Cerebrolysin potentiates the antidepressant effect of lithium in a rat model of depression.

RATIONALE: Depression is the most prevalent psychiatric disorder worldwide. Although numerous antidepressant treatments are available, there is a serious clinical concern due to their severe side effects and the fact that some depressed patients are resistant to them. Lithium is the drug of choice for bipolar depression and has been used as adjunct therapy with other groups of antidepressants. OBJECTIVES: The present study aims to investigate the effect of lithium augmentation with cerebrolysin on the neurochemical, behavioral and histopathological alterations induced in the reserpine model of depression. METHODS: The animals were divided into control and reserpine-induced model of depression. The model animals were further divided into rat model of depression, rat model treated with lithium, rat model treated with cerebrolysin and rat model treated with a combination of lithium and cerebrolysin. RESULTS: Treatment with lithium, cerebrolysin, or their combination alleviated most of the changes in behavior, oxidative stress parameters, acetylcholinesterase and monoamines in the cortex and hippocampus of the reserpine-induced model of depression. It also improved the alterations in brain-derived neurotrophic factor (BDNF) and histopathology induced by reserpine. CONCLUSIONS: The augmentation of lithium with cerebrolysin showed a clear beneficial effect in the present model of depression suggesting the use of cerebrolysin as an adjuvant in antidepressant treatment.

Evaluation of the therapeutic potential of cerebrolysin and/or lithium in the male Wistar rat model of Parkinson's disease induced by reserpine.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and represents a challenge for clinicians. The present study aims to investigate the effects of cerebrolysin and/or lithium on the behavioral, neurochemical and histopathological alterations induced by reserpine as a model of PD. The rats were divided into control and reserpine-induced PD model groups. The model animals were further divided into four subgroups: rat PD model, rat PD model treated with cerebrolysin, rat PD model treated with lithium and rat PD model treated with a combination of cerebrolysin and lithium. Treatment with cerebrolysin and/or lithium ameliorated most of the alterations in oxidative stress parameters, acetylcholinesterase and monoamines in the striatum and midbrain of reserpine-induced PD model. It also ameliorated the changes in nuclear factor-kappa and improved the histopathological picture induced by reserpine. It could be suggested that cerebrolysin and/or lithium showed promising therapeutic potential against the variations induced in the reserpine model of PD. However, the ameliorating effects of lithium on the neurochemical, histopathological and behavioral alterations induced by reserpine were more prominent than those of cerebrolysin alone or combined with lithium. It can be concluded that the antioxidant and anti-inflammatory effects of both drugs played a significant role in their therapeutic potency.

Novel lipid-coated mesoporous silica nanoparticles loaded with thymoquinone formulation to increase its bioavailability in the brain and organs of Wistar rats.

AIMS: The Blood-Brain Barrier (BBB) is a filter for most medications and blocks their passage into the brain. More effective drug delivery strategies are urgently needed to transport medications into the brain. This study investigated the biodistribution of thymoquinone (TQ) and the effect on enzymatic and non-enzymatic oxidative stress indicators in different brain regions, either in free form or incorporated into nanocarriers as mesoporous silica nanoparticles (MSNs). Lipid bilayer-coated MSNs. MATERIALS AND METHODS: MSNs and LB-MSNs were synthesized and characterized using a transmission electron microscope and dynamic light scattering to determine the particle size and zeta potential. TQ encapsulation efficiency and TQ's release profile from LB-MSNs were also examined. The impact of loading LB-MSNs with TQ-on-TQ delivery to different brain areas was examined using chromatographic measurement. Furthermore, nitric oxide, malondialdehyde (MDA), reduced glutathione, and catalase were evaluated as oxidant and antioxidant stress biomarkers. KEY FINDINGS: The LB-MSNs formulation successfully transported TQ to several areas of the brain, liver, and kidney, revealing a considerable increase in TQ delivery in the thalamus (81.74%) compared with that in the free TQ group and a considerable reduction in the cortex (-44%). The LB-MSNs formulation had no significant effect on TQ delivery in the cerebellum, striatum, liver, and kidney. SIGNIFICANCE: TQ was redistributed in different brain areas after being encapsulated in LB-MSNs, indicating that LB-MSNs have the potential to be developed as a drug delivery system for selective clinical application of specific brain regions. CONCLUSIONS: LB-MSNs are capable nanoplatforms that can be used to target medications precisely to specific brain regions.

Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.

Biallelic pathogenic variants in the nuclear gene DARS2 (MIM# 610956), encoding the mitochondrial enzyme aspartyl-tRNA synthetase (MT-ASPRS) cause leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL) (MIM# 611105), a neurometabolic disorder characterized by progressive ataxia, spasticity, developmental arrest or regression and characteristic brain MRI findings. Most patients exhibit a slowly progressive disease course with motor deterirartion that begins in childhood or adolescence, but can also occasionaly occur in adulthood. More severe LBSL presentations with atypical brain MRI findings have been recently described. Baker's yeast orthologue of DARS2, MSD1, is required for growth on oxidative carbon sources. A yeast with MSD1 knockout (msd1Δ) demonstrated a complete lack of oxidative growth which could be rescued by wild-type MSD1 but not MSD1 with pathogenic variants. Here we reported two siblings who exhibited developmental regression and ataxia with different age of onset and phenotypic severity. Exome sequencing revealed 2 compound heterozygous missense variants in DARS2: c.473A>T (p.Glu158Val) and c.829G>A (p.Glu277Lys); this variant combination has not been previously reported. The msd1Δ yeast transformed with plasmids expressing p.Glu259Lys, equivalent to human p.Glu277Lys, showed complete loss of oxidative growth and oxygen consumption, while the strain carrying p.Gln137Val, equivalent to human p.Glu158Val, showed a significant reduction of oxidative growth, but a residual ability to grow was retained. Structural analysis indicated that p.Glu158Val may interfere with protein binding of tRNAAsp, while p.Glu277Lys may impact both homodimerization and catalysis of MT-ASPRS. Our data illustrate the utility of yeast model and in silico analysis to determine pathogenicity of DARS2 variants, expand the genotypic spectrum and suggest intrafamilial variability in LBSL.

Thymoquinone-encapsulated chitosan nanoparticles coated with polysorbate 80 as a novel treatment agent in a reserpine-induced depression animal model.

Depression is a mental illness with a high prevalence in humans reaching 21% of the worldwide population.The present study aims to evaluate the antidepressant effect of different formulations of Thymoquinone; free Thymoquinone (TQ), Thymoquinone-loaded Chitosan nanoparticles (TQ-TPP-Cs NPs) and Thymoquinone-loaded Chitosan nanoparticles coated with polysorbate 80 (TQ-TPP-Cs NPs-PSb80) that have been prepared to avoid the low bioavailability of TQ. Rats were randomly separated into control rats, depression control induced by reserpine, rat model treated with TQ, rat model treated with TQ-TPP-Cs NPs and rat model treated with TQ-TPP-Cs NPs-PSb80. The results indicate that TQ-TPP-Cs NPs loaded with polysorbate 80 was more efficient in ameliorating the behavioral and neurochemical changes induced by reserpine than TQ and TQ-TPP-Cs NPs. Formulationswere characterized for size, morphology, encapsulation efficiency and in vitro drug release before their use in treatment. Reserpine induced a reduction in motor activity and swimming time and increased immobility time as indicated from the open field test (OFT) and forced swimming test (FST). In addition, a significant decrease in the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA) was recorded in the cortex, hippocampus and striatum of reserpine-treated rats. The present data suggest that the antidepressant efficacy of TQ could be enhanced by engaging TQ with chitosan nanoparticles as a drug carrier and the formulations were modified by coating with polysorbate 80.

Neuronal ablation of mt-AspRS in mice induces immune pathway activation prior to severe and progressive cortical and behavioral disruption.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (mt-AspRS, or DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brainstem, and spinal cord, the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease. Here, Dars2 disruption in CamKIIα-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at five months, and culminating by nine months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation. Interestingly, RNAseq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and defense response regulation. RNA transcript analysis demonstrates that activation of immune and cell stress pathways are initiated in advance of a behavioral phenotype and cerebral deficits. An understanding of these pathways and their contribution to significant neuronal loss in CamKII-Dars2 deficient mice may aid in deciphering mechanisms of LBSL pathology.

Plasma membrane proteins: A new probe for the characterization of breast cancer.

This work aimed to characterize normal, benign and malignant excised breast tissues through the analysis of the FTIR spectra of their plasma membrane proteins. Tissue characterization parameters such as peak position, peak intensity, area under the peak, relative peak intensity and relative area under peak were evaluated mainly for protein spectral peaks; 1150 cm-1, Amide I, Amide II, Amide III, and Amide A. The sensitivity, specificity and diagnostic accuracy for each parameter were obtained and Receiver Operating Characteristic (ROC) Curves were plotted. Results showed significant spectral differences between normal and benign tissues compared to malignant tissues at 1536 and 1645 cm-1. The three tissues could be distinguished at 2900 cm-1, where the malignant peak uniquely split into two separate peaks. ROC curves showed that the Amide A peak position yielded a higher accuracy compared to all other investigated characterization parameters. The deconvolution of Amide I revealed the conformational changes in plasma proteins characterizing the transformation to malignancy (a decrease in the percentage of alpha helix accompanied by an increase in the percentage of beta sheets). The use of the present structure-based analysis in conjunction with histopathological examination of excised breast tissues would offer an enhanced characterization that might reduce possible personal diagnostic mistakes.

Women's health in Northwestern Syria: Findings from Healthy-Syria 2017 study.

OBJECTIVES: Since the uprising in 2011, there have been limited health-care data from inside Syria regarding women's health. This study aimed to provide an updated account of women's health, including pregnancy, perinatal care, childbirth, and other conditions to identify obstacles and challenges to health-care delivery in Northwestern Syria. METHODS: This is a prospective data registry study, using a medical electronic records system that builds on the International Classification of Diseases, Tenth Revision (ICD-10) codes. We collected data from one medical center in Northwestern Syria during 2017. We conducted a survey to understand patients' knowledge of and barriers limiting antenatal care (ANC). RESULTS: We studied 7213 patients' health status and surveyed 134 regarding ANC. Prenatal care, delivery, and miscarriage treatment represented the most common (70%) reasons for women's health-care visits, followed by menstrual disorders (17%). From 2057 delivery records, 70% delivered vaginally and 30% required cesarean delivery. Our findings showed that 1169 (24%) of the pregnant women (4936) in 2017 were adolescents, of them 22 (0.44%) were 14 years old. Regarding ANC visits, 85% of respondents did not have a single ANC visit in the first trimester, 82% had no visits in the second trimester, and 44% had no visits in the third trimester. Thirty-one percent had no ANC visit throughout the entire pregnancy. Only 13% had postnatal care (PNC) visits. Women who live in the refugee camp are 2.7 times less likely to meet the World Health Organization (WHO) criteria for focused ANC (FANC = 4 visits) compared to those who reside in town (P < 0.001), with only 14% having met the FANC. The major barrier to ANC is related to transportation (34%), followed by factors related to the study center (29%) and knowledge and education (19%). We estimated the number of obstetrics-gynecology doctors per 1000 populations to be 0.02. CONCLUSIONS: We found a huge deficiency in ANC and PNC visits, a high adolescent birth rate, and a higher cesarean-to-vaginal delivery ratio than what is recommended by the WHO. We also found a severe shortage in the number of obstetrician-gynecologists serving this population.

Child and adolescent health in northwestern Syria: findings from Healthy-Syria 2017 study.

OBJECTIVES: Since the uprising in 2011, there has been limited health-care data from inside Syria in the academic literature. This study aims to provide an updated account of pediatric health needs in the northwestern part of Syria; this should help inform the management and delivery of health-care services in this population. METHODS: This is a prospective study, using a data registry, of all pediatric patients seen in a single center in northwestern Syria, between February and December 2017. We used international classification of diseases (ICD-10) codes to define cases, and tested several covariates, including age, sex, season of the year, and conditions of living for possible correlations with major illness categories. RESULTS: We included 11,819 patients, of whom 5,288 (45%) were male and 6,531 (55%) were female. Collectively, these patients had 23,427 encounters. Respiratory diseases were the most encountered illnesses among all age groups (6320 [27%]), except late teen females, among whom gynecological/obstetric complaints dominated. Infectious diseases caused the greatest disease burden across all age groups, with upper respiratory tract infections (URTIs), infectious diarrhea, and otitis media representing almost half (47%) of all cases in this category. Nutritional deficiencies were diagnosed in 978 patients (8%), mostly in infants and toddlers (92%). We identified 1192 (17%) cases of acute diarrhea among all age groups, making it the second most common condition after URTIs. As compared to town residents, patients living in camps for internally displaced people accounted for more cases of infectious diarrhea (58%), chronic anemia (60%), and malnutrition (66%), especially severe acute malnutrition (76% of malnutrition cases). Vaccine-preventable illnesses represented a sizable category; we reported 69 cases of hepatitis A, 2 of poliomyelitis, 9 of pertussis, 37 of varicella, 11 of mumps, 8 of rubella, and 1 case of measles. CONCLUSION: We have identified urgent health-care issues in this population, including extreme malnutrition, high rates of infectious diseases, and high rates of teenage pregnancy. Also, we observed a relapse of some vaccine-preventable illnesses, such as mumps and rubella, which are likely associated with the decline in vaccination rates.

Utilization of silkworm litter and pupal waste-an eco-friendly approach for mass production of Bacillus thuringiensis.

The objective of the present study was to investigate the utilization of pupal waste and silkworm litter separately as production media for the mass cultivation of the potential biopesticide, Bacillus thuringiensis (Bt). Bt is the most successful commercial biopesticide accounting for 90% of all biopesticides sold all over the world. Biochemical analysis of the dry pupal waste revealed to be consisting of 4% carbohydrates, 44.9% proteins and 40% lipids. Similarly the biochemical composition of dry silkworm litter was found to be 4% carbohydrates, 57.5% proteins and 30.5% lipids. B. thuringiensis NCIM No. 2159 was mass cultivated in a semi-solid-state fermentation at a pH 7.0 and temperature 32°C. Changes in the pH and biochemical composition of the substrates were evaluated during the course of the fermentation. The reliability of the two substrates as production media was evaluated by determination of growth at regular intervals. Maximum growth was recorded at 96h incubation showing a spore count in the order of 3.5×10(10) and 3.0×10(10)CFU/g in pupal waste and silkworm litter respectively.

Production, purification and characterization of L-asparaginase from Streptomyces gulbargensis

L-asparaginase is an anti-neoplastic agent used in the lymphoblastic leukaemia chemotherapy. In the present study a novel strain, Streptomyces gulbargensis was explored for the production of extra-cellular L-asparaginase using groundnut cake extract. The optimum pH, temperature, inoculum size and agitation speed for enzyme production were pH 8.5, 40ºC, 1x10(8)spores/ml and 200 rev/min respectively. Maltose (0.5 percent) and L-asparagine (0.5 percent) proved to be the best carbon and nitrogen sources respectively. The enzyme was purified 82.12 fold and the apparent molecular weight of the enzyme was found to be 85 kDa. The optima pH and temperature for the enzyme were 9.0 and 40ºC respectively. The enzyme was more stable at the alkaline pH than at the acidic one and it retained 55 percent of the activity at 80ºC for 60 min.

Production, purification and characterization of l-asparaginase from streptomyces gulbargensis.

L-asparaginase is an anti-neoplastic agent used in the lymphoblastic leukaemia chemotherapy. In the present study a novel strain, Streptomyces gulbargensis was explored for the production of extra-cellular L-asparaginase using groundnut cake extract. The optimum pH, temperature, inoculum size and agitation speed for enzyme production were pH 8.5, 40°C, 1x10(8)spores/ml and 200 rev/min respectively. Maltose (0.5%) and L-asparagine (0.5%) proved to be the best carbon and nitrogen sources respectively. The enzyme was purified 82.12 fold and the apparent molecular weight of the enzyme was found to be 85 kDa. The optima pH and temperature for the enzyme were 9.0 and 40°C respectively. The enzyme was more stable at the alkaline pH than at the acidic one and it retained 55% of the activity at 80°C for 60 min.