The potency of mesenchymal stem/stromal cells: does donor sex matter?

Mesenchymal stem/stromal cells (MSCs) are a promising therapeutic tool in cell therapy and tissue engineering because of their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential. To achieve optimal results as a therapeutic tool, factors affecting MSC potency, including but not limited to cell source, donor age, and cell batch, have been investigated. Although the sex of the donor has been attributed as a potential factor that can influence MSC potency and efficacy, the impact of donor sex on MSC characteristics has not been carefully investigated. In this review, we summarize published studies demonstrating donor-sex-related MSC heterogeneity and emphasize the importance of disclosing donor sex as a key factor affecting MSC potency in cell therapy.

Newly Synthesized Anticancer Purine Derivatives Inhibiting p-EIF4E Using Surface-Modified Lipid Nanovesicles.

Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated (p)-eIF4E overexpression. Once p-eIF4E binds to the cap structure of mRNA, it advocates a nonstop translation process. In this regard, 15 new-based GMP analogs were synthesized to target eIF4E and restrain its binding to cap mRNA. The compounds were tested against three types of cancer cell lines: Caco-2, HepG-2, MCF-7, and normal kidney cells (Vero cells). Most of the compounds showed high potency against breast cancer cells (MCF-7), characterized by the highest cancer type for overexpression of p-eIF4E. Compound 4b was found to be the most active against three cell lines, colon (Caco-2), hepatic (HepG-2), and breast (MCF-7), with positive IC50 values of 31.40, 27.15, and 21.71 µM, respectively. Then, chitosan-coated niosomes loaded with compound 4b (Cs/4b-NSs) were developed (as kinetically enhanced molecules) to improve the anticancer effects further. The prepared Cs/4b-NSs showed pronounced cytotoxicity compared to the free 4b against Caco2, Hepg2, and MCF-7 with IC50 values of 16.15, 26.66, and 6.90 µM, respectively. Then, the expression of both the phosphorylated and nonphosphorylated western blot techniques was conducted on MCF-7 cells treated with the most active compounds (based on the obtained IC50 values) to determine the total protein expression of both eIF4E and p-eIF4e. Interestingly, the selected most active compounds displayed 35.8-40.7% inhibition of p-eIF4E expression when evaluated on MCF-7 compared to Ribavirin (positive control). CS/4b-NSs showed the best inhibition (40.7%). The findings of the present joint in silico molecular docking, simulation dynamic studies, and experimental investigation suggest the potential use of niosomal nanovesicles as a promising nanocarrier for the targeted delivery of the newly synthesized compound 4b to eukaryotic initiation factor 4E. These outcomes support the possible use of Cs/4b-NSs in targeted cancer therapy.

Development of pyrolo[2,3-c]pyrazole, pyrolo[2,3-d]pyrimidine and their bioisosteres as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological evaluation and molecular dynamics investigations.

Inhibiting the CDK2/cyclin A2 enzyme has been validated in multiple clinical manifestations related to multiple types of cancer. Herein, novel series of pyrolo[2,3-c]pyrazole, pyrolo[2,3-c]isoaxazole and pyrolo[2,3-d]pyrimidine, pyrolo[3,2-c]pyridine & indole based analogs were designed, synthesized and biologically evaluated for their in vitro antiproliferative activity where the obtained results revealed that most of the newly synthesized compounds showed significant cytotoxic activity towards MCF-7 (breast cancer cell lines) and HepG-2 (hepatocellular carcinoma) with IC50 ranging from 3.20 µM to 10.05 µM & from 2.18 µM to 13.49 µM, respectively, compared to that of Sorafenib (IC50 9.76 & 13.19 µM, respectively). The in vitro inhibitory profile of the most promising compounds (9, 11, 14, 15, 16, 17 and 20) towards CDK2/CyclinA2 was evaluated. Compounds 14 & 15 exhibited potent inhibitory profile against CDK2 with (IC50 0.11 and 0.262 µM, respectively comparable to Sorafenib IC50 0.184 µM. Western blotting of 14 & 15 at MCF-7 cell line confirmed the diminishing activity on CDK2. Furthermore, both compounds exserted a significant cell cycle arrest and apoptosis. Moreover, the normal cell line cytotoxicity for both compounds revealed low cytotoxic results in normal cells rather than cancer cells. Molecular docking and dynamic simulation validated the potentiality of the newly synthesized compounds to have high binding affinity within CDK2 binding pocket. 3DQSAR pharmacophore, in-silico ADME/TOPKAT studies and drug-likeness showed proper pharmacokinetic properties and helped in structure requirements prediction. The obtained model and pattern of substitution could be used for further development of CDK2 inhibitors.

Comparison of human immunodeficiency virus and syphilis results in pooled sera versus individual samples of blood donors attending suez canal university hospital.

Egypt is one of the countries where sexually transmitted diseases like human immunodeficiency virus (HIV) and syphilis are least prevalent. HIV and syphilis count less than one percent of total Egyptian population. An ELISA protocol for pooling serum samples is simple and may provide a way to reduce the cost and time needed for analysis. This study aimed to investigate the applicability and reliability of testing pooled sera of blood donors for HIV and syphilis compared to testing their individual sera and to assess the cost-effectiveness of this procedure. The study included 75 sera from randomly selected blood donors attending Suez Canal University hospital. Sera were screened by two ELISA kits, HIV Ag-Ab ELISA kit, and syphilis total antibody ELISA kit. Screening protocols were done by two sequential steps. At first, samples in pools of five were screened for both HIV and syphilis then, samples in positive pools were individually retested. There was no significant difference between the mean optical density for samples tested HIV and syphilis positive either individually or in pooled sera. There was no difference between the number of individual sera, tested positive for both HIV and syphilis and their pooled sera results (100 % positivity). There was significant decrease of the mean cost in one pool of 5 samples (16.5 L. E) in comparison to 5 individual samples (82.5 L. E) by HIV ELISA. Also, there was significant decrease of the mean cost in one pool of 5 samples (16 L.E) in comparison to 5 individual samples (80 L.E) by syphilis ELISA. In conclusion, the studied pooling protocol appeared reliable and can save up to 80 % of the cost for testing either HIV or syphilis by regular procedures.

Radiographic quantification of the normal and near-normal coxofemoral conformation in Labrador Retrievers and German Shepherds: a comparative study.

BACKGROUND: Canine hip dysplasia (CHD) is a multifactorial disease affecting large breed dogs with associated joint laxity and incongruity that predisposes them to osteoarthritis. The purpose of the study is to objectively compare the conformation of normal and near-normal coxofemoral joints (CFJS) in Labrador Retrievers versus German Shepherds on the extended ventrodorsal radiograph. Investigated groups were categorized as normal and near-normal CFJS according to the morphometric criteria established by the FCI scoring system. Center-edge (CE) angle, Norberg angle (NA), indices of dorsal AFH coverage width and area, acetabular slope (AS) angle, and inclination angle were determined for each group. CE angle and AS angle were modified from previously described human techniques. The width and area of dorsal AFH coverage were standardized by the corresponding femoral head diameter and area. Variables were compared between groups using an unpaired, two-tailed t-test. A Spearman correlation coefficient determined the relationship between selected variables. RESULTS: In Labradors, CE angle (lateral coverage) and dorsal AFH coverage area index (dorsal coverage) were greater in normal versus near-normal CFJS. In German Shepherds, lateral AFH coverage (CE angle and NA) was greater in normal versus near-normal hip joints; whereas, dorsal AFH coverage did not differ between the two groups. Lateral AFH coverage was greater in normal versus near-normal CFJS of both breeds. In Labradors, the inclination angle was greater in near-normal versus normal CFJS. Normal CFJS of Labradors revealed greater lateral and dorsal AFH coverages compared to German Shepherds. Near-normal joints of Labradors showed greater lateral AFH coverage compared to those of German Shepherds; whereas, dorsal AFH coverage did not differ between the two breeds. A steeper acetabular slope angle was noted in normal and near-normal CFJS of German Shepherds compared to Labrador Retrievers. The inclination angle of near-normal joints was greater in Labrador Retrievers compared to German Shepherds. CONCLUSIONS: Overall, normal and near-normal CFJS of German Shepherds had lesser AFH coverage and steeper acetabular slope angle compared to Labrador Retrievers. Labrador Retrievers and German Shepherds with CE-angles < 27° and < 21.8°, dorsal AFH coverage width indices < 51 and < 49%, and/or dorsal AFH coverage area indices < 53 and < 50%, respectively, may be consistent with CHD. Thus, the authors would recommend excluding subjects with lower values from breeding. Validating the reported measurements is still warranted.

Quantitative assessment of hip morphology to enhance the identification of hip dysplasia in German Shepherd Dogs.

OBJECTIVE: To develop quantitative measures that, when combined with the Fédération Cynologique Internationale (FCI) score, would potentially enhance the accuracy of the scoring process. ANIMALS: 153 client-owned purebred German Shepherd Dogs with normal and near normal (71 dogs) and dysplastic coxofemoral joint (82 dogs). PROCEDURES: Center edge (CE) angle, Norberg angle (NA), indexes of dorsal acetabular femoral head (AFH) coverage width and area, acetabular index angle, and inclination angle were determined. We also investigated the correlation between selected variables. Coxofemoral joints were classified into normal, near normal, and mildly, moderately, and severely dysplastic joints based on the morphometric criteria previously established by the conventional FCI scoring. Variables were compared among the 5 groups using ANOVA. Linear relationships were determined using Spearman correlation coefficients. RESULTS: All radiographic measurements differed significantly (P < .0001) among the 5 assigned groups (normal, near normal, mildly dysplastic, moderately dysplastic, and severely dysplastic hip joints). NA was the only measure that differed significantly (P ≤ .03) between the 5 assigned groups. Positive correlations were identified between Norberg and CE angles (rs = 0.93), between width and area indexes of dorsal AFH coverage (rs = 0.92), and between the measurement techniques utilized to assess lateral versus dorsal AFH coverage (rs ≥ 0.65). CLINICAL RELEVANCE: Evaluation of lateral and dorsal AFH coverage may help to refine the scoring system used to select German Shepherd Dogs for breeding. German Shepherd Dogs with NA < 103°, CE angle < 20.8°, dorsal AFH coverage width index ≤ 49%, and/or dorsal AFH coverage area index ≤ 51% should be considered to have mild, moderate, or severe hip dysplasia and are therefore not good candidates for breeding. Borderline values between near normal and mildly dysplastic joints should be reevaluated.

Experimental and Computational Analysis of Newly Synthesized Benzotriazinone Sulfonamides as Alpha-Glucosidase Inhibitors.

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and it is prevalent among people of all ages, including young adults and children. Acarbose and miglitol are famous alpha-glucosidase inhibitors but they complicate patients with the problems of flatulence, pain, bloating, diarrhea, and loss of appetite. To overcome these challenges, it is crucial to discover new anti-diabetic drugs with minimal side effects. For this purpose, benzotriazinone sulfonamides were synthesized and their structures were characterized by FT-IR, 1H-NMR and 13C-NMR spectroscopy. In vitro alpha-glucosidase inhibition studies of all synthesized hybrids were conducted using the spectrophotometric method. The synthesized compounds revealed moderate-to-good inhibition activity; in particular, nitro derivatives 12e and 12f were found to be the most effective inhibitors against this enzyme, with IC50 values of 32.37 ± 0.15 µM and 37.75 ± 0.11 µM. In silico studies, including molecular docking as well as DFT analysis, also strengthened the experimental findings. Both leading compounds 12e and 12f showed strong hydrogen bonding interactions within the enzyme cavity. DFT studies also reinforced the strong binding interactions of these derivatives with biological molecules due to their lowest chemical hardness values and lowest orbital energy gap values.

The effectiveness of an orthogeriatric service in Ain Shams University, Egypt: a quality improvement study.

This quality improvement study assessed the effectiveness of an orthogeriatric service regarding fracture care and outcomes in terms of time to surgery, length of hospital stay, postoperative pain score improvement, depression and treatment decisions. The findings showed a significant reduction in time to surgery and mean length of stay following the implementation of orthogeriatric services (OGS). INTRODUCTION: Osteoporosis is a metabolic bone disease prevalent amongst the elderly, more commonly females, and puts them at increased risk of fragility fractures. OGS are recommended as a model of best practice for primary and secondary fracture care. METHODS: This quality improvement study, conducted in our facility at Ain Shams University Hospital, Cairo, aimed to determine the effectiveness of an orthogeriatric service. We compared fracture care and outcomes before and after the implementation of OGS in terms of time to surgery, length of hospital stay, degree of postoperative pain score improvement, depression and treatment decisions. We included 128 patients aged 60 and above presenting to the emergency department with a fracture. RESULTS: We found a significant reduction in the median time to surgery in the post-OGS group (p < 0.001) and a significant decrease in the mean length of stay in favour of the post-OGS group (p < 0.001). However, no significant difference was found between the two groups regarding the number of patients treated operatively, degree of postoperative pain improvement or susceptibility to depression. CONCLUSION: Since the orthogeriatric service began, preliminary data have been encouraging, with significant reductions in time to surgery and length of stay. This along with preoperative medical optimisation and collaborative discharge recommendations has improved overall patient outcomes even though more research is needed.

High-Efficacy Hierarchical Dy2O3/TiO2 Nanoflower toward Wastewater Reclamation: A Combined Photoelectrochemical and Photocatalytic Strategy.

Developing a sustainable photocatalyst is crucial to mitigate the foreseeable energy shortage and environmental pollution caused by the rapid advancement of global industry. We developed Dy2O3/TiO2 nanoflower (TNF) with a hierarchical nanoflower structure and a near-ideal anatase crystallite morphology to degrade aqueous rhodamine B solution under simulated solar light irradiation. The prepared photocatalyst was well-characterized using powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, energy-dispersive spectroscopy, scanning electron microscopy, Brunauer-Emmett-Teller, diffuse reflectance UV-vis spectra, and X-ray photoelectron spectroscopy. Further analysis was performed to highlight the photoelectrochemical activity of the prepared photocatalysts such as electrochemical impedance spectroscopy, linear sweep voltammetry, photocurrent response, and a Mott-Schottky study. The crystalline Dy2O3/TNF exhibits superb photocatalytic activity attributed to the improved charge transfer, reduced recombination rate of the electron-hole pairs, and a remarkable red-shift in light absorption.

Densità di popolazione e SARS-CoV-2: uno studio epidemiologico di urban health.

Despite SARS-CoV-2 transmission being a complex phenomenon, greater population density seems to be a risk factor. The aim of this study was to analyze through an epidemiologic urban health approach the relationship between population density and SARS-CoV-2 incidence using data which are comparable with regard to testing strategies. All 10,300 SARS-CoV-2 confirmed cases between October and December 2020 were included. We conducted separate analysis by gender standardizing and stratifying by age and month. In the Province Capital (p.d.=765 inhabitants/km2), standardized SARS-CoV-2 incidence rate was higher than the expected, both in men (SIR=1.17, 95%CI=1.12;1.22, p<0.0001) and women (SIR=1.20, 95%CI=1.15;1.25, p<0.0001). In municipalities with p.d. >200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was similar to the expected (p>0.05). In municipalities with p.d. <200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was lower than the expected, both in men (SIR=0.85, 95%CI=0.81;0.90, p<0.0001) and women (SIR=0.84, 95%CI=0.80;0.88, p<0.0001). Stratified analysis by months with likelihood ratio test showed heterogeneity of the p.d. effect in men and women (p<0.05). SARS-CoV-2 incidence rate seemed to be higher in most densely populated areas, both in men and women. Our results confirmed the great importance of restrictive measures as well as the importance of limiting the epidemic wave in the initial stages and could help guide pandemic management strategies according to urban context and population density.

Modified FCI (Fédération Cynologique Internationale) Scoring of the Coxofemoral Joint in Labrador Retrievers Without and With Hip Dysplasia.

The objective is to propose a modified FCI scoring protocol of the canine hip joint via: (1) providing morphometric criteria of each score; (2) quantifying the extent of lateral and dorsal acetabular femoral head (AFH) coverage; (3) evaluating the steepness of cranial acetabular edge (acetabular index angle) and inclination angle (IA) in normal and dysplastic coxofemoral joints of Labrador Retrievers. The long-term goal is to achieve a selective breeding protocol using parental phenotypically healthy coxofemoral joints based on the standard extended-leg VD radiograph to help reduce the prevalence of CHD among offspring. Investigated populations were classified into normal (grade A) and dysplastic coxofemoral joints (grades B to E) based on the morphometric criteria previously established by the conventional FCI scoring system. Center-edge (CE) angle, Norberg angle (NA), indices of dorsal AFH coverage width and area, acetabular index angle, and inclination angle were determined for each group. Variables were compared between groups using ANOVA. Spearman correlation coefficient was used to determine the linear relationship between selected variables. Overall, all radiographic measurements differed significantly (P < 0.0001) among the five tested groups using ANOVA test. Dorsal AFH coverage area index was the only measure that differed significantly (P ≤ 0.007) between every two consecutive groups using Tukey's test. Significant correlations were identified between the Norberg and CE angles (r s = 0.95, P < 0.0001), the width and area of dorsal AFH coverage (r s = 0.96, P < 0.0001), and the radiographic techniques utilized to assess lateral vs. dorsal AFH coverage (r s ≥ 0.80, P < 0.0001). Evaluation of CE-angle, dorsal AFH coverage area index and acetabular index angle is recommended during selective breeding to include parents with radiographically healthy joints and reduce the incidence of hip dysplasia among offspring. Dogs with CE-angle <27°, dorsal AFH coverage area index <53%, and/or acetabular index angle >9° may be consistent with hip dysplasia and are recommended to be excluded from potential breeding groups. Re-evaluation of coxofemoral joints with borderline values located between near-normal and mildly dysplastic coxofemoral joints is strongly recommended to be performed after 6 months.

Long COVID and chronic fatigue syndrome: A survey of elderly female survivors in Egypt.

OBJECTIVES: This study aimed to investigate post-COVID-19 symptoms amongst elderly females and whether they could be a risk factor for developing chronic fatigue syndrome (CFS) later on. METHODS: This was a retrospective cross-sectional study, in the form of an online survey. A total of 115 responses were finally included. RESULTS: The mean age was 73.18 ± 6.42. Eighty-nine reported symptoms in the post-recovery period; of these 54 had no symptoms of CFS, 60 were possible, and only 1 was probable. Fatigue was reported by 66, musculoskeletal symptoms by 56, and sleep problems by 73. Twenty-nine patients visited a doctor's office as a result. Post-recovery symptoms were significantly related to stress, sadness and sleep disturbances. Also, stress, sadness, sleep disturbances, fatigue, cognitive impairment, and recurrent falls were all significantly associated with CFS-like symptoms. CONCLUSIONS: From our findings, the presence of fatigue, cognitive impairment, stress, sadness, sleep disturbances and recurrent falls in the post-recovery period were all significantly associated with CFS-like symptoms. To conclude it would be reasonable to screen for long COVID and consider the potential for developing CFS later on. Whether it can be a risk factor for developing CFS-like other viral infections will need more larger scale studies to confirm this.

Nanomolar potency of imidazo[2,1-b]thiazole analogs as indoleamine 2,3-dioxygenase inhibitors.

Novel series of imidazo[2,1-b]thiazole analogs were designed, synthesized, and biologically evaluated as indoleamine 2,3-dioxygenase (IDO1) inhibitors. Imidazo[2,1-b]thiazoles 6, 7, and 8 showed inhibitory profiles against IDO1 at IC50 values of 68.48, 82.39, and 48.48 nM, respectively, compared with IDO5L at IC50 67.40 nM. Benzo[d]imidazo[2,1-b]thiazoles 17, 20, and 22 showed promising IDO1 inhibition at IC50 values of 53.58, 53.16, and 57.95 nM, respectively. Compound 7 showed a growth-inhibitory profile at GI of 39.33% against the MCF7 breast cancer cell line, while 8 proved lethal to ACHN renal cancer cells. Cells treated with compounds 17 and 22 showed a typical apoptosis pattern of DNA fragments that reflected the G0/G1, S, and G2/M phases of the cell cycle, together with a pre-G1 phase corresponding to apoptotic cells, which indicates that cell growth arrest occurred at the S phase. Molecular modeling simulations validated the potential of benzo[d]imidazo[2,1-b]thiazole analogs to chelate iron(III) within the IDO1 binding pocket and, hence, to have a better binding affinity via hydrophobic-hydrophobic interactions.

3-Methyl-imidazo[2,1-b]thiazole derivatives as a new class of antifolates: Synthesis, in vitro/in vivo bio-evaluation and molecular modeling simulations.

Inhibiting the Dihydrofolate reductase (DHFR) enzyme has been validated in multiple clinical manifestations related to bacterial infection, malaria, and multiple types of cancer. Herein, novel series of 3-methyl-imidazo[2,1-b] thiazole-based analogs were synthesized and biologically evaluated for their in vitro inhibitory profile towards DHFR. Compounds 22 and 23 exhibited potent inhibitory profile targeting DHFR (IC50 0.079 and 0.085 µM, respectively comparable to MTX IC50 0.087 µM). Compounds 22 and 23 showed promising cytotoxicity against MCF7 breast cancer cell lines inducing cell cycle arrest and apoptosis. Furthermore, Compound 23 showed its potential to reduce body weight and tumor volume significantly, using Ehrlich ascites carcinoma (EAC) solid tumor animal model of breast cancer, compared to control-treated groups. Further, molecular modeling simulations validated the potential of 22 and 23 to have high affinity binding towards Arg22 and Phe31 residues via π-π interaction and hydrogen bonding within DHFR binding pocket. Computer-assisted ADMET study suggested that the newly synthesized analogs could have high penetration to the blood brain barrier (BBB), better intestinal absorption, non-inhibitors of CYP2D6, adequate plasma protein binding and good passive oral absorption. The obtained model and pattern of substitution could be used for further development of DHFR inhibitors.

Imidazo[2',1':2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study.

New series of thiazolo[4,5-d]pyridazin and imidazo[2',1':2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 µM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 µM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23-25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2',1':2,3]-thiazolo[4,5-d]pyridazine (43-54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.

Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study.

A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06µM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8µM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.

Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors.

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01µM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5µg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.

Anti-apoptotic and antioxidant effects of low dose gamma irradiation against diabetes-induced brain injury in rats.

The current study aimed to investigate the effect of different low doses of gamma irradiation on hyperglycemia-induced brain injury. The aim was further extended to investigate the sub-chronic effect of low dose radiation on the neuronal damage induced by diabetes. To induce diabetes, male albino rats were injected with dexamethasone (10 mg/kg/day, for 9 successive days, subcutaneously). Different diabetic groups were irradiated with 0.1, 0.25 and 0.5 Gy. The effect of low dose gamma irradiation on the hyperglycemia-induced brain damage based was analyzed at two levels: oxidative stress and apoptosis. The brain contents of glutathione, malondialdhyde and total nitrate/nitrite were measured to assess the oxidative stress. In order to evaluate the extent of the apoptotic changes in brain, tissue caspase-3 expression was detected using immunohistochemistry and the degree of DNA fragmentation was estimated. Moreover, brain tissues were examined using light microscopy to evaluate the histological changes in different groups and serum lactate dehydrogenase activity was determined as an indicator for the brain tissue damage. Results indicated that exposure to 0.5 Gy ameliorated the hyperglycemia and subsequently inhibited oxidative stress and apoptosis. Radiation exposure at this dose level also increased the survival rate of diabetic animals.

The combined effect of metformin and L-cysteine on inflammation, oxidative stress and insulin resistance in streptozotocin-induced type 2 diabetes in rats.

Increasing evidence has established causative links between obesity, chronic inflammation and insulin resistance; the core pathophysiological feature in type 2 diabetes mellitus. This study was designed to examine whether the combination of L-cysteine and metformin would provide additional benefits in reducing oxidative stress, inflammation and insulin resistance in streptozotocin-induced type 2 diabetes in rats. Male Wistar rats were fed a high-fat diet (HFD) for 8 weeks to induce insulin resistance after which they were rendered diabetic with low-dose streptozotocin. Diabetic rats were treated with metformin (300 mg/kg/day), L-cysteine (300 mg/kg/day) and their combination along with HFD for another 2 weeks. Control rats were fed normal rat chow throughout the experiment. At the end of treatment, fasting blood glucose, fasting serum insulin, homeostasis model assessment-insulin resistance index (HOMA-IR) and serum free fatty acids (FFAs) were measured. Serum levels of the inflammatory markers; monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and nitrite/nitrate were also determined. The liver was isolated and used for determination of malondialdehyde (MDA), reduced glutathione (GSH), caspase-3 and cytochrome c levels. The hypoglycemic effect of the combination therapy exceeded that of metformin and L-cysteine monotherapies with more improvement in insulin resistance. All treated groups exhibited significant reductions in serum FFAs, oxidative stress and inflammatory parameters, caspase-3 and cytochrome c levels compared to untreated diabetic rats with the highest improvement observed in the combination group. In conclusion, the present results clearly suggest that L-cysteine can be strongly considered as an adjunct to metformin in management of type 2 diabetes.

Characteristics of Type 2 diabetic patients cared for by general practitioners either with medical nutrition therapy alone or with hypoglycaemic drugs.

The essential role of medical nutrition therapy (MNT) for people with diabetes is widely recognised, and its exclusive use is recommended in mild diabetes according to a stepwise therapeutic approach. We describe the characteristics of MNT-treated Type 2 diabetic patients (vs drugs) cared for by general practitioners (GPs) in order to check that appropriate differences did exist between the two groups, by auditing the data from our local shared-care program for diabetes. We had 16,000 diabetic patients (out of 630,000 inhabitants); 6,800 of them (42.5%) cared for by GPs. Thirty-one percent (2,079 out of 6,800 patients cared for by GPs) were treated with MNT and 69% with drugs. The MNT-treated patients (vs drugs) were younger (66.1 +/- 10.7 vs 67.7 +/- 11.0 yr, p<0.01), had shorter disease duration (8.2 +/- 6.6 vs 11.2 +/- 7.6 yr, p<0.01), lower HbA1c (7.0 +/- 1.1 vs 7.8 +/- 1.6%, p<0.01) and body mass index (BMI) (28.6 +/- 4.6 vs 29.0 +/- 4.9 kg/m2, p<0.01). They had less prevalence of high blood triglycerides (25.4% vs 29.0%, p<0.01). MNT-treated patients had less micro-albuminuria (5.3% vs 8.8%, p<0.01); less retinopathy both non-proliferant (6.5% vs 11.1%, p<0.01), and pre-proliferant (6.8% vs 12.7%, p<0.01), and proliferant (7.0% vs 12.9%, p<0.01); less peripheral neuropathy (3.9% vs 8.3%, p<0.01); and diabetic foot (1.0% vs 2.0%, p<0.01). They had less chronic heart failure (2.7% vs 4.6%, p<0.01), and claudicatio intermittens (3.3% vs 5.3%, p<0.01). In conclusion, the Type 2 diabetic patients cared for by GPs using MNT appropriately had a less severe form of diabetes.