and histopathology findings (p=0.8). Sensitivity , specificity , positive and negative predictive value of Pap smear were 43%, 65.9%, 75.4%, 32.2% and of colposcopy were 74.7%, 39.5%, 75%, 39.1%, and of clinical symptoms were 72.6%, 28.1%, 71.1%, 29.7%, respectively. CONCLUSION: Pap smear findings have the appropriate diagnostic accuracy in comparison with colposcopy and histopathology findings for screening and diagnosis of squamous intra-epithelial lesions. Also, there was higher sensitivity of colposcopy compared with Pap smear to detect cervical lesions. Therefore, it is advisable to use these methods simultaneously.

Royal jelly accelerates healing of acetate induced gastric ulcers in male rats.

AIM: This study examined the healing potential of royal jelly on the acetic acid induced wounds healing in male rat's gastric mucosa. BACKGROUND: Scientific reports suggest that, bee products can help in the wounds healing. METHODS: 96 adult male Wistar rats were divided into in 4 groups as follows: control, omeprazole 20 mg/kg, and royal jelly 50 and 200 mg/kg). Wound was induced in stomach mucosa of each rat with 100% acetic acid. Samples groups received omeprazole or royal jelly from 1st to 14th day after acetic ulcer induction. Gastric ulcer healing and histopathological parameters were evaluated on 4, 7, 10, 15th days after ulceration. Both descriptive and statistical analyses were used. P <0.05 was considered as significant. RESULTS: The royal jelly administration significantly reduced the depth of lesion in comparison with the control group (p<0.05) and attuned histopathological changes in the treatment groups. The largest healing effect was demonstrated with royal jelly on 10th treatment day, at a higher concentration (200 mg/kg). CONCLUSION: These findings supported that royal jelly had effectively contributed to the wound healing, valid gastroprotective activity, and can be used for peptic ulcer therapy.

Concurrence of Primary Cutaneous Extra Mammary Paget's Disease and Squamous Cell Carcinoma in situ of Vulva: A Case Report.

Extramammary Paget's disease and vulvar intraepithelial neoplasia are common lesions of vulve, but synchronous occurrence is rare in a same location. Herein we describe a concurrence of primary cutaneous extra mammary Paget's disease and squamous cell carcinoma in situ of vulva in an Iranian women. A 59 year old woman, initially presented to Kosar teaching hospital gynecology clinic April 2017 with a single, well defined, scaly, white ulcerated mass, 2 cm in diameter on right minor labia, but other examinations were normal. She had no urinary or gastrointestinal symptoms. Incisional biopsies from the mass represented concurrence extramammary Paget's disease and VIN3. She underwent radical vulvectomy .No evidence of disease recurrence was noted after 16 months follow up. Participant consent was obtained before patient was enrolled in this study. There are lot of diseases that involve genitalia and lead to vulvar lesions. But in this rare case, we diagnosed concurrence of extramammary Paget's disease and vulvar intraepithelial neoplasia in a same location. Additionally, the clinical presentation as a vulvar mass was found unusual. Therefore, we report the case to sensitize gynecologists and pathologists for uncommon pathologies and their manifestations in vulva.

Concurrence of Papillary Thyroid Carcinoma and Hürthle Cell Carcinoma in an Iranian Woman with Hashimoto's Thyroiditis.

The most usual form of the endocrine carcinoma is thyroid cancer (TC). In addition to papillary thyroid carcinoma (PTC), recent studies revealed incidence of RET/PTC rearrangement in other tumors, like Hürthle cell carcinoma (HCC) and even in non-carcinomatous disorders like Hashimoto's thyroiditis. Here, we present a case with concurrence of papillary thyroid carcinoma and Hürthle cell carcinoma. A 60-year-old woman referred to our hospital with a mass in her neck. Physical examinations revealed painful swelling in the thyroid. Ultrasonographic examination showed two hypoechoic nodules in the right lobe. Hürthle cell variant papillary carcinoma was suggested in the cytology report of the fine needle aspiration. Permanent histopathological diagnosis was co-existence of papillary thyroid carcinoma and Hürthle cell carcinoma. The patient was asymptomatic in 14 months follow up. Concurrence of papillary carcinoma and Hürthle cell carcinoma is a rare form of thyroid malignancies, with doubtful cytogenetic findings and biological behaviors. The results showed that it is necessary for the surgeons and pathologists to be aware of lesions for the optimal diagnostic and therapeutic interventions. Also, it is vital to follow up patients with the Hashimot's thyroiditis who have multiple nodules to detect occult thyroid cancers and decide for better therapeutic programs.

Acute Esophageal Necrosis: A Case of Black Esophagus with DKA.

Acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding, usually caused by hypoperfusion. In this report, we present a 34-year-old male patient suffering from acute esophageal necrosis presenting as hematemesis in a patient with Diabetic ketoacidosis. Diabetic ketoacidosis is rarely reported as a cause of acute esophageal necrosis and it is vital to diagnose it in a patient with Diabetic Ketoacidosis as a potential cause of mortality.

Comparison of topical sucralfate and silver sulfadiazine cream in second degree burns in rats.

BACKGROUND: The most prevalent topical treatment for partial thickness burns is silver sulfadiazine 1% (SSD). Recent studies have shown that the healing of partial thickness burns is delayed with the use of SSD. One of the potential burn dressings is sucralfate. OBJECTIVES: With this study the authors have aimed to analyze comparatively the effects of sucralfate and SSD on second degree burn wounds in rats. MATERIAL AND METHODS: Forty-eight male rats were divided into three equal groups. A burn model was constituted on the back of all rats. The burned areas in the first, second and third groups were covered daily with sucralfate, SSD and cold cream (control), respectively. At the end of the 7th, 14th, 21st and 28th day, the rats were anesthetized and the burned skin tissue samples were collected for histopathological examination. RESULTS: At the end of the study, the epidermis and horny layer was completely formed in the SSD and sucralfate group; however the appendix of skin was just formed in the sucralfate group. Also the percentage of wound healing was calculated at 76%, 91% and 100% respectively in the control, silver sulfadiazine and sucralfate groups. CONCLUSIONS: Sucralfate is known to have multiple beneficial effects on wound healing. Using topical sucralfate accelerates the burn wound healing process in comparison with both the control and SSD groups and can be used as an adjunctive or alternative agent in the future.