Lung molecular and histological changes in type 2 diabetic rats and its improvement by high-intensity interval training.

BACKGROUND: Type 2 diabetes (T2D) leads to serious respiratory problems. This study investigated the effectiveness of high-intensity interval training (HIIT) on T2D-induced lung injuries at histopathological and molecular levels. METHODS: Forty-eight male Wistar rats were randomly allocated into control (CTL), Diabetes (Db), exercise (Ex), and Diabetes + exercise (Db + Ex) groups. T2D was induced by a high-fat diet plus (35 mg/kg) of streptozotocin (STZ) administration. Rats in Ex and Db + Ex performed HIIT for eight weeks. Tumor necrosis factor-alpha (TNFα), Interleukin 10 (IL-10), BAX, Bcl2, Lecithin, Sphingomyelin (SPM) and Surfactant protein D (SPD) levels were measured in the bronchoalveolar lavage fluid (BALF) and malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured in lung tissue. Lung histopathological alterations were assessed by using H&E and trichrome mason staining. RESULTS: Diabetes was significantly associated with imbalance in pro/anti-inflammatory, pro/anti-apoptosis and redox systems, and reduced the SPD, lecithin sphingomyelin and alveolar number. Performing HIIT by diabetic animals increased Bcl2 (P < 0.05) and IL10 (P < 0.01) levels as well as surfactants components and TAC (P < 0.05) but decreased fasting blood glucose (P < 0.001), TNFα (P < 0.05), BAX (P < 0.05) and BAX/Bcl2 (P < 0.001) levels as well as MDA (P < 0.01) and MDA/TAC (P < 0.01) compared to the diabetic group. Furthermore, lung injury and fibrosis scores were increased by T2D and recovered in presence of HIIT. CONCLUSION: These findings suggested that the attenuating effect of HIIT on diabetic lung injury mediated by reducing blood sugar, inflammation, oxidative stress, and apoptosis as well as improving pulmonary surfactants components.

Stabilization of d-lactate dehydrogenase diagnostic enzyme via immobilization on pristine and carboxyl-functionalized carbon nanotubes, a combined experimental and molecular dynamics simulation study.

The most important mode of enzyme inactivation is thermal inactivation. Immobilization technology is an efficient approach to elongate the life-time of enzymes. d-lactate dehydrogenase (D-LDH) was stabilized at high temperatures with immobilization on CNT and fCNT. The kinetic and thermodynamic parameters, optimum temperature and pH, and the intrinsic fluorescence of free and immobilized enzymes were examined in the present study. Also, an attempt was made to investigate the effect of CNT and fCNT on the adsorption and conformation of d-lactate dehydrogenase using molecular dynamics (MD) simulations. In comparison with free enzyme, the immobilized enzyme displayed an improved stability at high temperatures and, therefore, the immobilized enzyme is suitable for use in the industry because most reactions in the industry happen at high temperatures. Results of the present study showed that the adsorption of enzyme on CNT is mediated through the van der Waals and π-π stacking interactions, whereas in the adsorption of enzyme on fCNT in addition to hydrophobic interactions, the hydrogen bonding between enzyme and functional groups of fCNT is involved. Moreover, RMSD, RMSF and secondary structure analysis indicate that the fCNT protects the conformation of enzyme more than CNT. Therefore, D-LDH can be efficiently immobilized upon the fCNT compared to the pristine CNT.

Hospitalized Pregnant Women Who Leave Against Medical Advice: Attributes and Reasons.

OBJECTIVES: To identify the contributing factors for discharge against medical advice (DAMA) among pregnant women in Sistan and Balouchestan Province, southeastern Iran. METHODS: This hospital-based case-control study included a total of 168 DAMA pregnant women and 191 pregnant women who left hospital with medical approval. The participants were recruited between August 2012 and August 2013. Logistic regression models were used for data analysis. RESULTS: Factors that increased the chance of DAMA in pregnant women included older age, younger spouse age, low level of education, low income level and having a health insurance. History of DAMA in previous hospitalizations, referral from other clinics, emergency admission and admission advice from non-physician individuals for hospitalization, and giving birth at home during previous pregnancies, were associated with an increase in the risk of DAMA. The most common hospital-related reason for DAMA was the teaching environment of the hospital (26.2%) followed by hospital staff misconduct (23.8%) and overcrowding in the hospital wards (23.2%). The most frequent patient-related factors for DAMA were willingness of the patients to continue treatment at home (58.9%) and feeling relative improvement (58.3%). CONCLUSIONS FOR PRACTICE: We found that both hospital and patient related factors contribute to DAMA among pregnant women. Early identification of women at risk of DAMA and improvement of medical staff communication skills may decrease the occurrence of DAMA and improve health outcomes of pregnant women.

Breast-feeding Continuation in South-Eastern of Iran: the Associated Factors.

BACKGROUND: Breast-feeding not only promotes health in an infancy period, but also leads to human vigor and safety at varied life periods viz. adolescence, youth, middle-age, or even adulthood. AIM: The present study was aimed to determine the factors affecting the breast-feeding continuation effectively for a selected region of Iran. METHODS: This cross-sectional study was performed on 523 women having less than two year old babies from the selected counties covered by the Zahedan University of Medical Sciences (Khash, Saravan, Sarbaz, Chabahar, Zahedan, Nikshahr, Iranshahr, and Konark) using the stratified sampling method. The Data was completed for the target group by using the check-list which included 3 parts: demographic data, case history of pregnancy, childbirth and mother's statue, and previous records of the newborn up to two years. The obtained data were fed into SPSS software, and all parametric and non-parametric statistical methods were used to analyze the data, especially appropriate to the data type. RESULTS: The results showed that the most important factors associated with breast-feeding discontinuation were infant's illness (only up to six months), mother's consciousness, parental support, practical breastfeeding training to the mother, mother's educational level, child's gender, place of birth, pregnancies' interval, mother's ethnicity and residence and the statue of taking (using) narcotics. The data also indicated that on maternal reasons the main factor which impelled most of the mothers to discontinue their breast-feeding up to six months or even before two years was milk shortage in mother's breasts. Moreover, the main child- related factor that compelled most of the mothers for non-continuance of their breast-feeding up to six months or even before two years was child's crying and discomfort. CONCLUSIONS: It can be safely concluded that promotion of parental education, neglecting child's gender as far as cultural context and preference of a son is considered, observance of pregnancy interval for more than three years, non-smoking in nursing mothers, practical training of breast-feeding to mothers besides conductance of educative programs via maternity hospitals and health centers to educate parents about the importance of breast-feeding and benefits of spouse's support can be considered as the influential factors in continuation of breast-feeding.

Exploring the impact of taurine on the biochemical properties of urate oxidase: response surface methodology and molecular dynamics simulation.

This paper investigates the impact of taurine as an additive on the structural and functional stability of urate oxidase. First, the effect of the processing parameters for the stabilization of Urate Oxidase (UOX) using taurine was examined using the response surface methodology (RSM) and the central composite design (CCD) model. Also, the study examines thermodynamic and kinetic parameters as well as structural changes of urate oxidase with and without taurine. Fluorescence intensity changes indicated static quenching during taurine binding. The obtained result indicates that taurine has the ability to preserve the native structural conformation of UOX. Furthermore, molecular dynamics simulation is conducted in order to get insights into the alterations in the structure of urate oxidase in the absence and presence of taurine under optimal conditions. The molecular dynamics simulation section investigated the formation of hydrogen bonds (H-bonds) between different components as well as analysis of root mean square deviation (RMSD), root mean square fluctuations (RMSF) and secondary structure. Lower Cα-RMSD and RMSF values indicate greater stabilization of the taurine-treated UOX structure compared to the free enzyme. The results of molecular docking indicate that the binding of taurine to the UOX enzyme through hydrophobic interactions is associated with a negative value for the Gibbs free energy.

New insight into the molecular mechanism of the trehalose effect on urate oxidase stability.

Urate oxidase (EC 1.7.3.3) is a key enzyme in the purine metabolism which is applied in the treatment of gout and also, as a diagnostic reagent for uric acid detection. In the current study, the trehalose (TRE) effects as an additive on the structural stability and function of uricase were investigated. For recombinant expression of UOX in E. coli BL21 cells, firstly the coding sequence was subcloned into the pET-28a vector and after induction with IPTG, the recombinant UOX was purified by affinity chromatography using a Ni-NTA agarose column. To specify the trehalose effects on the urate oxidase (UOX) structure, optimum pH, optimum temperature, kinetic and thermodynamic parameters and also, the intrinsic fluorescence of UOX in the absence and presence of trehalose were examined. The UOX half-life is 24.32 min at 40 °C, whereas the UOX-TRE has a higher half-life (32.09 min) at this temperature. Generally, our findings confirm that trehalose has a protective effect on the enzyme structure. Optimum pH and temperature were 9 and 25 °C, respectively for both the naked and treated enzymes and their activity retained 42.18 and 64.80%, respectively after 48 h of incubation at room temperature. Also, theoretical results indicate that the random coil of the enzyme was converted to α-helix and ß-sheet in the presence of trehalose which may preserve the integrity of the active site of the enzyme and increased the enzymatic activity. The MD simulation results indicated greater stability of the uricase structure in the presence of trehalose.Communicated by Ramaswamy H. Sarma.

Investigation of nanotubes as the smart carriers for targeted delivery of mercaptopurine anticancer drug.

Mercaptopurine (MCP) is an anticancer drug that is used to treat acute lymphoblastic leukemia. The therapeutic effect of the mercaptopurine limits its severe side effects like other cytotoxic (anti-cancer) drugs. Nanostructures or nanoparticles can be widely used as potential drug carriers for diagnosis and treatment of cancer. In the current study, the boron nitride nanotube (BNNT) and carbon nanotube (CNT) were studied as the delivery carriers of MCP using the density functional theory (DFT) calculations and molecular dynamics (MDs) simulation studies. To further understand the electronic properties of mercaptopurine, the partial density of states (PDOS) was calculated. The PDOS results depicted that the electronic features of the MCP do not change after the adsorption on the surface of the nanotubes. More stability of the MCP/BNNT complexes may be attributed to the existence of the intermolecular hydrogen bonds (H-bonds) between the hydrogen atoms of the MCP molecule and the N atoms of the BNNT. The results of the quantum theory of atoms in molecules (QTAIM) confirmed the presence of H-bonds in these complexes. Moreover, MD simulation studies were done in the presence of five drug molecules. The results revealed that the strongest van der Waals (vdW) interaction energy was found between the BNNT and MCP among the studied nanotubes, indicating the BNNT is a better nanocarrier than carbon nanotube for delivery of the MCP drug within the biological systems. In general, the obtained results may present helpful information on the nature of the interactions between mercaptopurine anticancer drug with BNNT and/or CNT.Communicated by Ramaswamy H. Sarma.

Study Factors Involved in Maternal Deaths Attributed to COVID-19 in a Disadvantaged Area in Southeast of Iran.

Objective: It is a fact that coronavirus disease of 2019 (COVID-19) infection mortality rate is high, but the question is "what is the role of other factors in maternal death with COVID-19?" The present study aimed to understand the factors that prevent women from timely use of healthcare services and also the potential weaknesses of the healthcare system that cause the lack of quality healthcare services for women. Materials and methods: This case-series study was performed in the southeast of Iran. In total, 12 cases of maternal deaths attributed to COVID-19 were identified through the Iranian Maternal Mortality Surveillance System. The required information was collected through existing verbal autopsy data sets. In some cases, the family members had to be re-contacted and healthcare workers were asked to supply the missing information. The root cause analysis method was employed for data analysis. Results: From March 2020 to March 2021, the deaths of 12 women were attributed to COVID-19. The majority of these women lived in rural areas (58%) and had a secondary school education level or less (83.3%). The contributing factors were divided into three categories: barriers at the community level (no prenatal care, lack of trust, lack of recognition of the severity of disease, and attribution of symptoms to something else), at the primary health system level, and at the hospital level (fear of staff of being infected, non-compliance with guidelines, lack of team working, and problem with telehealth). Conclusion: The socio-cultural context and unmet healthcare needs hinder the utilization of available services. Moreover, factors at the level of the healthcare system prevent the timely detection and referral of women with COVID-19 to receive quality healthcare services. Using telehealth also did not help to appropriately triage pregnant women.

Biochemical, Ameliorative and Cytotoxic Effects of Newly Synthesized Curcumin Microemulsions: Evidence from In Vitro and In Vivo Studies.

Curcumin is known to exhibit antioxidant and tissue-healing properties and has recently attracted the attention of the biomedical community for potential use in advanced therapies. This work reports the formulation and characterization of oil-in-water F127 microemulsions to enhance the bioavailability of curcumin Microemulsions showed a high encapsulation efficiency and prolonged release. To investigate the interactions of curcumin with one unit of the polymeric chain of surfactant F127, ethyl butyrate, and sodium octanoate, as well as the interaction between ethyl butyrate and one unit of the F127 polymer chain, the Density Functional Theory (DFT) calculations at the M06-2X level of theory, were performed in water solution. The MTT assay was used to assess the cytotoxicity of free and encapsulated curcumin on non-malignant and malignant cell lines. Combination effects were calculated according to Chou-Talalay's principles. Results of in vitro studies indicated that MCF7 and HepG2 cells were more sensitive to curcumin microemulsions. Moreover, a synergistic relationship was observed between curcumin microemulsions and cisplatin in all affected fractions of MCF7 and HepG2 cells (CI < 0.9). For in vivo investigation, thioacetamide-intoxicated rats received thioacetamide (100 mg/kg Sc) followed by curcumin microemulsions (30 mg/kg Ip). Thioacetamide-intoxicated rats showed elevated serum liver enzymes, blood urea nitrogen (BUN), and creatinine levels, and a significant reduction in liver superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.05). Curcumin microemulsions reduced liver enzymes and serum creatinine and increased the activity of antioxidant enzymes in thioacetamide-treated rats in comparison to the untreated thioacetamide-intoxicated group. Histopathological investigations confirmed the biochemical findings. Overall, the current results showed the desirable hepatoprotective, nephroprotective, and anti-cancer effects of curcumin microemulsions.

From in vitro to in silico: Modeling and recombinant production of DT-Diaphorase enzyme.

DT-Diaphorase (DTD) belonging to the oxidoreductase family, is among the most important enzymes and is of great significance in present-day biotechnology. Also, it has potential applications in glucose and pyruvate biosensors. Another important role of the DTD enzyme is in the detection of Phenylketonuria disease. According to the above demands, at first, we tried to study molecular cloning and production of recombinant DTD in E. coli BL21 strain. We have successfully cloned, expressed, and purified functionally active diaphorase. The amount of enzyme was increased in 10-h using IPTG induction, and the recombinant protein was purified by Ni-NTA agarose affinity chromatography. After that, the kinetic and thermodynamic parameters of the enzyme, optimum temperature and pH were also investigated to find more in-depth information. In the end, to represent the connections between the structures and function of this enzyme, the molecular dynamics simulations have been considered at two temperatures in which DTD had maximum and minimum activity (310 and 293 K, respectively). The results of MD simulations indicated that the interaction between NADH with phenylalanine 232 residue at 310 K is more severe than other residues. So, to investigate the interaction details of NADH/PHE 232 the DFT calculations were done.

Empowering midwives to manage postpartum haemorrhage in rural areas of Islamic Republic of Iran: lessons learnt from cases of maternal death.

BACKGROUND: Postpartum haemorrhage is the main cause of maternal mortality in rural areas of low-income countries. AIMS: This study investigated the causes of maternal death from postpartum haemorrhage in rural areas of Sistan and Baluchestan, Islamic Republic of Iran, and determined the effect of three interventions on midwives' management of haemorrhage. METHODS: Maternal deaths in women with postpartum haemorrhage between 9 April 2012 and 9 April 2013 were reviewed to determine what contributed to the death. Following the review, prostaglandin was permitted for use in rural maternity units. A flowchart on managing haemorrhagic shock and a training workshop on management of postpartum haemorrhage were also developed for midwives working in rural areas. After the interventions, all cases of postpartum haemorrhage (n = 81) that occurred during 23 September 2014-23 February 2015 in rural maternity facilities were reviewed based on 19 indicators. A control group (n = 81) was selected from women with postpartum haemorrhage who had been admitted to the same maternity units before the interventions. RESULTS: After the training interventions, more midwives used more than one method to estimate blood loss and higher doses of oxytocin to control haemorrhage. They showed improvements in the use of intravenous fluid therapy, pulse and blood pressure checks, external uterine massage, and uterotonic drugs. Following training, more women were admitted to hospital in a stable condition and recovered and were discharged (P = 0.002), and fewer had surgical interventions (P = 0.007). CONCLUSION: Midwives' management of postpartum haemorrhage improved after the interventions. Training programmes should be based on study of the local situation to identify shortcomings. Regular monitoring of outcomes is needed to detect and resolve failures.

In silico and in vitro study of magnetic niosomes for gene delivery: The effect of ergosterol and cholesterol.

A low transfection efficiency and failure to deliver therapeutic genes to target organs limit the use of vesicular systems in gene therapy. In this study, magnetic niosomes were used to improve transfection efficiency and overcome limitations. In this light, Tween 60 and Span 60 molecules were employed as the bilayer component and ergosterol and/or cholesterol as membrane-stabilizing agents. We studied the structural and dynamical properties of cholesterol-containing niosomes (ST60/Chol) and ergosterol-containing vesicles (ST60/Ergo) using the molecular dynamics (MD) simulation technique. In in vitro experiments, the protamine-condensed DNA along with magnetic nanoparticles were prepared and incorporated into the niosome to form magnetic niosome-entrapped protamine-condensed DNA (M-NPD). The MD simulation comparison of two bilayers showed that the ST60/Ergo vesicles have better properties for gene delivery. Our in vitro results confirmed the in silico results and revealed that Ergo-niosomes have smaller size, better polydispersity, and slower release of plasmid than Chol-niosome. Moreover, M-NPD-Ergo showed higher cellular uptake and gene expresssion in HEK-293T cell line compared to M-NPD-Chol vesicles.

A combined molecular dynamics simulation and quantum mechanics study on mercaptopurine interaction with the cucurbit [6,7] urils: Analysis of electronic structure.

In the current study, the probability of complex formation between mercaptopurine drug with cucurbit[6]urils and cucurbit[7]urils has been investigated. The calculations for geometry optimization of complexes have been carried out by means of DFT (B3LYP), DFT-D (B3LYP-D) and M06-2X methods. The Atoms In Molecules (AIM), Natural Bond Orbital (NBO), NMR, the density of states (DOSs) and frontier molecular orbital (MO) analyses have been done on the inclusion complexes. In addition, the UV-Vis spectra of the first eight states have been obtained by CAM-B3LYP/TD-DFT calculation. The obtained results of the complexation process reveal that CB[7]-DRG complexes are more favorable than that of CB[6]-DRG interactions. Furthermore, our theoretical results show that configurations III and I are the most stable configurations related to the CB[6]/DRG and CB[7]/DRG interactions, respectively. The positive ∇2ρ(r) and HC values at the bond critical points indicate that exist the weak H-bonds between CB[6] and CB[7] with H atoms of the drug molecule. The obtained negative binding energy values of CB[7]-DRG interaction in solution phase show the stability of these complexes in the aqueous medium. Also, all of the observed parameters of molecular dynamics simulation such as the number of contacts, hydrogen bonding, center-of-mass distance and van der Waals energy values confirm the encapsulation of mercaptopurine molecule inside the cucurbit[7]urils cavity at about 3.2ns.

Substance Abuse and its Associated Factors among Pregnant Women: A Cross-Sectional Study in the Southeast of Iran.

BACKGROUND: The data on the prevalence of substance abuse in Iranian pregnant women is scarce in the current literature. This study investigated the prevalence of and the factors associated with substance abuse among pregnant women, and compared self-reported use with urine test results. METHODS: This cross-sectional study included data for 2000 pregnant women admitted to a tertiary care hospital in the southeast of Iran. Data were collected on socio-demographic characteristics and the patterns of substance use. Multivariate logistic regression analysis was used to identify factors associated with opiate use. A subsample (200 women) was randomly selected to provide urine samples for toxicological screening. FINDINGS: The lifetime prevalence of substance abuse and tobacco smoking was 15% and 31%, respectively. Overall, 3.3% of the participants reported using at least one substance during the previous month. One third of pregnant women reported using substances as a home remedy for treatment of pregnancy related health problems. Overall, 23% of the urine screening tests were positive. The agreement between self-reported substance abuse and the results of the urine tests was poor. Factors associated with opiates use in pregnant women were age at the first pregnancy of less than 20 years, living in rural areas, unwanted pregnancy, lack of healthcare during pregnancy, and having a spouse and/or first-degree family member with substance abuse. CONCLUSION: This study showed a high prevalence of substance abuse among the studied women. Thus, a multidisciplinary approach to provide preventive educational programs during pregnancy, and interviews and urinary screening of all pregnant women is recommended.

Selection and validation of reference genes for normalization of qRT-PCR gene expression in wheat (Triticum durum L.) under drought and salt stresses.

Eight candidate housekeeping genes were examined as internal controls for normalizing expression analysis of durum wheat (Triticum durum L.) under drought and salinity stress conditions. Quantitative real-time PCR was used to analyse gene expression of multiple stress levels, plant ages (24 and 50 days old), and plant tissues (leaf and root). The algorithms BestKeeper, NormFinder, GeNorm, the delta Ct method and the RefFinder were applied to determine the stability of candidate genes. Under drought stress, the most stable reference genes were glyceraldehyde-3 phosphate, ubiquitin and ß-tubulin2, whereas under salinity stress conditions, eukaryotic elongation factor 1-α, glyceraldehyde-3 phosphate and actin were identified as the most stable reference genes. Validation with stress-responsive genes NAC29 and NAC6 demonstrated that the expression level of target genes could be determined reliably with combinations of up to three of the reference genes. This is the first report on reference genes appropriate for quantification of target gene expression in T. durum under drought and salt stresses. Results of this investigation may be applicable to other Triticum species.

The influence of nicotine on pioglitazone encapsulation into carbon nanotube: the investigation of molecular dynamic and density functional theory.

In this work, molecular dynamics simulations of the insertion of pioglitazone into the nanotube with chirality (10, 10) at 400 K and 1 bar in the presence and absence of nicotine molecules and in different drug concentrations have been studied. The main aim is consideration of the effect of nicotine in the drug encapsulation process. The results indicate that encapsulation of pioglitazone could be attributed to the water flow via van der Waals and hydrophilic interactions. Because of the existence of the partial π-π interactions between aromatic rings of pioglitazone and the conjugated aromatic rings of nanotube, pioglitazone molecule can enter inside the nanotube. Some physical properties such as hydrogen bonding, number of contacts, also, the diffusion coefficient of the pioglitazone and water molecules, and variation of the center of mass have been calculated during the simulation. Furthermore, computing the electronic structure has also been done on model systems for quantitative determination of the adsorption energy (Eads). The B3LYP/6-31G* level calculations on four different configurations of pioglitazone/carbon nanotube (CNT) and nicotine/CNT show that the interaction of drug with the inside of the nanotube is stronger than the other forms.