Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications

Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agent

Synthesis and evaluation of some new 1,3,4-oxadiazoles bearing thiophene, thiazole, coumarin, pyridine and pyridazine derivatives as antiviral agents

In an attempt to produce heterocyclic compounds based on 1,3,4-oxadiazole derivatives with potential antiviral activity, the synthesis of compound 1 [2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile] was performed through the reaction of cyanoacetic acid hydrazide with carbon disulfide in alcoholic potassium hydroxide. Compound 1 has an activating methylene group, so it was directed toward some specific reactions. Thus, aryldiazonium chlorides reacted with compound 1 affording hydrazono derivatives 2a,b,c. Also, aromatic aldehydes reacted with compound 1 to produce compounds 3a,b. Furthermore, cyclic ketones were subjected to synthesis of fused thiophene derivatives 4a,b via the reaction with compound 1 in the presence of elemental sulfur. In addition, 1,3,4-oxadiazole derivative 1 when reacted with isothiocyanates, salicylaldehyde or 1,3-dicarbonyl compounds formed thiazole derivatives 5a,b, coumarin derivative 6 and alkenyl derivatives 7a,b resp. Compound 7b underwent cyclization to afford pyridine derivative 8. Arylhydrazono derivatives 9a,b were produced through the reaction of compound 7a with aryldiazonium chlorides. The latter products 9a,b underwent cyclization to produce pyridazine derivatives 10a,b. Finally 1,3,4-oxadiazole derivative 1 was directed toward the reaction with hydrazine derivatives, bromoacetophenone and ethylchloroacetate affording compounds 11a,b, 12 and 13, resp. The fused thiophene derivatives 14a,b were produced via the reaction of compounds 4a,b with a mixture of malononitrile and ethylorthoformate. Antiviral activity of the synthesized products showed that 5-(4-amino-3-ethyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5a) and 5-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5b) act as the most active agents against Feline herpes virus, Feline corona virus, Herpes simplex virus-1 and Herpes simplex virus-2, whereas compound 2-(5-(2-phenyl- hydrazono)-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile (11b) was the most effective against Vaccinia virus, Herpes simplex virus (TK-KOS-ACVr ), Coxsackie virus B4 and Vesicular stomatitis virus

Hydration, kidney injury and clinical outcome

Studies in health care professional (HCPs) have demonstrated a high prevalence of dehydration, which has been linked with morphological brain changes as well as cognitive impairment in other groups. Moreover, many age-related pathophysiological changes result in increased susceptibility to fluid and electrolyte imbalance, rendering older adults vulnerable to dehydration which may be associated with poor outcome. This thesis investigates the prevalence of dehydration and impact on cognitive function amongst HCPs. It also investigates the prevalence of dehydration in hospitalised older adults and the association between dehydration, acute kidney injury (AKI) and clinical outcome. Hydration status and cognition were objectively assessed in nurses and doctors working on emergency medical and surgical wards. This study demonstrated that a significant proportion of HCPs were dehydrated at the start and end of their shifts and many were oliguric. The prevalence of dehydration varied with level of experience and speciality and was associated with short-term memory impairment. Using serum osmolality, the key regulated variable in fluid homeostasis as a measure of hydration status in hospitalised older adults, prospective assessment of 200 patients demonstrated that over a third had hyperosmolar dehydration (HD) at admission, two-thirds of which were dehydrated 48 hours later. Dehydration at admission was independently associated with a six-fold increase in 30-day mortality. Subsequent retrospective assessment of 32,980 hospitalised older adults demonstrated that dehydration was diagnosed clinically in 8.9% of patients and was independently associated with a two fold increase in mortality. Nearly half of those dehydrated had a concomitant diagnosis of AKI and the median length of hospital stay (LOS) was nearly three times greater than those without the condition. Despite the widespread use of serum osmolality in human physiology studies, it is rarely used clinically to assess hydration. Analysis of published equations estimating osmolality, demonstrated that an equation by Khajuria and Krahn was 90% sensitivity and 97% specificity at diagnosing hyperosmolar dehydration. Using this equation, we demonstrated that 27.2% of 6632 older adults had HD at admission to hospital and the risk of developing AKI 12-24 hours after admission in these patients was five times those euhydrated at admission. Moreover, the 30-day mortality was nearly twice that of euhydrated patients, independent of key confounders. The median LOS in dehydrated patients was almost double. This work has highlighted the need to educate both patients and HCPs on the importance of hydration. Further work is required to prospectively assess the use of serum osmolality as a predictor of dehydration, AKI and outcomes. Given that hydration and nutrition are the hallmarks of compassionate care, there is clear room for improvement with findings from this thesis suggesting the need for further investigation and intervention in both community and hospital settings

Hydration, kidney injury and clinical outcome

Studies in health care professional (HCPs) have demonstrated a high prevalence of dehydration, which has been linked with morphological brain changes as well as cognitive impairment in other groups. Moreover, many age-related pathophysiological changes result in increased susceptibility to fluid and electrolyte imbalance, rendering older adults vulnerable to dehydration which may be associated with poor outcome. This thesis investigates the prevalence of dehydration and impact on cognitive function amongst HCPs. It also investigates the prevalence of dehydration in hospitalised older adults and the association between dehydration, acute kidney injury (AKI) and clinical outcome. Hydration status and cognition were objectively assessed in nurses and doctors working on emergency medical and surgical wards. This study demonstrated that a significant proportion of HCPs were dehydrated at the start and end of their shifts and many were oliguric. The prevalence of dehydration varied with level of experience and speciality and was associated with short-term memory impairment. Using serum osmolality, the key regulated variable in fluid homeostasis as a measure of hydration status in hospitalised older adults, prospective assessment of 200 patients demonstrated that over a third had hyperosmolar dehydration (HD) at admission, two-thirds of which were dehydrated 48 hours later. Dehydration at admission was independently associated with a six-fold increase in 30-day mortality. Subsequent retrospective assessment of 32,980 hospitalised older adults demonstrated that dehydration was diagnosed clinically in 8.9% of patients and was independently associated with a two fold increase in mortality. Nearly half of those dehydrated had a concomitant diagnosis of AKI and the median length of hospital stay (LOS) was nearly three times greater than those without the condition. Despite the widespread use of serum osmolality in human physiology studies, it is rarely used clinically to assess hydration. Analysis of published equations estimating osmolality, demonstrated that an equation by Khajuria and Krahn was 90% sensitivity and 97% specificity at diagnosing hyperosmolar dehydration. Using this equation, we demonstrated that 27.2% of 6632 older adults had HD at admission to hospital and the risk of developing AKI 12-24 hours after admission in these patients was five times those euhydrated at admission. Moreover, the 30-day mortality was nearly twice that of euhydrated patients, independent of key confounders. The median LOS in dehydrated patients was almost double. This work has highlighted the need to educate both patients and HCPs on the importance of hydration. Further work is required to prospectively assess the use of serum osmolality as a predictor of dehydration, AKI and outcomes. Given that hydration and nutrition are the hallmarks of compassionate care, there is clear room for improvement with findings from this thesis suggesting the need for further investigation and intervention in both community and hospital settings

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone (14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1 H NMR, 13C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities

Analysis of product distribution and characteristics of bio-oil and bio-char from fast pyrolysis of date palm tree waste

According to recent reports, there are more than 120 million date palm trees worldwide, with the estimated Middle East and North Africa combined share of more than 80%. Date palm trees produce huge amounts of waste amounting to 15-35 kg per tree per year. This represents a challenging environmental problem, since disposal is so far mainly based on landfill and uncontrolled combustion. Please click on the file below for full content of the abstract

Bart Syndrome with Ear Malformation

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A reproducible protocol for regeneration and transformation in canola (Brassica napus L.)

The objective of the present study is to develop an efficient protocol for shoot and plant regeneration using five commercial canola cultivars grown under the Egyptian agricultural conditions. The regeneration efficiency from hypocotyl explants was examined. The data indicated that embryonic calli were formed within two weeks in the presence of 1 mgl-1 2,4-D. Adventitious shoots emerged from the embryonic callus in the presence of 4.5 mgl-1 BA. The cultivars showed a varied response to shoot regeneration. Regeneration frequency was high in the cultivar Sarow-4 (68%) followed by Masrri L-16 (64%) compared with the other cultivars tested. Hypocotyl explants from the cultivars Sarow-4 and Semu-249 were inoculated and co-cultivated with Agrobacterium tumefaciens strain LBA4404 harboring a binary vector pBI-121 containing the neomycin phosphotransferase-II gene (NPT-II). The resulted putative transgenic plantlets were able to grow under knanamycin containing medium. The stable integration of the NPT-II gene into the plant genomes was tested by PCR using NPT-II -specific primers. The GUS gene expression can be detected only in the transgenic plants. The reported protocol in the present study is repeatable and can be used to regenerate transgenic canola plants expressing the genes present in A. tumifaciens binary vectors.Keywords: Agrobacterium, canola, GUS assay, regeneration, fransformation, NPT II gen

Parathormone (PTH) is strongly related to left ventricular mass index (LVMI) in hypertensives, obese, and normal control

No Abstrac