Novel tetrahydroisoquinolines as DHFR and CDK2 inhibitors: synthesis, characterization, anticancer activity and antioxidant properties.

In this study, we synthesized new 5,6,7,8-tetrahydroisoquinolines and 6,7,8,9-tetrahydrothieno[2,3-c]isoquinolines based on 4-(N,N-dimethylamino)phenyl moiety as expected anticancer and/or antioxidant agents. The structure of all synthesized compounds were confirmed by spectral date (FT-IR, 1H NMR, 13C NMR) and elemental analysis. We evaluated the anticancer activity of these compounds toward two cell lines: A459 cell line (lung cancer cells) and MCF7 cell line (breast cancer cells). All tested compounds showed moderate to strong anti-cancer activity towards the two cell lines. Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC50: 0.155 µM) while compound 8d showed the most potent one against MCF7 cell line (IC50: 0.170 µM) in comparison with doxorubicin. In addition, we examined the effect of compounds 7e and 8d regarding the growth of A549 and MCF7 cell lines, employing flow cytometry and Annexin V-FITC apoptotic assay. Our results showed that compound 7e caused cell cycle arrest at the G2/M phase with a 79-fold increase in apoptosis of A459 cell line. Moreover, compound 8d caused cell cycle arrest at the S phase with a 69-fold increase in apoptosis of MCF7 cell line. Furthermore, we studied the activity of these compounds as enzyme inhibitors against several enzymes. Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 µM, compared to the Roscovitine control drug with IC50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 µM, compared to Methotrexate control drug with IC50 of 0.131 µM. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1, 3, 6, 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs.

Ultrasounds assisted one-pot oxidative desulfurization of model fuel using green synthesized aluminum terephthalate [MIL-53(Al)].

Oxidative desulfurization (ODS) is considered to be one of the most promising desulfurization processes as it is energy-efficient and requires mild operating conditions. In this study, a novel green synthesized Al- based metal-organic framework with high surface area has been synthesized hydrothermally using waste polyethylene terephthalate bottles (PET) as a source of terephthalic acid as an organic linker. The prepared Al based MOF have been characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscopy (TEM). The catalytic activity of the prepared Al-MOF was evaluated in the oxidative desulfurization (ODS) of both modeled and real crude oil samples. The different operating parameters (temperature, time, catalyst dose, oxidant loading and sonication) on the ODS performance have been optimized. The optimal conditions for maximum removal of thiophene from modeled oil samples were found to be 30 min, 0.5 g of catalyst and 1:3 oil to oxidant ratio. Under the optimized conditions, sulfur removal in real oil samples obtained from Alexandria petroleum company was 90%. The results revealed that, the presented approach is credited to cost-effectiveness, environmental benignity, and ease of preparation, predicting great prospects for desulfurization of fuel oils on a commercial level.

Nitrophenyl-Group-Containing Heterocycles. I. Synthesis, Characterization, Crystal Structure, Anticancer Activity, and Antioxidant Properties of Some New 5,6,7,8-Tetrahydroisoquinolines Bearing 3(4)-Nitrophenyl Group.

Regioselective cyclocondensation of 2,4-diacetyl-5-hydroxy-5-methyl-3-(3-nitrophenyl/4-nitrophenyl)cyclohexanones 1a,b with cyanothioacetamide afforded the corresponding 7-acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8-(3- and -4-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones 2a,b. Reaction of compounds 2a,b with ethyl iodide, 2-chloroacetamide (4a), or its N-aryl derivatives 4b-e in the presence of sodium acetate trihydrate gave 3-ethylthio-5,6,7,8-tetrahydroisoquinoline 3 and (5,6,7,8-tetrahydroisoquinolin-3-ylthio)acetamides 5a-i, respectively. Cyclization of compounds 5b-d,f,g into their isomeric 1-amino-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxamides 6b-d,f,g was achieved by heating in ethanol containing a catalytic amount of sodium carbonate. Structures of all synthesized compounds were characterized on the basis of their elemental analyses and spectroscopic data. The crystal structure of 5,6,7,8-tetrahydroisoquinoline 5d was determined by X-ray diffraction analysis. In addition, the biological evaluation of some synthesized compounds as anticancer agents was performed, and only six compounds showed moderate to strong activity against PACA2 (pancreatic cancer cell line) and A549 (lung carcinoma cell line). Moreover, the antioxidant properties of most synthesized compounds were examined. The results revealed high antioxidant activity for the most tested compounds.

Ameliorating effects of probiotics on alterations in iron homeostasis and inflammation in COVID-19.

INTRODUCTION: The coronavirus disease (COVID-19) is caused by the severe acute syndrome coronavirus-2 (SARS-COV-2) and still threatens human life. This pandemic is still causing increased mortality throughout the world. Many recent studies have been conducted to discover the pathophysiology of this virus. MATERIAL AND METHODS: However, in this narrative review, we attempted to summarize some of the alterations in physiological pathways that were evident in this viral invasion. Excessive inflammation that progresses to cytokine storm, changes in humoral and cell-mediated immunity, and observed alterations in iron metabolism are included in the pathogenesis of the virus. Iron homeostasis disturbances may persist for more than two months after the onset of COVID-19, which may lead to reduced iron bioavailability, hypoferremia, hyperferritinemia, impaired hemoglobin, and red blood cell synthesis. Furthermore, hypoferriemia may impair immune system function. Until now, the traditional treatments discovered are still being tried. RESULTS: However, using probiotics as an adjuvant was shown to have beneficial effects on both iron homeostasis and immunity in COVID-19. Herein, we discussed the possible mechanisms achieved by probiotics to ameliorate iron and immunity changes based on the available literature. CONCLUSION: We concluded that supplementing probiotics with conventional therapy may improve COVID-19 symptoms and outcomes. Taking into consideration the use of good quality probiotics and appropriate dosage, undesirable effects can be avoided.

Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-4-cyano-6-hy-droxy-8-(4-meth-oxy-phen-yl)-1,6-dimethyl-5,6,7,8-tetra-hydro-iso-quino-lin-3-yl]sulfan-yl}-N-phenyl-acetamide.

The title mol-ecule, C29H29N3O4S, adopts a conformation with the two phenyl substituents disposed on opposite sides of the mean plane of the iso-quinoline unit. In the crystal, corrugated layers of mol-ecules are formed by N-H⋯O, C-H⋯N and C-H⋯S hydrogen bonds together with C-H⋯π(ring) inter-actions. These layers are connected by C-H⋯O contacts. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (45.2%), C⋯H/H⋯C (20.2%), O⋯H/H⋯O (15.8%) and N⋯H/H⋯N (11.0%) inter-actions.

Dietary conjugated linoleic acid and medium-chain triglycerides for obesity management.

Obesity is considered a serious global health issue. Patients have been predisposed to comorbidities such as dyslipidemia, cardiovascular diseases, diabetes, cancers, and osteoarthritis. Certain fats in the diet have been linked with an increase in obesity, such as saturated and trans-fats. Meanwhile, some dietary fats such as conjugated linoleic acids (CLAs) and medium-chain triglycerides (MCTs) could potentially reduce energy intake. Various mechanisms for reducing weight by CLAs and MCTs, such as increased lipolysis, improved intestinal microbiota, up-regulating peroxisome proliferator-activated receptors (PPARs), increased the expression of uncoupling protein of respiratory chain-1 (UCP-1), and affected satiety hormones are included. These bioactive compounds, CLAs and MCTs, should be used in moderate concentrations to prevent harmful effects such as insulin resistance for CLAs and hypercholesterolemia for MCTs. However, several studies have proposed CLAs or MCTs as adjuvants to the protocol used to minimize bodyweight. Our objective is to summarize the different causes of obesity and to discuss the effects of CLAs or MCTs on body weight and fat deposition in obese animals or humans.

The effect of white kidney bean fertilized with nano-zinc on nutritional and biochemical aspects in rats.

This study aims to estimate the safety of white kidney bean (WKB) fertilized by zinc oxide nanoparticles (ZnO-NPs) via studying changes of liver and kidney function, lipid profile and histological examination for the liver and kidney tissue in rats fed on it. Twenty Four male albino rats were used in this study divided into four groups; the first fed balanced diet (control group), the second fed WKB treated with normal ZnO (nWKB), the third fed WKB treated with 20 ppm ZnO-NPs (tWKB-1), and the fourth fed WKB treated with 40 ppm ZnO-NPs (tWKB-2). The results revealed that WKB treated with ZnO-NPs reduced body weight, food efficiency ratio, relative liver weight, and relative spleen weight were increased as well as the most biochemical parameters exhibited non-significant changes as compared to control group. Meanwhile, tWKB-2 group demonstrated a decrease in alkaline phosphatase and aspartate transaminase activities as compared to nWKB group.

The Impact of Thyme and Rosemary on Prevention of Osteoporosis in Rats.

Osteoporosis poses an important public health problem which affects millions of people worldwide. There is a direct link between calcium deficiency in diet and induction of osteoporosis and bone loss. The current study was conducted to evaluate the protective effect of thyme (Thymus vulgaris L.) and rosemary (Rosmarinus officinalis L.) against osteoporosis in rats with low calcium intake. Essential oils of rosemary and thyme were analyzed. The experiment was carried out on growing male Sprague-Dawley rats; the experimental animals were divided into 5 groups: 1, control negative was fed standard balanced diet; 2, control positive was fed balanced diet with low calcium level (L Ca) (Ca 0.1% w/w); 3, (L Ca) + thyme powder (5% w/w); 4, (L Ca) + rosemary powder (5% w/w); 5, (L Ca) + orally administration with CaCO3 (27 mg/kg body weight). Blood samples were collected for different biochemical analyses in plasma (calcium (Ca), phosphorus (P), magnesium (Mg), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), malondialdehyde (MDA), parathyroid hormone (PTH), C-terminal telopeptide (CTX), and 1,25-(OH)2-vitamin D3). Femur mass, length, and bone mineral density (BMD) were recorded, and histopathological studies for femurs were examined. Low-calcium diet induced osteoporotic changes in positive control rats (decrease in Ca, vitamin D3, and BMD and increase in CTX, PTH, TNF-α, CRP, and MDA). Supplementation with thyme and rosemary inhibited significantly the development of bone loss, increased Ca and vitamin D3 in plasma, improved BMD, and also prevented the inflammation and oxidative stress (improved TNF-α, CRP and MDA) compared to the positive control. The histopathological examination of treated groups showed an improvement in bone histology and protection against bone loss. However, thyme powder showed more effective impact than rosemary. Our study demonstrates that thyme and rosemary effectively mitigated calcium deficiency-induced bone loss and maybe considered as promising candidates for preventing bone resorption and osteoporosis.

Dietary antioxidant for disease prevention corroborated by the Nrf2 pathway.

Dietary antioxidants are widely distributed in various types of our food. They are strongly associated with reduced risk of many chronic diseases such as atherosclerosis, cancer, and Alzheimer's diseases. They include vitamins such as vitamins A, E, C, and carotenoids. Also, some minerals like; zinc, manganese, copper, iron, and selenium are essential for the activity of antioxidant enzymes. Furthermore, dietary polyphenols and flavonoids are considered as potent antioxidant compounds. Vegetables, fruits, and edible herbs are the richest sources of such antioxidants. Antioxidants reduce oxidative stress, either directly by reducing reactive species or indirectly by enhancing the body antioxidant defense mechanisms in different ways. These may include upregulating gene expression of some antioxidant enzymes via a nuclear factor erythroid 2 related factor2 pathway. Administration of a mixture of antioxidants is beneficial since they act synergistically in various phases. The aims of this review are to summarize the different antioxidants from dietary sources and their role in the prevention of different diseases.

Potential Role of L-Arginine and Vitamin E Against Bone Loss Induced by Nano-Zinc Oxide in Rats.

The purpose of this study was to illustrate the effects of zinc oxide nanoparticles (ZnO-NPs) administration on bone turnover and bone resorbing agents in rats and how L-arginine (L-arg) or vitamin E (vit E) co-administrations might affect them. Fasting rats were randomly divided into four groups (n = 10): G1-normal healthy animals; G2-ZnO-NPs-exposed rats (600 mg/kg-1/day-1); G3-ZnO-NPs-exposed rats co-administrated L-arg (200 mg/kg-1/day-1); G4-ZnO-NPs-exposed rats co-administrated vit E (200 mg/kg-1/day-1). The ingredients were orally administered daily. The body weight and food consumption of rats were recorded during the administration period and the experiment continued for three consecutive weeks. The results demonstrated that ZnO-NPs administration induced bone loss in rats as manifested by reduced activity of bone alkaline phosphatase (B-ALP) and increased level of C-terminal peptide type I collagen (CTx). The increase of inflammatory markers, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by ZnO-NPs suggests that deleterious effects of ZnO-NPs on bone turnover were, in part, due to inflammation. Confirming to this suggestion, both L-arg and vit E reduced TNF-α and IL-6 levels and consequently decreased bone resorption as indicated by reduced serum CTx level. This study proved that ZnO-NPs can induce bone turnover, which may be reduced by L-arg or vit.E co-administration, partly by anti-inflammatory mechanism.

Potential Renoprotective Effects of Rosemary and Thyme Against Gentamicin Toxicity in Rats.

Gentamicin (GM) is a drug used commonly against gram-negative bacteria. Its therapeutic use is mainly limited by its nephrotoxicity. This investigation was aimed at evaluating the nephroprotective effects of rosemary (RM; Rosmarinus officinalis) and thyme (TV; Thymus vulgaris) against GM toxicity. Rats were divided into four groups. Normal control group was treated intraperitoneally (i.p.) with saline; positive control group was administered GM 60 mg/kg/day i.p.; RM group was co-administered 8% RM aqueous extract, 10 mL/kg/day, orally with GM; and TV group was co-administered 8% TV aqueous extract orally, 10 mL/kg/day with GM. Both RM and TV groups extracted significantly ameliorated plasma kidney function biomarkers, and reduced malondialdhyde and glucose levels. Meanwhile, RM extract significantly modulated the electrolyte concentration and increased plasma insulin levels as compared with the GM group. However, the aqueous extract of RM showed more pronounced effects than TV extract. Our data were confirmed by histopathological examination and deoxyribonucleic acid (DNA) fragmentation analysis. Deleterious histopathological changes and increased DNA fragmentation induced by GM treatment were markedly controlled by the co-administration of RM and TV. Such renoprotective influence of RM and TV suggests their concurrent supplementation with GM therapy to limit GM toxicity.

Second-hand tobacco smoke and children.

Cigarette smoke contains harmful chemicals with hazardous adverse effects on almost every organ in the body of smokers as well as of nonsmokers exposed to environmental tobacco smoke (ETS). There has been increasing interest in the effects of passive smoking on the health of children. In order to detect the magnitude of passive smoking in children, parental questionnaires, measuring nicotine and cotinine body levels, and evaluating expired carbon monoxide (CO) concentrations, have been used. Passive smoking causes respiratory illness, asthma, poor growth, neurological disorders, and coronary heart diseases. Herein, we focused on the deleterious influences of passive smoking on immunity and liver. Besides, its effects on the concentrations of various biomarker levels related to the oxidant/antioxidant status were considered. Understanding these effects may help clinicians to counsel parents on smoking cessation and smoke exposure elimination. It may also help to develop interventions to improve the health of children. This review potentially demonstrated some nutraceuticals with a promising role in the prevention of smoking-related diseases.

Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats.

Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required.

Proposed remedies for some developmental disorders.

Developmental disorders (DDs) are important leading cause of disability in developed countries and also in the United States. DDs are a group of individual conditions that result from abnormal nervous system development and cause altered function. They can begin at any time from prenatal to 22 years of age and the disability usually presents itself throughout a person's life time. Down syndrome, autism, neural tube defects, schizophrenia, cretinism, and attention-deficit hyperactivity disorder are among the most common DDs that currently plague numerous countries and have varying incidence rates. Their occurrence may be partially attributable to the lack of certain dietary nutrients. Notably, essential vitamins, minerals, and ω-3 fatty acids are often deficient in the general population of America and developed countries and are exceptionally deficient in patients suffering from mental disorders. Typically, most of these disorders are treated with prescription drugs, but many of these drugs cause unwanted side effects. Therefore, psychiatrists recommend alternative or complementary nutritional remedies to overcome the adverse effects of those drugs. Studies have shown that daily supplements of vital nutrients, such as that contain amino acids, often effectively reduce symptoms of the patients, because they are converted into neurotransmitters that alleviate depression and other mental disorders. The aim of this article is to discuss the role of dietary imbalances in the incidence of DD and to emphasize which dietary supplements can aid in the treatment of the above-mentioned DD.

Homocysteine and oxidative stress in Egyptian children with Down syndrome.

OBJECTIVE: To assess homocysteine, folic acid and vitamin B12, trace element levels and oxidant/antioxidant status in Down syndrome (DS) mothers and children. DESIGN AND METHODS: 42 mothers with previous history of bearing DS baby with karyotypically confirmed full trisomy 21 were included. 48 healthy mothers with their healthy children were considered as control. Serum B12, folic acid, total homocysteine (tHcy), vitamins E and C, TBARS and trace elements were estimated. RESULTS: DS mothers showed higher levels of tHCy, lower levels of folic acid and vitamin B12 than controls. tHCy and folic acid concentrations were significantly decreased, while vitamin B12 exhibited a slight decrease in DS children versus control. Vitamins E and C, zinc and copper levels were markedly reduced in DS mothers. By contrast, TBARS showed significant elevation in them. Furthermore, DS children had severe reduction of vitamin C and zinc levels relative to healthy children. However, vitamin E showed slight reduction and TBARS displayed a slight rise in DS children. CONCLUSION: Abnormal folic acid-homocysteine metabolism is a potent marker to identify women at risk for having DS child and it also exposes them to oxidant/antioxidant imbalance.

Effect of Ruta graveolens L. and Euphorbia peplus L. anti-inflammatory extracts on nutritional status of rats and the safety of their use.

A significant increase in body weight with remarkable increase in total food intake and significant increase in protein efficiency ratio were observed following oral administration of R. graveolens ether extract (500 mg/kg body wt) to growing rats for 3 weeks. Serum albumin was significantly decreased after administration of declofenac (15 mg/kg body wt). Albumin/globulin ratio decreased significantly on administration of E. peplus ether extract (500 mg/kg body wt). No significant changes were observed in other biochemical and nutritional parameters on administration of either of the extracts or declofenac. However, only a significant elevation of alkaline phosphatase was noticed during treatment with R. graveolens. The results suggest that both plant extracts have no harmful effect on nutritional status and are safe towards kidney functions, while Euphorbia is more safe than Ruta in relation to liver functions.