Loading of zinc and iron in grains of different wheat genotypes in the calcareous and floodplain soils of Bangladesh.

Major malnutrition in Bangladesh is zinc (Zn) and iron (Fe) deficiency as most people commonly depend on cereals, chiefly rice and wheat. The main objectives are to enhance Zn and Fe concentrations through the use of selected varieties and the application of respective fertilizers. Field experiments were conducted at Bangladesh Agricultural University (BAU) farm, Mymensingh (AEZ 9, non-calcareous soil) and at Bangladesh Institute of Nuclear Agriculture (BINA) substation, Ishwardi (AEZ 11, calcareous soil) for two consecutive wheat seasons (2014-15 and 2015-16) with 10 varieties and 15 advanced lines. Varieties BARI Gom 25, 27, 28 & 29 and breeding lines Vijay, HPYT-5, 15 & 21 and BL-1883 have been recognized as Zn-enriched wheat varieties (24-30 µg g-1). Among the genotypes, Zn further increased by 4-8 µg g-1 due to Zn fertilization. Concerning Fe-enriched wheat genotypes (24-30 µg g-1), five varieties viz. Shatabdi, Prodip, BARI Gom 25 & 28 and Sufi, and four lines such as HPYT-12, BL-1883, BL-1040 and Fery-60 have been identified. The grain Fe concentration of wheat genotypes increased when Fe was added, the increment being 6-12 µg g-1. A positive relationship between Zn and N is observed with increased protein content. The grain yield of wheat was increased by 3.8-25.7% due to Zn application over the varieties and locations but Fe addition had no effect. The result of the current study showed that a potential breeding line with appropriate fertilization can improve Zn and Fe levels in wheat grain, without incurring loss to wheat yield.

The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain.

Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.

Association of Circulating Levels of Hypoxia-Inducible Factor-1α and miR-210 with Photosensitivity in Systemic Lupus Erythematosus Patients.

BACKGROUND: miR-210, a key hypoxamiR, regulates hypoxia and inflammation-linked hypoxia. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is responsible for many pathological disorders, including photosensitivity. OBJECTIVE: This study aimed to find the correlation between circulating miR-210/HIF-1α levels and photosensitivity in SLE patients and other SLE-associated pathological complications in a single-center case-control study. METHODS: The study population comprised 104 SLE Egyptian patients with photosensitivity, 32 SLE patients without photosensitivity, and 32 healthy subjects. SLE activity was assessed for all patients using the SLE Disease Activity Index (SLEDAI). Clinical complications/manifestations and hematological/serological analyses were recorded. HIF-α concentration was investigated by ELISA, and miR-210 expression was analyzed by qRT-PCR. RESULTS: The results revealed that circulating miR-210 was significantly increased in the SLE/photosensitivity group versus the SLE and control groups. The additional occurrence of malar rash, oral ulcers, renal disorders, or hypertension resulted in a higher expression of miR-210. SLEDAI activity status showed no effect on miR-210. Erythrocyte sedimentation rate, white blood cells, hemoglobin, platelets, patient age, and disease duration were positively correlated with circulatory miR-210. HIF-α concentration was significantly induced in the SLE/photosensitivity group versus the SLE and control groups. In SLE/photosensitivity, the presence of renal disorders and hypertension resulted in the highest HIF-α concentrations. A strong positive correlation was recorded between HIF-α concentration and circulatory miR-210 in SLE/photosensitivity patients (r = 0.886). CONCLUSION: The dysregulation of circulating miR-210/HIF-1α levels in SLE/ photosensitivity patients is controlled by the presence of additional pathological complications, and results suggest that the hypoxia pathway might interact positively with the pathogenesis and disease progression of SLE.

Circulating Levels of Hypoxia-regulating MicroRNAs in Systemic Lupus Erythematosus Patients with Hemolytic Anemia.

OBJECTIVE: MicroRNAs are fine regulators for gene expression during the post-transcriptional stage in many autoimmune diseases. HypoxamiRs (miR-210 and miR-21) play an important role in hypoxia and in inflammation-associated hypoxia. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that would potentiate many pathological complications, including hemolytic anemia. This study aimed to investigate the role of hypoxamiRs in SLE/hemolytic anemia patients. METHODS: This work was designed to analyze the circulating levels of↱ the miR-210 and miR-21 expressions and hypoxia-inducible factor-1α (HIF-α) in SLE/hemolytic anemia patients. SLE activity was evaluated for all patients by SLE Disease Activity Index (SLEDAI). Clinical manifestations/complications and serological/hematological investigations were reported. HIF-α concentration was assayed by ELISA and expression of miR-21 and miR-210 was analyzed by qRT-PCR. RESULTS: The results indicated that the fold change of the miR-210/miR-21 expressions in plasma was significantly elevated in SLE/hemolytic anemia patients. A strong positive correlation between the miR-210 and miR-21 expression levels was also recorded. Among the associated-disease complications, hypertension, arthritis, oral ulcers, and serositis were associated with a high circulating miR-210 expression, while the occurrence of renal disorders was associated with the increased miR-21 expression. Furthermore, the HIF-α level was remarkably elevated in SLE/hemolytic anemia patients. A high positive correlation was recorded between the HIF-α concentration and miR-210/miR-21 expression levels. The occurrence of oral ulcers, arthritis, and hypertension was associated with the increased HIF-α concentration. On the other hand, SLEDAI and white blood cell count were positively correlated with miR-21/ miR-210. The erythrocyte sedimentation rate was positively correlated with miR-21. CONCLUSION: The dysregulation of the circulating miR-210/miR-210/HIF-1α levels in SLE/hemolytic anemia patients advocated that the hypoxia pathway might have an essential role in the pathogenesis and complications of these diseases.

Role of polycystic ovarian syndrome in developing psychological burden in Saudi Arabian females: A case control study.

It is well known that polycystic ovarian syndrome (PCOS) may elevate psychological problems in patients, but there is a scarcity of the studies among Saudi Arabian population. This research was designed to investigate the influence of PCOS on the development of psychological load in terms of depression, anxiety, and stress in comparison to normal women who have no PCOS. Further, a correlation of psychological distress in PCOS females was done with their educational level. This is case-control research carried out in one of Riyadh's multispecialty hospitals. In the PCOS patients and control groups (each with 84 samples), samples were collected using convenience sampling and a simple random approach, respectively. The psychological burden was determined using DASS-21. The data obtained were analyzed using SPSS-IBM 25. Most participants (52.9%) were between the ages of 26 and 35 and had a university education (68.4%). A significantly higher percentage of PCOS patients (P = 0.001) had irregular menses, hirsutism, infertility, and acne in comparison to the mothers without PCOS. There was a significantly higher possibility of depression (P = 0.003), anxiety (P = 0.016), and stress (P = 0.001) among PCOS patients than in control subjects. Among the psychological domain tested in the study, the risk of developing stress (odds ratio, OR = 8.32) was high when compared to depression (OR = 3.12) and anxiety (OR = 2.127) in PCOS patients. Furthermore, when compared to PCOS females with less education, a significantly lower number of university-educated PCOS females developed depression. The study demonstrates a high prevalence of psychological burden among the PCOS population. Higher education has been shown to help in alleviating depression in PCOS females. Meeting PCOS women's psychological needs will improve their overall health status.

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

Attempting to Increase the Effectiveness of the Antidepressant Trazodone Hydrochloride Drug Using π-Acceptors.

Major depressive disorder is a prevalent mood illness that is mildly heritable. Cases with the highest familial risk had recurrence and onset at a young age. Trazodone hydrochloride is an antidepressant medicine that affects the chemical messengers in the brain known as neurotransmitters, which include acetylcholine, norepinephrine, dopamine, and serotonin. In the present research, in solid and liquid phases, the 1:1 charge-transfer complexes between trazodone hydrochloride (TZD) and six different π-acceptors were synthesized and investigated using different microscopic techniques. The relation of dative ion pairs [TZD+, A-], where A is the acceptor, was inferred via intermolecular charge-transfer complexes. Additionally, a molecular docking examination was utilized to compare the interactions of protein receptors (serotonin-6BQH) with the TZD alone or in combination with the six distinct acceptor charge-transfer complexes. To refine the docking results acquired from AutoDock Vina and to better examine the molecular mechanisms of receptor-ligand interactions, a 100 ns run of molecular dynamics simulation was used. All the results obtained in this study prove that the 2,6-dichloroquinone-4-chloroimide (DCQ)/TZD complex interacts with serotonin receptors more efficiently than reactant donor TZD only and that [(TZD)(DCQ)]-serotonin has the highest binding energy value of all π-acceptor complexes.

Multispectral and Molecular Docking Studies Reveal Potential Effectiveness of Antidepressant Fluoxetine by Forming π-Acceptor Complexes.

Poor mood, lack of pleasure, reduced focus, remorse, unpleasant thoughts, and sleep difficulties are all symptoms of depression. The only approved treatment for children and adolescents with major depressive disorder (MDD) is fluoxetine hydrochloride (FXN), a serotonin selective reuptake inhibitor antidepressant. MDD is the most common cause of disability worldwide. In the present research, picric acid (PA); dinitrobenzene; p-nitro benzoic acid; 2,6-dichloroquinone-4-chloroimide; 2,6-dibromoquinone-4-chloroimide; and 7,7',8,8'-tetracyanoquinodimethane were used to make 1:1 FXN charge-transfer compounds in solid and liquid forms. The isolated complexes were then characterized by elemental analysis, conductivity, infrared, Raman, and 1H-NMR spectra, thermogravimetric analysis, scanning electron microscopy, and X-ray powder diffraction. Additionally, a molecular docking investigation was conducted on the donor moiety using FXN alone and the resulting charge transfer complex [(FXN)(PA)] as an acceptor to examine the interactions against two protein receptors (serotonin or dopamine). Interestingly, the [(FXN)(PA)] complex binds to both serotonin and dopamine more effectively than the FXN drug alone. Furthermore, [(FXN)(PA)]-serotonin had a greater binding energy than [FXN]-serotonin. Theoretical data were also generated by density functional theory simulations, which aided the molecular geometry investigation and could be beneficial to researchers in the future.

Prenatal Exposure to Gabapentin Alters the Development of Ventral Midbrain Dopaminergic Neurons.

Background: Gabapentin is widely prescribed as an off-label drug for the treatment of various diseases, including drug and alcohol addiction. Approximately 83-95% of the usage of gabapentin is off-label, accounting for more than 90% of its sales in the market, which indicates an alarming situation of drug abuse. Such misuse of gabapentin has serious negative consequences. The safety of the use of gabapentin in pregnant women has always been a serious issue, as gabapentin can cross placental barriers. The impact of gabapentin on brain development in the fetus is not sufficiently investigated, which poses difficulties in clinical decisions regarding prescriptions. Methods: The consequences effect of prenatal gabapentin exposure on the development of ventral midbrain dopaminergic neurons were investigated using three-dimensional neuronal cell cultures. Time-mated Swiss mice were used to isolate embryos. The ventral third of the midbrain was removed and used to enrich the dopaminergic population in 3D cell cultures that were subsequently exposed to gabapentin. The effects of gabapentin on the viability, ATP release, morphogenesis and genes expression of ventral midbrain dopaminergic neurons were investigated. Results: Gabapentin treatment at the therapeutic level interfered with the neurogenesis and morphogenesis of vmDA neurons in the fetal brain by causing changes in morphology and alterations in the expression of key developmental genes, such as Nurr1, Chl1, En1, Bdnf, Drd2, and Pitx3. The TH + total neurite length and dominant neurite length were significantly altered. We also found that gabapentin could halt the metabolic state of these neuronal cells by blocking the generation of ATP. Conclusion: Our findings clearly indicate that gabapentin hampers the morphogenesis and development of dopaminergic neurons. This implies that the use of gabapentin could lead to serious complications in child-bearing women. Therefore, caution must be exercised in clinical decisions regarding the prescription of gabapentin in pregnant women.

Increasing the Efficacy of Seproxetine as an Antidepressant Using Charge-Transfer Complexes.

The charge transfer interactions between the seproxetine (SRX) donor and π-electron acceptors [picric acid (PA), dinitrobenzene (DNB), p-nitrobenzoic acid (p-NBA), 2,6-dichloroquinone-4-chloroimide (DCQ), 2,6-dibromoquinone-4-chloroimide (DBQ), and 7,7',8,8'-tetracyanoquinodi methane (TCNQ)] were studied in a liquid medium, and the solid form was isolated and characterized. The spectrophotometric analysis confirmed that the charge-transfer interactions between the electrons of the donor and acceptors were 1:1 (SRX: π-acceptor). To study the comparative interactions between SRX and the other π-electron acceptors, molecular docking calculations were performed between SRX and the charge transfer (CT) complexes against three receptors (serotonin, dopamine, and TrkB kinase receptor). According to molecular docking, the CT complex [(SRX)(TCNQ)] binds with all three receptors more efficiently than SRX alone, and [(SRX)(TCNQ)]-dopamine (CTcD) has the highest binding energy value. The results of AutoDock Vina revealed that the molecular dynamics simulation of the 100 ns run revealed that both the SRX-dopamine and CTcD complexes had a stable conformation; however, the CTcD complex was more stable. The optimized structure of the CT complexes was obtained using density functional theory (B-3LYP/6-311G++) and was compared.

Enhancement of Haloperidol Binding Affinity to Dopamine Receptor via Forming a Charge-Transfer Complex with Picric Acid and 7,7,8,8-Tetracyanoquinodimethane for Improvement of the Antipsychotic Efficacy.

Haloperidol (HPL) is a typical antipsychotic drug used to treat acute psychotic conditions, delirium, and schizophrenia. Solid charge transfer (CT) products of HPL with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have not been reported till date. Therefore, we conducted this study to investigate the donor-acceptor CT interactions between HPL (donor) and TCNQ and PA (π-acceptors) in liquid and solid states. The complete spectroscopic and analytical analyses deduced that the stoichiometry of these synthesized complexes was 1:1 molar ratio. Molecular docking calculations were performed for HPL as a donor and the resulting CT complexes with TCNQ and PA as acceptors with two protein receptors, serotonin and dopamine, to study the comparative interactions among them, as they are important neurotransmitters that play a large role in mental health. A molecular dynamics simulation was ran for 100 ns with the output from AutoDock Vina to refine docking results and better examine the molecular processes of receptor-ligand interactions. When compared to the reactant donor, the CT complex [(HPL)(TCNQ)] interacted with serotonin and dopamine more efficiently than HPL only. CT complex [(HPL)(TCNQ)] with dopamine (CTtD) showed the greatest binding energy value among all. Additionally, CTtD complex established more a stable interaction with dopamine than HPL-dopamine.

Phthalimide Analogs Enhance Genotoxicity of Cyclophosphamide and Inhibit Its Associated Hypoxia.

Cyclophosphamide (CP) is a mutagen that is used in cancer chemotherapy, due to its genotoxicity and as an immunosuppressive agent. Thalidomide (TH) is another cancer chemotherapeutic drug. In this study, the cytogenotoxicity and hypoxia modulatory activities of two phthalimide analogs of TH have been evaluated with/without CP. Both analogs have increased CP-stimulated chromosomal aberrations than those induced by TH, including gaps, breaks/fragments, deletions, multiple aberrations, and tetraploidy. The analogs have elevated the cytotoxic effect of CP by inhibiting the mitotic activity, in which analog 2 showed higher mitosis inhibition. CP has induced binucleated and polynucleated bone marrow cells (BMCs), while micronuclei (MN) are absent. TH and analogs have elevated the CP-stimulated binucleated BMCs, while only analogs have increased the CP-induced polynucleated BMCs and inhibited the mononucleated BMCs. MN-BMCs were shown together with mononucleated, binucleated, and polynucleated cells in the CP group. Both analogs have elevated mononucleated and polynucleated MN-BMCs, whereas in presence of CP, TH and analogs have enhanced mononucleated and binucleated MN-BMCs. The analogs significantly induce DNA fragmentation in a comet assay, where analog 1 is the strongest inducer. The treatment of mice with CP has resulted in a high hypoxia status as indicated by high pimonidazole adducts and high HIF-1α and HIF-2α concentrations in lymphocytes. Analogs/CP-treated mice showed low pimonidazole adducts. Both analogs have inhibited HIF-1α concentration but not HIF-2α. Taken together, the study findings suggest that both analogs have a higher potential to induce CP-genotoxicity than TH and that both analogs inhibit CP-hypoxia via the HIF-1α-dependent mechanism, in which analog 1 is a more potent anti-hypoxic agent than analog 2. Analog 1 is suggested as an adjacent CP-complementary agent to induce CP-genotoxicity and to inhibit CP-associated hypoxia.

Perftoran ® Inhibits Hypoxia-Associated Resistance in Lung Cancer Cells to Carboplatin.

Perftoran® (perfluorodecalin) is an oxygen carrier, and carboplatin is a common chemotherapy drug used worldwide for lung cancer treatment. Hypoxia is one of the factors that induce resistance of lung cancer cells to carboplatin. This study explored the role of Perftoran®, as an oxygen carrier, in lowering the resistance of lung cancer cells to carboplatin through suppression of hypoxia pathway mediators. The effect of Perftoran® on the resistance of human lung cancer A549 cells to carboplatin was investigated through the evaluation of cytotoxicity by MTT, cell death mode by dual DNA staining, DNA damage by comet assay, DNA platination (DNA/carboplatin adducts) by atomic absorption spectroscopy, hypoxia degree by pimonidazole, HIF-1α/HIF-2α concentrations by ELISA, expression of miRNAs (hypoxamiRs miR-210, miR-21, and miR-181a) by qRT-PCR, and the content of drug resistance transporter MRP-2 by immunocytochemical staining. Results indicated that compared to carboplatin, Perftoran®/carboplatin decreased cell resistance to carboplatin by potentiating its cytotoxicity using only 45% of carboplatin IC50 and inducing apoptosis. Perftoran® induced DNA platination and DNA damage index in cells compared to carboplatin alone. Moreover, compared to treatment with carboplatin alone, co-treatment of cells with Perftoran® and carboplatin inhibited cellular pimonidazole hypoxia adducts, diminished HIF-1α/HIF-2α concentrations, suppressed hypoxamiR expression, and decreased MRP-2. In conclusion, Perftoran® inhibited resistance of lung cancer cells to carboplatin through the inhibition of both hypoxia pathway mediators and the drug resistance transporter MRP-2 and through the induction of DNA/carboplatin adduct formation.

Effect of Combined Perftoran and Indocyanine Green-Photodynamic Therapy on HypoxamiRs and OncomiRs in Lung Cancer Cells.

Indocyanine green (ICG) is a nontoxic registered photosensitizer used as a diagnostic tool and for photodynamic therapy (PDT). Hypoxia is one the main factors affecting PDT efficacy. Perfluorodecalin emulsion (Perftoran®) is a known oxygen carrier. This study investigated the effect of Perftoran® on ICG/PDT efficacy in presence and absence of Perftoran® via evaluation of phototoxicity by MTT; hypoxia estimation by pimonidazole, HIF-1α/ß by ELISA, and 17 miRNAs (tumor suppressors, oncomiRs, and hypoxamiRs) were analyzed by qPCR. Compared to ICG/PDT, Perftoran®/ICG/PDT led to higher photocytotoxicity, inhibited pimonidazole hypoxia adducts, inhibited HIF-1α/ß concentrations, induced the expression of tumor-suppressing miRNAs let-7b/d/f/g, and strongly inhibited the pro-hypoxia miRNA let-7i. Additionally, Perftoran®/ICG/PDT suppressed the expression of the oncomiRs miR-155, miR-30c, and miR-181a and the hypoxamiRs miR-210 and miR-21 compared to ICG/PDT. In conclusion, Perftoran® induced the phototoxicity of ICG/PDT and inhibited ICG/PDT-hypoxia via suppressing HIF-α/ß, miR-210, miR-21, let-7i, miR-15a, miR-30c, and miR-181a and by inducing the expression of let-7d/f and miR-15b.

Anti-hypoxic Effect of Polysaccharide Extract of Brown Seaweed Sargassum dentifolium in Tongue Squamous Cell Carcinoma.

Sargassum dentifolium, (Turner) C. Agarth, 1820, is an edible brown alga collected from red seashores, Egypt. Oral tongue squamous cell carcinoma (OTSCC) is an aggressive malignancy. Hypoxia leads to chemotherapeutic resistance. This work aimed to explore the anti-hypoxia effect of water-soluble polysaccharide fractions of S. dentifolium (SD1-SD3) in CAL-27 OTSCC cells. Cell cytotoxicity assay (MTT); cell death mode (DNA staining); total hypoxia (pimonidazole), HIF-1α (ELISA and immunocytochemistry), HIF-1ß (ELISA), and hsa-miRNA-21-5p and hsa-miRNA-210-3p (qRT-PCR) were investigated. SD1 and SD2 showed a cytotoxic effect due to apoptosis. SD2 and SD3 decreased total cell hypoxia, inhibited miR-210 (p < 0.001 and p < 0.01), miR-21 (p < 0.01 and p < 0.05), and HIF-1α (p < 0.01 and p < 0.05), respectively. However, only SD3 suppressed HIF-1ß (p < 0.05). In conclusion, SD2 showed a potential anti-hypoxia effect through amelioration of HIF-1α regulators, which may help in decreasing hypoxia-induced therapeutic resistance.

Enhancing the Antipsychotic Effect of Risperidone by Increasing Its Binding Affinity to Serotonin Receptor via Picric Acid: A Molecular Dynamics Simulation.

The aim of this study was to assess the utility of inexpensive techniques in evaluating the interactions of risperidone (Ris) with different traditional π-acceptors, with subsequent application of the findings into a Ris pharmaceutical formulation with improved therapeutic properties. Molecular docking calculations were performed using Ris and its different charge-transfer complexes (CT) with picric acid (PA), 2,3-dichloro-5,6-dicyanop-benzoquinon (DDQ), tetracyanoquinodimethane (TCNQ), tetracyano ethylene (TCNE), tetrabromo-pquinon (BL), and tetrachloro-p-quinon (CL), as donors, and three receptors (serotonin, dopamine, and adrenergic) as acceptors to study the comparative interactions among them. To refine the docking results and further investigate the molecular processes of receptor-ligand interactions, a molecular dynamics simulation was run with output obtained from AutoDock Vina. Among all investigated complexes, the [(Ris) (PA)]-serotonin (CTcS) complex showed the highest binding energy. Molecular dynamics simulation of the 100 ns run revealed that both the Ris-serotonin (RisS) and CTcS complexes had a stable conformation; however, the CTcS complex was more stable.

The Effects of Prenatal Exposure to Pregabalin on the Development of Ventral Midbrain Dopaminergic Neurons.

Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes Lmx1a and Nurr1 and the mature dopaminergic gene Pitx3. Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 µM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.

Association between interferon-gamma (IFN-γ) gene polymorphisms (+874A/T and +2109A/G), and susceptibility to hepatitis B viral infection (HBV).

BACKGROUND: Interferon-gamma (IFN-γ) is a chief proinflammatory cytokine with a significant role in the immune response against viral infections. Today there is increasing evidence about the association between individual genetic polymorphisms and cytokines in predicting HBV infection susceptibility. AIM: This study aimed to investigate the association between IFN-γ gene polymorphisms and susceptibility to hepatitis B viral infection (HBV), and the impact of these genetic polymorphisms on IFN-γ production. IFN-γ (+874A/T, rs2430561, and +2109A/G, rs1861494) was genotyped by single-stranded polymorphism-polymerase chain reaction (SSP-PCR) in 126 Egyptians with chronic HBV infection and in 100 healthy control subjects. The plasma levels of IFN-γ were measured by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to the control subjects there was a slight increase in +874TT genotype frequency in HBV patients. However, no statistical significance in IFN-γ (+874A/T and +2109A/G) genotype/allele distribution was demonstrated, indicating the lack of association between these SNPs and susceptibility to HBV infection. In +2109A/G, only AG genotype was observed with a complete abrogation of GG and AA genotypes. Haplotypes between different loci on selected genes showed insignificant changes in their frequency in patients and control subjects. HBV patients had a significantly higher level of IFN-γ (P < 0.001) compared to controls. The maximum significant increase in IFN-γ production was observed in subjects harboring the +874TA genotype. CONCLUSIONS: As no association could be characterized between the polymorphism in IFN-γ (+874A/T and +2109A/G) and susceptibility to chronic HBV infection, our data support the concept that IFN-γ gene polymorphisms are not predictors of HBV susceptibility in this segment of the Egyptian population.

Sulfated Extract of Abelmoschus Esculentus: A Potential Cancer Chemo-preventive Agent.

BACKGROUND: Abelmoschus esculentus (AE) (okra), is an edible plant used in many food applications. OBJECTIVE: This study explored whether sulfated AE (SAE) has promising cancer chemopreventive activities that may recommend it as a functional food supplement instead of (or in addition to) AE for the population at risk of cancer and in the health food industry. METHODS: Cytochrome P450-1A (CYP1A) was estimated by fluorescence enzymatic reaction, using ß-naphthoflavone-treated cells (CYP1A inducer). Peroxyl and hydroxyl radical scavenging was assayed by oxygen radical absorbance capacity assay. Flow cytometry was used to analyze apoptosis/necrosis in MCF-7 cells, cell cycle phases in MCF-7 cells, and macrophage binding to fluorescein isothiocyanate-lipopolysaccharide (FITC-LPS). Nitric oxide was determined by Griess assay in LPS-stimulated macrophages, and cytotoxicity was determined by MTT assay. Diethylnitrosamine (DEN) was used to induce hepatic tumor initiation in rats. Placental glutathione-S-transferase (GSTP; an initiation marker) was stained in a fluorescence immunohistochemical analysis of liver sections, and histopathological changes were examined. RESULTS: SAE exhibited strong antitumor initiation and antitumor promotion activities. It suppressed CYP1A, scavenged peroxyl and hydroxyl radicals, induced macrophage proliferation, suppressed macrophage binding to FITC-LPS, inhibited nitric oxide generation, showed specific cytotoxicity to human breast MCF-7 adenocarcinoma cells, and disturbed the cell cycle phases (S and G2/M phases) in association with an increased percentage of apoptotic/necrotic MCF-7 cells. Over a short time period, DEN stimulated liver cancer initiation, but SAE treatment reduced the DEN-induced histopathological alterations and inhibited CYP1A and GSTP. CONCLUSION: SAE extract has the potential for use as an alternative to AE in health foods to provide cancer chemoprevention in populations at risk for cancer.

Angelica archangelica and Ginkgo biloba Extracts Recover Functional Blood Hemoglobin Derivatives in Rabbits Exposed to High Altitude.

BACKGROUND: Shortage of oxygen is a common condition for residents of high-altitude (HA) areas. In mammals, hemoglobin (Hb) has four derivatives: oxyhemoglobin (Hb-O2), carboxyhemoglobin (Hb-CO), sulfhemoglobin (Hb-S), and methemoglobin (Met-Hb). In HA areas, aberrant physiological performance of blood hemoglobin is well-established. OBJECTIVES: The study aimed to investigate the influence of 30 days of HA residence on rabbits' total Hb, Hb derivatives, Hb autooxidation rate, and antioxidant enzymes in comparison to low-altitude control rabbits. Further, the study aimed to investigate the effect of antioxidant-rich Angelica archangelica and/or Ginkgo biloba extracts on the same parameters in HA-resident rabbits. METHODS: Rabbits subjected to 30 days of HA residence were compared to low-altitude control rabbits. HA-residence rabbits were then orally administered 0.11 g/kg b.wt. of Angelica archangelica and/or Ginkgo biloba extract for 14 days. Hb derivatives and Hb autooxidation rate were measured spectrophotometrically. Antioxidant enzymes were estimated using specialized kits. RESULTS: Compared to low-altitude rabbits, 30-day HA-residence rabbits showed a noticeable increase (p<0.05) in Hb-O2 and Hb-CO concentration. In addition, Met-Hb concentration, autooxidation rate of Hb molecules, and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) exhibited a remarkable increase in HA-residence rabbits (p<0.01), reflective of rapid ROS generation. In HA-residence rabbits, both individual and combined treatment with antioxidant-rich extracts for 14 days resulted in recovery to near-normal functional levels of Hb-O2 and Met-Hb, Hb autooxidation rate, and activities of SOD and GPx, while only combined treatment led to Hb-O2 recovery. CONCLUSION: The findings suggest that functional Hb levels may be recovered by oral administration of A. archangelica, G. biloba, or combined treatments. In conclusion, oxidative stress due to living in HA areas may be avoided by supplementation with natural antioxidants.