Therapeutic potential of targeting mirnas to prostate cancer tumors: using psma as an active target.

Prostate cancer (PC) is a commonly diagnosed malignancy in men and is associated with high mortality rates. Current treatments for PC include surgery, chemotherapy, and radiation therapy. However, recent advances in targeted delivery systems have yielded promising new approaches to PC treatment. As PC epithelial cells express high levels of prostate-specific membrane antigen (PSMA) on the cell surface, new drug conjugates focused on PSMA targeting have been developed. microRNAs (miRNAs) are small noncoding RNAs that regulate posttranscriptional gene expression in cells and show excellent possibilities for use in developing new therapeutics for PC. PSMA-targeted therapies based on a miRNA payload and that selectively target PC cells enhances therapeutic efficacy without eliciting damage to normal surrounding tissue. This review discusses the rationale for utilizing miRNAs to target PSMA, revealing their potential in therapeutic approaches to PC treatment. Different delivery systems for miRNAs and challenges to miRNA therapy are also explored.

Association Between Satisfaction with Nasal Appearance and Olfactory Function in Patients Undergoing Septorhinoplasty Surgery.

BACKGROUND: Any surgery has some complications, and septorhinoplasty is not an exception. The aim of this study was to highlight the relationship between satisfaction with nasal appearance and olfactory function in patients undergoing septorhinoplasty. METHODS: This is a cohort study. In this study, 384 patients aged 18 to 45 years who referred to the Ear, Nose and Throat department at Rasoul Akram hospital and private clinics in 2019 underwent septorhinoplasty. All patients were tested by the Persian Smell Identification Test (PSIT) or Rapid Smell Test (RST) before surgery. They were also reassessed one and three months after surgery. Those patients with dissatisfaction with olfactory function after surgery were also followed up for three months and assessed by PSIT or RST to determine their olfactory dysfunction. RESULTS: One month after surgery, 73.5% of patients who were not satisfied with their nasal appearance also complained about the olfactory sense. In addition, 1.5% of patients who were satisfied with their nasal appearance also complained about the olfactory sense. There was a significant difference regarding complaints of the olfactory sense between patients satisfied with their nasal appearance and those not satisfied with their appearance (P<0.05). Three months after surgery, 78.9% patients who were not pleased with their nasal appearance also had an olfactory complaint. Besides, 0.9% of patients who were pleased with their nasal shape also had an olfactory complaint. There was a significant difference regarding olfactory complaints between patients who were pleased with their nasal shape and those who were not (P<0.05). CONCLUSION: One and three months after septorhinoplasty, most patients who are satisfied with their nasal appearance have no complaints about their olfactory sense, and most patients who are not satisfied with their nasal appearance complain about the olfactory sense. An appropriate outcome of septorhinoplasty with regard to improving olfactory functional status is accompanied by patients' satisfaction level of achieving good nasal appearance.

Association Between Serum Vitamin D Concentration with Spermiogram Parameters and Reproductive Hormones Among Infertile Iranian Males: a Cross-sectional Study.

Infertility is a health concern affecting more than 186 million people globally, and male factors play a role in almost half of cases. Recently, the possible impact of vitamin D on male reproduction has become the center of attention. Our study intended to assess the correlation between serum vitamin D concentrations with sperm parameters and sex hormones in infertile Iranian men compared to fertile men. This cross-sectional study was performed among the 114 couples who were referred to the Urology Clinic of Imam Reza hospital in Mashhad, Iran. According to the inclusion criteria, 57 patients were entered into the infertility group, and 57 cases entered into the fertile group. Semen quality assessment was performed based on WHO guidelines, and the serum was analyzed for 25-hydroxy vitamin D, LH (luteinizing hormone), FSH (follicle-stimulating hormone), and testosterone by ELISA method. Vitamin D level was significantly higher in the fertile group compared with infertile males (p < 0.001). Moreover, vitamin D level was positively correlated with some fertility indicators assessed by spermiogram test including sperm motility (p < 0.001, r = 0.483) and sperm count (p = 0.019, r = 0.216). Additionally, vitamin D was positively associated with testosterone level (p = 0.025, r = 0.210). There was no significant correlation between vitamin D concentrations with sperms morphology, LH, and FSH level. Our study showed a significantly lower vitamin D level in infertile males compared to the fertile group. In conclusion, our study results showed a positive correlation between serum vitamin D with sperm motility, sperm count, and serum testosterone level in fertile males compared to infertile men and suggest the beneficial effects of vitamin D on male reproduction.

Protective effects of quercetin against hyperglycemia-induced oxidative stress in hepatic HepG2 cell line.

OBJECTIVE: Hyperglycemia is a severe consequence of diabetes mellitus (DM). Throughinduction of oxidative stress, it plays a major role in the pathogenesis of several complications in DM. Therefore, new strategies and antioxidants should be implemented inthe treatment of DM. Quercetin is a flavonoid with strong antioxidant capacity found dominantly in vegetables, fruits, leaves, and grains. The current study aimed to investigate quercetin protective effects under D-glucose-induced oxidative stress by assessing antioxidant defense enzymes inHepG2 cells as an in vitro model. MATERIALS AND METHODS: HepG2 cells were cultured with different concentrations of D-glucose (5.5, 30 and 50 mM) and/or 25 µM quercetin for 48 and 72 hr, respectively. The effect of treatments on cellular integrity, antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) activity, andcellular levels of glutathione (GSH) and malondialdehyde (MDA) wasdetermined. RESULTS: D-glucose had various effects on intracellular antioxidant defense atdifferent doses and time-points and quercetin could attenuate oxidative stress and modulate antioxidant defenses. CONCLUSION: The results of this study indicated that flavonoid quercetin could be proposed as an agent protecting hepatic HepG2 cells against oxidative stress associated with hyperglycemia.

The effect of platelet-rich plasma-fibrin glue dressing in combination with oral vitamin E and C for treatment of non-healing diabetic foot ulcers: a randomized, double-blind, parallel-group, clinical trial.

OBJECTIVE: The current study assesses the effects of platelet-rich plasma-fibrin glue (PRP-FG) dressing along with oral vitamin E and C on wound healing and biochemical markers in patients with non-healing diabetic foot ulcers (non-healing DFU). METHODS: This randomized controlled trial was performed on 25 patients with non-healing DFU. Patients were treated with PRP-FG dressing plus oral vitamin E and C (intervention group) or PRP-FG dressing plus placebo (control group) for 8 weeks. RESULTS: Eight weeks after treatment, six wounds in the intervention group and two wounds in the control group were completely closed, and also wound size significantly reduced in both intervention and control groups (p < 0.05). This reduction in wound size was significantly greater in the intervention group compared to the control group (p = 0.019). Also, a significant decrease in prooxidant-antioxidant balance (PAB) , ESR, and hs-CRP was observed in the intervention group compared to the control group (p < 0.05). CONCLUSION: Our results showed that PRP-FG dressing along with oral vitamin E and C could be used to increase wound healing in patients with non-healing DFU by enhancing the wound healing process and reducing oxidative stress. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04315909).

Association between Clinical Characteristics and Laboratory Findings with Outcome of Hospitalized COVID-19 Patients: A Report from Northeast Iran.

Coronavirus disease 2019 (COVID-19) was first discovered in December 2019 in China and has rapidly spread worldwide. Clinical characteristics, laboratory findings, and their association with the outcome of patients with COVID-19 can be decisive in management and early diagnosis. Data were obtained retrospectively from medical records of 397 hospitalized COVID-19 patients between February and May 2020 in Imam Reza Hospital, northeast Iran. Clinical and laboratory features were evaluated among survivors and nonsurvivors. The correlation between variables and duration of hospitalization and admission to the intensive care unit (ICU) was determined. Male sex, age, hospitalization duration, and admission to ICU were significantly related to mortality rate. Headache was a more common feature in patients who survived (p=0.017). It was also related to a shorter stay in the hospital (p=0.032) as opposed to patients who experienced chest pain (p=0.033). Decreased levels of consciousness and dyspnea were statistically more frequent in nonsurvivors (p=0.003 and p=0.011, respectively). Baseline white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were significantly higher in nonsurvivors (p < 0.001). Patients with higher WBC and CRP levels were more likely to be admitted to ICU (p=0.009 and p=0.001, respectively). Evaluating clinical and laboratory features can help clinicians find ways for risk stratifying patients and even make predictive tools. Chest pain, decreased level of consciousness, dyspnea, and increased CRP and WBC levels seem to be the most potent predictors of severe prognosis.

Role of mTOR Complex 1 Signaling Pathway in the Pathogenesis of Diabetes Complications; A Mini Review.

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine-protein kinase that senses and combines various environmental signals to regulate the growth and homeostasis of human cells. This signaling pathway synchronizes many critical cellular processes and is involved in an increasing number of pathological conditions such as diabetes, cancer, obesity, and metabolic syndrome. Here, we review different complications of diabetes that are associated with mTOR complex 1 imbalance. We further discuss pharmacological approaches to treat diabetes complications linked to mTOR deregulation.

MicroRNAs in diabetic nephropathy: From molecular mechanisms to new therapeutic targets of treatment.

Despite considerable investigation in diabetic nephropathy (DN) pathogenesis and possible treatments, current therapies still do not provide competent prevention from disease progression to end-stage renal disease (ESRD) in most patients. Therefore, investigating exact molecular mechanisms and important mediators underlying DN may help design better therapeutic approaches for proper treatment. MicroRNAs (MiRNAs) are a class of small non-coding RNAs that play a crucial role in post-transcriptional regulation of many gene expression within the cells and present an excellent opportunity for new therapeutic approaches because their profile is often changed during many diseases, including DN. This review discusses the most important signaling pathways involved in DN and changes in miRNAs profile in each signaling pathway. We also suggest possible approaches for miRNA derived interventions for designing better treatment of DN.

Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial.

COVID-19 is a global catastrophic event that causes severe acute respiratory syndrome. The mechanism of the disease remains unclear, and hypoxia is one of the main complications. There is no currently approved protocol for treatment. The microbial threat as induced by COVID-19 causes the activation of macrophages to produce a huge amount of inflammatory molecules and nitric oxide (NO). Activation of macrophages population into a pro-inflammatory phenotype induces a self-reinforcing cycle. Oxidative stress and NO contribute to this cycle, establishing a cascade inflammatory state that can kill the patient. Interrupting this vicious cycle by a simple remedy may save critical patients' lives. Nitrite, nitrate (the metabolites of NO), methemoglobin, and prooxidant-antioxidant-balance levels were measured in 25 ICU COVID-19 patients and 25 healthy individuals. As the last therapeutic option, five patients were administered methylene blue-vitamin C-N-acetyl Cysteine (MCN). Nitrite, nitrate, methemoglobin, and oxidative stress were significantly increased in patients in comparison to healthy individuals. Four of the five patients responded well to treatment. In conclusion, NO, methemoglobin and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease. MCN treatment seems to increase the survival rate of these patients. Considering the vicious cycle of macrophage activation leading to deadly NO, oxidative stress, and cytokine cascade syndrome; the therapeutic effect of MCN seems to be reasonable. Accordingly, a wider clinical trial has been designed. It should be noted that the protocol is using the low-cost drugs which the FDA approved for other diseases. TRIAL REGISTRATION NUMBER: NCT04370288.

The Application of a Reduced Dye Used in Orthopedics as a Novel Treatment against Coronavirus (COVID-19): A Suggested Therapeutic Protocol.

The severe acute respiratory syndrome caused by COVID-19 is now a global catastrophic event. Currently there is no approved drug or vaccine for the disease. Methylene blue (MB, oxidized form, blue color) has been used in many different areas of clinical medicine, ranging from malaria to orthopedics. Leucomethylene Blue (reduced form of MB, colorless) may be applied for the treatment of COVID-19 according to the scientific evidences. In severe patients, there is a cytokine storm (hyperinflammation) and high oxidative stress (OS). Inflammation and OS has a mutual correlation and exacerbate each other. In human body, MB first induces OS through absorbing electron (like a free radical) from other molecules, if the body could counteract to this OS, then reduced MB decreases OS through other mechanisms. Reduced MB could prevent inflammation, propagation of the virus RNA, and also improves hypoxia through reducing methemoglobin. Therefore, to avoid the increment of OS, we suggest using Leucomethylene Blue through the following protocol: The IV cocktail contains 50 mg MB (1mg/kg, 50-kg weight), 1000-2000 mg vitamin C, 500-1000 mg N-Acetylcysteine (or glutathione or cysteine or α-lipoic acid) and 10-20 gr urea (optional) in 100 ml dextrose 5%. Before the injection, the cocktail should be kept in a dark place for 1-2 hour to become fade or colorless.

Nicotine attenuates global genomic DNA methylation by influencing DNMTs gene expression in human endometrial stromal cells.

BACKGROUND: There is increasing evidence indicating an incidence of infertility and also the risk of endometrial cancers among smokers. However, the mechanism underlying nicotine adverse effect on female reproduction remains unclear. Growing evidence has suggested that environmental exposures such as nicotine could modulate the epigenome. No study has yet been published to evaluate the direct effect of nicotine on the epigenome profiling of human endometrial stromal cells (HESC). Herein, we decided to examine the direct effects of nicotine on global genomic DNA methylation status and DNA methyl- transferases (DNMTs) gene expression in HESC. HESC were treated with different doses of nicotine (0 or control, 10- 11, 10- 8 and 10- 6) M for 24 h and their genomic global DNA methylation and gene expression of DNMTs (DNMT1, DNMT3A, and DNMT3B) were investigated using ELISA and real-time PCR, respectively. RESULTS: Nicotine treatments reduced the average level of DNMTs gene expression by 90, 79, and 73.4% in 10- 11, 10- 8 and 10- 6 M of nicotine treated cells as compared to control cells, respectively (p < 0.05). Also, 10- 8 and 10- 6 M of nicotine concentrations effectively reduced the amounts of 5-methylated cytosine (5-mC) by 1.09 and 1.87% compared to control cells, respectively (p < 0.05). The 5-mC percentages were positively correlated with the relative cellular DNMTs expression in HESC as verified by the Pearson correlation test. CONCLUSION: An interesting possibility raised by the current study is that the reduced genomic global DNA methylation level in HESC may be partly due to the suppression of DNMTs gene expression caused by nicotine in these cells.

In-Vitro Analysis of Glucose and Quercetin Effects on m-TOR and Nrf-2 Expression in HepG2 Cell Line (Diabetes and Cancer Connection).

Some types of cancers show a strong relationship with diabetes and play a central role in mortality in the patient population suffering from diabetes mellitus. In this study, HepG2 cells have been used to investigate the toxic effects of hyperglycemia and/or quercetin (Q) on mammalian target of rapamycin (m-TOR) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression as central molecules involved in cancer. HepG2 cells were cultured with different concentrations of glucose (5.5, 30, and 50 mM) and/or Q (25 µM) for 48 and 72 h. Effects of glucose and/or Q on m-TOR and Nrf-2 expression were assayed by quantitative real-time PCR (qRT-PCR). qRT-PCR results revealed that 30 and 50 mM of glucose increased m-TOR expression at 48 h, although after 72 h, only 30 mM had an increasing effect. At 50 mM, glucose-induced Nrf-2 gene expression after both 48 and 72 h. The results also showed that 25 µM of Q reduced m-TOR and Nrf-2 expression at both 30 and 50 mM after 48 and 72 h incubation. Q has potential effects on reducing oxidative stress caused by hyperglycemia and during diabetes may be able to modulate some carcinogenic signaling pathways.

Protective effects of quercetin on nicotine induced oxidative stress in 'HepG2 cells'.

Nicotine is a natural component of tobacco plants and is responsible for the addictive properties of tobacco. Nicotine has been recognized to result in oxidative stress by inducing the generation of reactive oxygen species (ROS). The purpose of this work was to estimate the hepatotoxicity effect of nicotine on viability and on antioxidant defense system in cultures of HepG2 cell line and the other hand, ameliorative effect of quercetin (Q) as an antioxidant was analyzed. Nicotine induced concentration dependent loss in HepG2 cell line viability. The results indicated that nicotine decreased activity of superoxide dismutase (SOD) and glutathione reductase (GR) and increased activities of catalase (CAT) and glutathione peroxidase (GPx) and glutathione (GSH) content in the HepG2 cells. Q significantly increased activity of SOD, GR and GSH content and decreased activity of GPX in nicotine + Q groups. Our data demonstrate that Q plays a protective role against the imbalance elicited by nicotine between the production of free radicals and antioxidant defense systems, and suggest that administration of this antioxidant may find clinical application where cellular damage is a consequence of ROS.