Comparison of cytotoxicity of Miltefosine and its niosomal form on chick embryo model.

Various drugs have been used for the treatment of leishmaniasis, but they often have adverse effects on the body's organs. In this study, we aimed to explore the effects of one type of drug, Miltefosine (MIL), and its analogue or modifier, liposomal Miltefosine (NMIL), on several fetal organs using both in silico analysis and practical tests on chicken embryos. Our in silico approach involved predicting the affinities of MIL and NMIL to critical proteins involved in leishmaniasis, including Vascular Endothelial Growth Factor A (VEGF-A), the Kinase insert domain receptor (KDR1), and apoptotic-regulator proteins (Bcl-2-associate). We then validated and supported these predictions through in vivo investigations, analyzing gene expression and pathological changes in angiogenesis and apoptotic mediators in MIL- and NMIL-treated chicken embryos. The results showed that NMIL had a more effective action towards VEGF-A and KDR1 in leishmaniasis, making it a better candidate for potential operative treatment during pregnancy than MIL alone. In vivo, studies also showed that chicken embryos under MIL treatment displayed less vascular mass and more degenerative and apoptotic changes than those treated with NMIL. These results suggest that NMIL could be a better treatment option for leishmaniasis during pregnancy.

Exploring mesoporous silica nanoparticles as oral insulin carriers: In-silico and in vivo evaluation.

The advancements in nanoscience have brought attention to the potential of utilizing nanoparticles as carriers for oral insulin administration. This study aims to investigate the effectiveness of synthesized polymeric mesoporous silica nanoparticles (MSN) as carriers for oral insulin and their interactions with insulin and IR through in-silico docking. Diabetic rats were treated with various MSN samples, including pure MSN, Amin-grafted MSN/PEG/Insulin (AMPI), Al-grafted MSN/PEG/Insulin (AlMPI), Zinc-grafted MSN/PEG/Insulin (ZNPI), and Co-grafted MSN/PEG/Insulin (CMPI). The nanocomposites were synthesized using a hybrid organic-inorganic method involving MSNs, graphene oxide, and insulin. Characterization of the nanocomposites was conducted using X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). In vivo tests included the examination of blood glucose levels and histopathological parameters of the liver and pancreas in type 1 diabetic rats. The MSN family demonstrated a significant reduction in blood glucose levels compared to the diabetic control group (p < 0.001). The synthesized nanocomposites exhibited safety, non-toxicity, fast operation, self-repairing pancreas, cost-effectiveness, and high efficiency in the oral insulin delivery system. In the in-silico study, Zn-grafted MSN, Co-grafted MSN, and Al-grafted MSN were selected. Docking results revealed strong interactions between MSN compounds and insulin and IR, characterized by the formation of hydrogen bonds and high binding energy. Notably, Co-grafted MSN showed the highest docking scores of -308.171 kcal/mol and -337.608 kcal/mol to insulin and IR, respectively. These findings demonstrate the potential of polymeric MSN as effective carriers for oral insulin, offering promising prospects for diabetes treatment.

Mindfulness-based stress reduction (MBSR) effects on the worries of women with poly cystic ovary syndrome (PCOS).

INTRODUCTION: Polycystic ovary syndrome is one of the women's most common endocrine disorders that can cause anxiety, psychological distress, and reduced quality of life. Therefore, the present study aimed to determine the effect of mindfulness-based stress reduction counseling on the worries of women with polycystic ovary syndrome. MATERIALS AND METHODS: This quasi-experimental was implemented on 60 women with polycystic ovary syndrome, referring to health centers in Kerman, Iran, from April to September 2021. In the intervention group, MBSR was conducted in eight 90-minute sessions twice a week. A researcher-made questionnaire with 34 questions (with six domains including worries related to mental complications, interpersonal problems, non-pregnancy physical complications, pregnancy complications, sexual complications, and religious issues) on the worries of women with polycystic ovary syndrome was completed by the participants in two intervention and control groups as pre-and post-test and one month later. 22 SPSS statistical software was used for analysis. RESULTS: The mean score of worries in the intervention group (48.18 ± 5.18) compared to the control group (75.73 ± 8.08) was significantly reduced in total and all six domains immediately after the intervention (P < 0.0001). One month later also, the total mean score of worries and subtitles decreased significantly (P < 0.0001) in the intervention group (38.27 ± 3.58) in comparison with the control group (76.13 ± 7.52). CONCLUSION: Results showed that the method of reducing stress based on mindfulness had caused a significant reduction in worries in the intervention group. Therefore, this method can be used to improve the mental health of this group of patients in health centers.

The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity: In silico, in vitro, and in vivo.

Background: Epithelial ovarian cancer is very common in women and causes hundreds of deaths per year worldwide. Chemotherapy drugs including cisplatin have adverse effects on patients' health. Complementary treatments and the use of herbal medicines can help improve the performance of medicine. 6-Gingerol is the major pharmacologically active component of ginger. In this study, we compared the effects of 6-gingerol, cisplatin, and their combination in apoptotic and angiogenetic activities in silico, in test tubes, and in in vivo assays against two ovarian cancer cell lines: OVCAR-3 and human umbilical vein endothelial cells (HUVECs). Methods: The drug-treated cell lines were evaluated for their cytotoxicity, cell cycle, and apoptotic and angiogenetic gene expression changes. Results: The proportion of apoptosis treated by 6-gingerol coupled with cisplatin was significantly high. In the evaluation of the cell cycle, the combination therapy also showed a significant promotion of a higher extent of the S sequence. The expression of p53 level, Caspase-8, Bax, and Apaf1 genes was amplified again with combination therapy. Conversely, in both cell lines, the cumulative drug concentrations reduced the expression of VEGF, FLT1, KDR, and Bcl-2 genes. Similarly, in the control group, combination treatment significantly decreased the expression of VEGF, FLT1, KDR, and Bcl-2 genes in comparison to cisplatin alone. Conclusions: The findings of the present study demonstrated that the cisplatin and 6-gingerol combination is more effective in inducing apoptosis and suppressing the angiogenesis of ovarian cancer cells than using each drug alone.

Comparison of Prenatal and Neonatal Outcomes of Selective Fetal Growth Restriction in Monochorionic Twin Pregnancies with or Without Twin-to-Twin Transfusion Syndrome After Radiofrequency Ablation.

Background: This study aimed to investigate and compare the prenatal and neonatal outcomes of monochorionic twin pregnancies complicated with fetal growth restriction (sFGR) with or without twin-to-twin transfusion syndrome (TTTS) after cord occlusion by radiofrequency ablation (RFA). Methods: This prospective cross-sectional study was conducted in women with monochorionic twin pregnancies of 16 to 26 weeks of gestational age (GA) in an academic hospital from 2016 to 2020. Demographic and obstetrical characteristics such as cervical length, GA of RFA and delivery, amnioreduction, cesarean section (C/S) rate, and maximum vertical pocket as well as prenatal, neonatal, and maternal outcomes were evaluated and compared between groups using Statistical Package for the Social Sciences (SPSS). Mann-Whitney U test or independent t test was used for quantitative data and Chi square test was applied for comparing qualitative variables. The significance level of tests was 0.05. Results: Totally 213 (106 sFGR and 107 TTTS+sFGR) cases were enrolled. The mean of maternal age (P=0.787), body mass index (P=0.932), gestational age at RFA (P=0.265), as well as gestational age of delivery (P=0.482), and C/S rate (P=0.124) were not significant between the two groups, but a significant difference (P<0.001) in cervical length was observed between the two groups. No significant differences were found in newborn and fetal outcomes such as fetal demise (P=0.827), PPROM (P=0.233), abortion (P=0.088), and admission to intensive care unit (P=0.822) between the groups. Conclusion: Although worse fetal and neonatal outcomes were expected in the TTTS+sFGR group after RFA, no significant difference was observed between groups.

Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model.

Leishmaniasis has been identified as a significant disease in tropical and subtropical regions of the world, with Iran being one of the disease-endemic areas. Various treatments have been applied for this disease, and amphotericin B (Amp B) is the second line of treatment. Side effects of this drug have been reported in various organs. The present study investigated the effects of different types of Amp B on fetal organs using in silico and in vivo assays (chicken embryos). In vivo analysis was done by checking pathological changes, angiogenesis, and apoptosis alterations on eggs treated by Amp B and AmBisome. In silico approach was employed to predict the affinity of Amp B and AmBisome to the vascular endothelial growth factor A (VEGF-A), its receptor (KDR1), apoptotic-regulator proteins (Bcl-2-associated X protein (Bax), B-cell lymphoma (Bcl-2), and Caspase-8. The ADME-toxicity prediction reveals that AmBisome possesses a superior pharmacological effect to Amp B. The best result of all the dockings in the Molegro Virtual Docker (MVD) was obtained between Bax, Bcl-2, Caspase-8, KDR1, and VEGF-A targets. Due to the lower Egap (HOMO-LUMO) of AmBisome, the chemical reactivity of AmBisome was higher than that of Amp B. In vivo analysis showed that embryos that received Amp B exhibited less vascular density than AmBisome. Amp B alone significantly increased the expression of apoptosis and decreased angiogenesis genes compared to AmBisome. The histopathology analysis of the treated embryos showed a reduction in the blood vessel collapse and an increase in degenerative and apoptotic-necrotic changes in the embryonic tissues. Overall, the results suggest the potential benefits of AmBisome over Amp B, which might be a better treatment strategy to treat leishmaniasis during pregnancy.

Predictive role of Doppler indices of cerebral-placental-uterine ratio and umbilico-cerebral ratio for late-onset fetal growth restriction: a prospective cohort study.

Predicting late-onset foetal growth restriction (FGR) has proven to be rather challenging. In this study, we propose a new parameter, cerebral-placental-uterine (CPU) ratio and umbilico-cerebral (UC) ratio for this matter. Results of this study which included a total of 227 nulliparous women showed that an increase in CPU ratio (OR = 0.45; 95% CI: 0.23-0.88; p=.020) was associated with lower odds of foetal weight above the 10th percentile at birth. CPU ratio measured at 35-37 weeks of gestation had an AUC of 0.78 (95% CI: 0.58, 0.98), sensitivity of 0.62 (95% CI: 0.24, 0.91) and specificity of 0.90 (95% CI: 0.79, 0.96) for prediction of late-onset FGR, which showed higher accuracy than UC ratio. As some cases of the late-onset FGR are not diagnosed by foetal biometry, it is important to find Doppler parameters that can help us predict these cases and CPU ratio may help physicians in detection of high-risk foetuses that will benefit from earlier intervention. Impact StatementWhat is already known on this subject? Late-onset foetal growth restriction (FGR) defined by an FGR diagnosis after 32 weeks of gestational age, can lead to short- and long-term morbidities and early diagnosis is the key to prevent these complications.What do the results of this study add? Results showed that each unit increase in numeric variables including CP ratio (OR = 0.29, p=.006), and CPU ratio (OR = 0.40, p=.006) was associated with lower odds of the foetal weight above the 10th percentile in the second ultrasound at 35-37 weeks. In other words, CPU ratio can prove to be useful marker in prediction of late-onset FGR.What are the implications of these findings for clinical practice and/or further research? Our prospective cohort study confirms the added value of low CPU ratio, with higher predictive accuracy than UC ratio, in predicting late-onset FGR. Detection of late FGR remains poor, but it is important to prevent stillbirth so further studies on the role of CPU ratio in predicting FGR and perinatal outcomes are needed.

Partridge and embryonated partridge egg as new preclinical models for candidiasis.

Candida albicans (C. albicans) is the most common cause of candidiasis in humans and animals. This study was established to a new experimental infection model for systemic candidiasis using partridge and embryonated partridge egg. First, we tested the induction of systemic candidiasis in partridge and embryonated partridge egg. Finally, interaction between virulence factors of C. albicans and Bcl-2 family members was predicted. We observed that embryonic infection causes a decrease in survival time and at later embryonic days (11-12th), embryos showed lesions. Morphometric analysis of the extra-embryonic membrane (EEM) vasculature showed that vascular apoptotic effect of C. albicans was revealed by a significant reduction in capillary area. In immunohistochemistry assay, low expression of Bcl-2 and increased expression of Bax confirmed apoptosis. The gene expression of Bax and Bcl-2 was also altered in fungi-exposed EEM. Ourin silico simulation has shown an accurate interaction between aspartic proteinase, polyamine oxidase, Bcl-2 and BAX. We observed that the disease was associated with adverse consequences, which were similar to human candidiasis. Acquired results support the idea that partridge and embryonated partridge egg can be utilized as appropriate preclinical models to investigate the pathological effects of candidiasis.

Embryo-toxicity of docosahexaenoic and eicosapentaenoic acids: In vivo and in silico investigations using the chick embryo model.

OBJECTIVE: The objective of the current study was to evaluate the embryo-toxicity of omega-3 fatty acids. METHODS: Firstly, the embryo-toxicity of docosahexaenoic (DHA) and eicosapentaenoic acids (EPA), as well as their interaction with Bcl-2 family members, were predicted using an in silico assay. In the next step, the embryonic pathological lesions and amniotic fluid biochemical changes following omega-3 treatment were investigated using a chick embryo model. Finally, the drug's vascular apoptotic effect on the chick's yolk sac membrane (YSM) was assessed. RESULTS: In silico simulations revealed the embryo-toxicity, tissue-toxicity (respiratory and cardiovascular), and vascular-toxicity (apoptotic activity) of DHA and EPA. There was also an accurate interaction between DHA and EPA with Bax (Binding affinity: -7.6 and -10.6 kcal/mol) and Bcl-2 (Binding affinity: -8.0 and -12.2 kcal/mol), respectively. Moreover, DHA and EPA administrations were related to various adverse consequences, including weight loss and lesions in the respiratory and cardiovascular systems. Histopathological findings consisted of pulmonary edema, airway dilatation, increased interstitial tissue, and hyperemia in the lungs, heart, liver, kidney, and brain. Morphometric evaluation of the YSM vasculature revealed that the vascular apoptotic effect of omega-3was associated with a significant reduction in mean capillary area. In immunohistochemistry assay, increased expression of BAX and low expression of Bcl-2 affirmed apoptosis in YSM vessels. CONCLUSION: According to the results of this study, one could confirm that the possible embryo-toxicity of omega-3 was approved by data presented in this research. The obtained results also support the suspicion that alteration of the apoptotic-related proteins in vessels is an essential pathway in embryo-toxicity of omega-3.

Vascular alteration in relation to fosfomycine: In silico and in vivo investigations using a chick embryo model.

Fosfomycin residues are found in the egg following administration in the layer hen. In this regard, some aspects of embryo-toxicity of fosfomycin have been documented previously. The exact mechanism by which fosfomycin causes embryo-toxicity is not clearly understood. We hypothesis that fosfomycin may alter vasculature as well as normal expression of genes, which are associated with vascular development. Therefore, the present study aimed to address these issues through in silico and in vivo investigations. At first, embryo-toxicity and anti-angiogenic effects of fosfomycin were tested using computerized programs. After that, fertile chicken eggs were treated with fosfomycin and chorioallantoic membrane vasculature was assessed through morphometric, molecular and histopathological assays. The results showed that fosfomycin not only interacted with VEGF-A protein and promoter, but also altered embryonic vasculature and decreased expression level of VEGF-A. Reticulin staining of treated group was also confirmed decreased vasculature. The minor groove of DNA was the preferential binding site for fosfomycin with its selective binding to GC-rich sequences. We suggested that the affinity of fosfomycin for VEGF-A protein and promoter as well as alteration of the angiogenic signaling pathway may cause vascular damage during embryonic growth. Hence, veterinarians should be aware of such effects and limit the use of this drug during the developmental stages of the embryo, particularly in breeder farms. Considering the anti-angiogenic activity and sequence selectivity of fosfomycin, a major advantage that seems to be very promising is the fact that it is possible to achieve a sequence-selective binding drug for cancer.

Quantification of circulating miR-517c-3p and miR-210-3p levels in preeclampsia.

MicroRNAs (miRNAs, miRs) are small regulatory non-coding RNAs that regulate gene expression by incomplete complementary attachment to the 3'UTR, 5'UTR, ORF and promoter regions of target mRNAs. We compared plasma levels of miR-210-3p and miR-517c-3p as cell-free microRNAs (cfmiRNAs) in preeclamptic (n = 20) and healthy women (n = 20). These miRs are responsible for cell growth and proliferation, placental hypoxia, immune response and apoptosis. We found higher expression levels of miR-210 and miR-517c in preeclamptic cases (+3.34 and +2.27 fold change, respectively). This is the first study that evaluates the plasma levels of miR-517c in preeclamptic cases by real time PCR (RT-PCR) technique. This study can lead to new opportunities for research about the roles of miRNAs in preeclampsia etiology or new biomarkers.

Toxico-pathological effects of meglumine antimoniate on human umbilical vein endothelial cells.

Leishmaniasis is one of the most important parasitic diseases after malaria. The standard treatment of leishmaniasis includes pentavalent antimonials (SbV); however, these drugs are associated with serious adverse effects. There have been very few studies pertaining to their side effects and mechanism of action in the fetus. This investigation examines the effects of meglumine antimoniate (MA) on the survival rate, angiogenesis and cellular apoptosis in the human umbilical vein endothelial cells (HUVECs). HUVECs were treated with varying doses of MA (100-800 µg/ml) for 24, 48 and 72 h and the survival rate was studied by colorimetric assay, flow cytometry, immunocytochemistry, migration (scratch) assay and tube formation assay. The results of quantitative real-time PCR (qPCR) studies indicated that the most important genes involved in presenting angiogenesis included VEGF and its receptors (Kdr and Flt-1), NP1 and Hif-1α genes including the anti-apoptotic gene of Bcl2, were significantly reduced compared to the control group (p < 0.05). In contrast, the most leading genes involved in the phenomenon of apoptosis were P53, Bax, Bak, Apaf-1 and caspases 3, 8 and 9, which were significantly up regulated compared to the control group (p < 0.05).

Vascular apoptosis associated with meglumine antimoniate: In vivo investigation of a chick embryo model.

The vasculo-toxic effect of meglumine antimoniate (MA) was confirmed in our previous investigation. The current study investigates the association of this effect with altered VEGF-A and VEGF-R2 expression. Additional mechanisms by which MA causes vascular toxicity are not clearly understood. We hypothesized that MA may alter normal expression of apoptotic genes and cause vascular toxicity. The current investigation was designed to address this issue using a chick embryo model. Fertile chicken eggs were treated with MA and the extra-embryonic membrane (EEM) vasculature was evaluated by morphometric, molecular and immunohistochemistry assays. The results showed that MA not only altered apoptotic gene expression, but that this alteration may disturb the normal development of the vascular network and cause embryo malformation. The relative expression level of the CASP3, CASP7, CASP9, APAF1, AIF1 and TP53 genes increased in drug-exposed EEMs. In addition, IHC assay confirmed the low expression BCL2 and increased expression of Bax, which are associated with a high rate of apoptosis. We suggest that induction of an apoptotic signaling pathway can lead to vascular defects during embryo development and the consecutive cascade of events can lead to the embryo malformation.

Embryonic toxico-pathological effects of meglumine antimoniate using a chick embryo model.

Leishmaniasis is one of the diverse and neglected tropical diseases. Embryo-toxicity of drugs has always been a major concern. Chick embryo is a preclinical model relevant in the assessment of adverse effects of drugs. The current study aimed to assess embryonic histopathological disorders and amniotic fluid biochemical changes following meglumine antimoniate treatment. The alteration of vascular branching pattern in the chick's extra-embryonic membrane and exploration of molecular cues to early embryonic vasculogenesis and angiogenesis were also quantified. Embryonated chicken eggs were treated with 75 or 150 mg/kg of meglumine antimoniate. Embryo malformations, growth retardation and haemorrhages on the external body surfaces were accompanied by histopathological lesions in the brain, kidney, liver and heart in a dose-dependent manner. Significant rise occurred in the biochemical indices of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and amylase in the amniotic fluid. Quantification of the extra-embryonic membrane vasculature showed that the anti-angiogenic and anti-vasculogenic effects of the drug were revealed by a significant decrease in fractal dimension value and mean capillary area. The relative expression levels of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 mRNA also significantly reduced. Concerns of a probable teratogenicity of meglumine antimoniate were established by data presented in this study. It is concluded that tissue lesions, amniotic fluid disturbance, altered early extra-embryonic vascular development and gene expression as well as the consecutive cascade of events, might eventually lead to developmental defects in embryo following meglumine antimoniate treatment. Therefore, the use of meglumine antimoniate during pregnancy should be considered as potentially embryo-toxic. Hence, physicians should be aware of such teratogenic effects and limit the use of this drug during the growing period of the fetus, particularly in rural communities. Further pharmaceutical investigations are crucial for planning future strategies.

Comparison Between the Transobturator Tape Procedure and Anterior Colporrhaphy With the Kelly's Plication in the Treatment of Stress Urinary Incontinence: a Randomized Clinical Trial.

BACKGROUND: Stress urinary incontinence in women is a common problem that impairs the quality of life in patients. The extraordinary number of procedures to treat stress urinary incontinence reflects a lack of consensus on an appropriate intervention for this problem. OBJECTIVES: The current study aimed to compare the results of transobturator tape (TOT) procedure and anterior colporrhaphy with the Kelly's Plication to treat women with stress urinary incontinence. PATIENTS AND METHODS: This randomized clinical trial was conducted on 60 patients with stress urinary incontinence referred to Afzalipour Hospital in Kerman, Iran. The patients were randomly divided into two surgery groups and were subsequently assessed regarding the outcomes of the procedures, incontinence symptoms and complications during the follow-up period. RESULTS: The cure rates at follow-up period of one month, six months and one year after surgery were 86.7%, 80% and 80% in the TOT group versus 80%, 70% and 66.7% in the anterior colporrhaphy with the Kelly's Plication group, respectively. There were no significant differences between the two groups in the aforementioned follow-up periods (P = 0.68, P = 0.54 and P = 0.22, respectively). CONCLUSIONS: The current results showed no significant differences between the outcomes of the two procedures at short-term follow-up. However, the results might have changed in the long term.

Identifying types of domestic violence and its associated risk factors in a pregnant population in Kerman hospitals, Iran Republic.

The objective of this study was to estimate the prevalence of different kinds of physical and emotional violence in an Iranian pregnant population and to examine its associated risk factors. This cross-sectional study was done from March through July 2005 in the 4 main hospitals of Kerman, Iran, which had maternity units. In total, 416 out of 460 women who were asked to participate agreed to be interviewed, a 90.4% response rate. All respondents were interviewed privately during the first 48 hours after delivery. The mean age (+/- SD) was 28.0 +/- 5.6, and all were married. Most of the women were urban residents (89.2%), and the majority of them were multiparous (78.8%). Nearly 16% of mothers said the pregnancies were unintended. In total, 35% (95% confidence interval: 30%-40%) of women had experienced 1 or more episodes of emotional violence during the pregnancy inflicted by their husbands, and 106 women (25%; 95% confidence interval: 21%-30%) had experienced at least 1 episode of physical violence. The highest odds of domestic violence during pregnancy was associated with unintended pregnancies (odds ratio: 7.66; 95% confidence interval: 3.45-16.99) and multiparous pregnancies (odds ratio: 6.88; 95% confidence interval: 3.46-13.68). Considering the high prevalence of different types of domestic violence during pregnancy, it should be regarded as a priority for health policy experts in Kerman and possibly Iran.