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1.
Egypt J Immunol ; 31(3): 123-130, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38995717

ABSTRACT

Cancer immunotherapy is a promising strategy in cancer management, including hepatocellular carcinoma (HCC). This experimental study aimed to evaluate interleukin-10 (IL-10) as a biomarker for monitoring the response of tumor-derived autophagosomes vaccine in inducing antitumor immunity in HCC induced mice. It was conducted on 56 BALB/c mice; divided into 20 normal and 36, cancer induced with human liver cancer cell line (HepG2) cells. The latter group was subdivided into a positive control group (n=6) and a treated group (n=30), that was subdivided into 3 subgroups: (A) treated with dendritic cells (DC) vaccine only, (B) treated with vaccine named Dribbles only, and (C) treated with DC plus Dribbles. Serum IL-10 was assessed after immunotherapy. The mean percentage of tumor volume reduction in mice vaccinated by DC plus Dribbles was significantly superior to DC and Dribbles groups (p= 0.013, and p= 0.043, respectively). There was a statistically significant difference in IL-10 levels between different immunotherapy groups (p= 0.0003). As the mean IL-10 level was 19.50 pg/ml for the positive control group, 13 pg/ml for Dribbles group, 10 pg/ml for DCs group and 3.50 pg/ml for DCs plus Dribbles group. We conclude that DC-Dribbles vaccine has a remarkable efficacy superior to either Dribbles alone or DC alone in the decline of HCC development and survival improvement. IL-10 is a predictive biomarker for response after immunotherapy.


Subject(s)
Cancer Vaccines , Carcinoma, Hepatocellular , Dendritic Cells , Immunotherapy , Interleukin-10 , Liver Neoplasms , Mice, Inbred BALB C , Animals , Interleukin-10/blood , Interleukin-10/immunology , Dendritic Cells/immunology , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/therapy , Mice , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Humans , Cancer Vaccines/immunology , Cancer Vaccines/administration & dosage , Immunotherapy/methods , Hep G2 Cells , Disease Models, Animal , Biomarkers, Tumor/blood , Biomarkers, Tumor/immunology
2.
J Enzyme Inhib Med Chem ; 39(1): 2304625, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38348824

ABSTRACT

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 µM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.


Subject(s)
Antineoplastic Agents , Leukemia , Humans , Molecular Structure , Structure-Activity Relationship , Cell Line, Tumor , Drug Screening Assays, Antitumor , Cell Proliferation , Antineoplastic Agents/pharmacology , Apoptosis , Molecular Docking Simulation
3.
East Mediterr Health J ; 30(1): 3-4, 2024 Jan 21.
Article in English | MEDLINE | ID: mdl-38415330

ABSTRACT

Access to reliable and timely information is key for healthcare decision-making at the regional, national and sub-national levels. However, lack of access to such information hampers to progress towards achievement of the Sustainable Development Goals (SDGs) in the Eastern Mediterranean Region (EMR), as indicated in the Regional Progress Report on Health-Related Sustainable Development Goals.


Subject(s)
Sustainable Development , Humans , Mediterranean Region/epidemiology
4.
Lasers Med Sci ; 38(1): 187, 2023 Aug 18.
Article in English | MEDLINE | ID: mdl-37592125

ABSTRACT

Acne vulgaris is challenging to treat for several individuals. Laser therapy may be a desirable alternative to traditional therapies with limited success. This study aimed to assess efficacy of fractional CO2 laser versus Nd:YAG laser for acne vulgaris therapy. Thirty cases with acne vulgaris underwent both fractional CO2 laser and Nd: YAG laser treatments in a randomized split face design at a 14-day interval for four sessions. The clinical efficacy was evaluated by counting acne lesions and utilizing the Global Acne Severity Scale (GEA Scale). GEAs decreased significantly after both fractional CO2 and Nd:YAG modalities after treatment and at a 3-month follow-up; fractional CO2 demonstrated significant more decrease in GEAs with (P = 0.006, 0.00 (respectively. Moreover, fractional CO2 showed a significantly higher satisfaction level (P = 0.004) and a better clinical improvement percentage regarding inflammatory and noninflammatory acne lesions (P = 0.007 and 0.000, respectively) after 3 months of follow-up. Apart from transient erythema, there were insignificant adverse effects concerning both treated sides. Fractional CO2 and Nd:YAG lasers are efficient physical modalities of acne treatment. However, fractional CO2 laser was more effective and more satisfying to the patients.


Subject(s)
Acne Vulgaris , Lasers, Solid-State , Low-Level Light Therapy , Humans , Carbon Dioxide , Lasers, Solid-State/therapeutic use , Acne Vulgaris/radiotherapy , Light
5.
Antibiotics (Basel) ; 12(2)2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36830314

ABSTRACT

Carbapenem-resistant Enterobacteriaceae (CRE) is an important emerging threat among pediatric cancer patients, with a high mortality rate. This retrospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSIs) at a children's cancer hospital in Egypt (2013-2017). Two hundred and fifty-four pediatric cancer patients with CRE BSI were identified; 74% had hematological malignancies, and 26% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (50%). The main clinical features for acquiring CRE-BSI were previous antibiotics exposure (90%), profound neutropenia (84%), prolonged steroid use (45%), previous colonization with a resistant pathogen (35%), ICU admission within 90 days (28%), and central venous catheter use (24%). E. coli was the most common isolated pathogen (56%), followed by Klebsiella pneumoniae (37%). All isolates were resistant to carbapenem with an MIC < 4-8 µg/mL in 100 (45%) and >8 µg/mL in 153 (55%). The overall mortality rate was 57%, and 30 day mortality was reported in 30%. Upon multivariate analysis, for the patients with Klebsiella pneumoniae BSI, carbapenem resistance with an MIC > 8 µg/mL and associated typhlitis or pneumonia were predictors of poor outcome. In conclusion, CRE-BSI is a major threat among pediatric cancer patients in limited resource countries with limited options for treatment. Antimicrobial stewardship for early detection through routine screening, adequate empirical treatment, and timely adequate therapy may impact the outcome for such high-risk patient groups.

6.
Molecules ; 28(4)2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36838913

ABSTRACT

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4-9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a-d, thiosemicarbazone derivatives 5a-d, pyridine derivatives 6a-d and 7a-d, bromo acetyl derivative 8, and thiazole derivatives 9a-d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.


Subject(s)
Antioxidants , Arachidonate 15-Lipoxygenase , Humans , Antioxidants/chemistry , Molecular Docking Simulation , Structure-Activity Relationship , Arachidonate 15-Lipoxygenase/metabolism , Hydrogen Peroxide , Sulfonamides , Ascorbic Acid , Molecular Structure
7.
J Cosmet Dermatol ; 22(4): 1286-1296, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36762396

ABSTRACT

INTRODUCTION: Alopecia areata (AA) is a challenging disease with variable treatment outcomes. Hair follicles express vitamin D receptors. Therefore, vitamin D3 may be promising for AA treatment through immunomodulatory mechanisms. The efficacy of bimatoprost in scalp AA treatment was reported by few studies. OBJECTIVE: To evaluate the efficacy and safety of microneedling (MN) with topical vitamin D3 versus MN with bimatoprost in comparison with MN alone in the treatment of localized AA. PATIENTS AND METHODS: Seventy-five patients with localized AA were divided into three groups. The first group: 25 patients were treated with MN alone. The second group: 25 patients treated with MN combined with topical vitamin D3. The third group: 25 patients treated with MN combined with bimatoprost solution. The response was evaluated clinically and dermoscopically. RESULTS: At the end of the study, all groups showed a statistically significant decrease in the SALT score compared to the baseline. The clinical response (regrowth scale): vitamin D and bimatoprost groups showed a statistically significant higher regrowth scale compared to MN alone group (p-value = 0.000). After treatment, hair regrowth was significantly higher in MN combined with bimatoprost than in MN combined with topical vitamin D3. However, after 3 months of follow-up, there was no statistically significant difference between both groups. Side effects were mild and transient in all groups. CONCLUSION: Topical vitamin D3 and bimatoprost combined with MN are safe and effective therapeutic options for localized AA.


Subject(s)
Alopecia Areata , Bimatoprost , Cholecalciferol , Dermatologic Agents , Dry Needling , Humans , Alopecia Areata/drug therapy , Alopecia Areata/therapy , Bimatoprost/administration & dosage , Bimatoprost/adverse effects , Cholecalciferol/administration & dosage , Cholecalciferol/adverse effects , Hair/drug effects , Hair/growth & development , Treatment Outcome , Dry Needling/methods , Dermatologic Agents/administration & dosage , Dermatologic Agents/adverse effects , Combined Modality Therapy , Administration, Topical
8.
Arch Med Sci ; 18(6): 1467-1474, 2022.
Article in English | MEDLINE | ID: mdl-36457982

ABSTRACT

Introduction: The current study was designed to analyze whether polymorphisms of miR-146a and miR-155 are related to Behçet's disease (BD) in the Egyptian population. Material and methods: A total of 96 unrelated BD patients and 100 healthy subjects were genotyped for miR-146a (rs2910164) and miR-155 (rs767649) using real-time polymerase chain reaction. Results: The results showed significant elevation in the frequency of rs2910164 GG and CC genotypes in BD patients compared with controls (adjusted OR = 22.156, 95% CI: 4.728-103.818; p < 0.001 and adjusted OR = 40.358, 95% CI: 8.928-182.440; p < 0.001, respectively). Also, the rs2910164 G allele conferred a higher risk of developing BD (adjusted OR = 3.665, 95% CI: 2.013-6.671; p < 0.001). MiR-146a (rs2910164) polymorphism was a risk factor for susceptibility to BD in dominant, recessive and additive models of inheritance (all p < 0.001), while the miR-155 (rs767649) polymorphism was a risk factor in the recessive model only (p = 0.021). GG and CG genotypes of rs2910164 were associated with higher Behcet's disease current activity index (BDCAI) and ocular involvement compared with CC genotype (p = 0.005 and p = 0.004, respectively). Genotype AT of rs767649 was related to higher BDCAI (p = 0.026) compared with TT and AA genotypes. Conclusions: miR-146a (rs2910164) and miR-155 (rs767649) are likely to play an important role in the Egyptian population in development of BD and also influence disease severity.

9.
Saudi Dent J ; 34(6): 464-472, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36092520

ABSTRACT

Background: Glucocorticoids are used in different conditions such as autoimmune disorders and organ transplantation and their administration is the most common cause of secondary osteoporosis. Rutin is a flavonoid found in many plants. Flavonoids are natural products with various therapeutic and biological effects. Objective: Is to investigate the effect of Rutin Hydrate as a form of Rutin on glucocorticoid induced osteoporosis in mandibular alveolar bone radiologically, histologically and histochemically. Methods: Twenty-one adult male Albino rats were randomly divided into three groups. Group I (control), group II (osteoporotic) and group III (Rutin Hydrate treated). In both group II and III rats received 21 mg/kg of methylprednisolone daily for four weeks. Then group III received 50 mg/kg of rutin hydrate in distilled water daily for another four weeks. At the end of the experiment, mandibles were dissected for radiographic assessment, then processed for histological and histochemical examination and statistical analysis. Results: Radiologically, administration of Rutin Hydrate was able to enhance bone density than osteoporotic group. Histological examination revealed preserved cortical bone thickness that had been statistically proved. Apparently normal sized marrow cavities, some plump osteoblasts and normal osteocytes were seen in group III. Histochemical examination showed statistical increase in the area percentage of newly formed collagen in group III than group II. Conclusions: Rutin Hydrate was able to modify the radiological and histological picture of osteoporotic alveolar bone. This was achieved by the ability of Rutin Hydrate to increase bone density, preserve cortical plates thickness and enhance new collagen formation that was proved histochemically.

10.
Saudi Dent J ; 34(6): 449-457, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36092527

ABSTRACT

Background: Amitriptyline is a tricyclic antidepressant drug accustomed to treat depressive disorders. It recorded many side effects on different tissues. Objective: To investigate reaction of Albino rats' periodontium after oral administration of Amitriptyline histologically and radiographically. Methods: Fourteen adult male albino rats (150-200 g) were divided into two groups, control and experimental. Rats of experimental group received 10 mg/kg/day of Amitriptyline hydrochloride by oral gavage for four weeks. Mandibles were prepared for hematoxylin and eosin (H&E) and anti-osteopontin (Anti-OPN) immunohistochemistry staining. Bone mineral density was measured in mandibular alveolar bone. Statistical analysis for Anti-OPN and relative Hounsfield unit value (HU value) was performed using independent-samples t-test. Results: Gingiva of experimental group showed epithelial degeneration with pyknotic nuclei and disintegration in lamina propria. Areas of separation in alveolar bone and degeneration of some regions in cementum were seen with apparent increase in periodontal ligament (PDL) thickness and its detachment from bone and cementum at some regions. Immunohistochemical examination of experimental group showed apparently increased immunopositivity in gingiva, cementocytes, osteocytes, cementum, bone matrices, fibroblasts and PDL fibers when compared to control group. Statistical analysis revealed insignificant difference of Anti-OPN area% in gingiva between both studied groups. While there was statistical significant increase of Anti-OPN area% in the other periodontium tissues and high statistical significant decrease of relative HU value in experimental group when compared to control. Conclusions: Amitriptyline has destructive effect on periodontal tissues and statistically increases the expression of Anti-OPN in all periodontal tissues except gingiva and decreases bone mineral density.

11.
J Cosmet Dermatol ; 21(3): 1023-1030, 2022 Mar.
Article in English | MEDLINE | ID: mdl-33998772

ABSTRACT

BACKGROUND: Acanthosis nigricans (AN) is a common dermatological issue with several therapeutic modalities to treat. Despite retinoid is the first drug of choice in the treatment, the fractional-ablative carbon dioxide (CO2 ) laser has revealed as a promising procedure for the management of neck-AN, outstanding to its ability for superficial ablation of the skin surface, with trans-epidermal melanin elimination. OBJECTIVES: To decide whether fractional-ablative CO2 laser or retinoic acid (5%) peel is the more effective and safe choice for AN treatment. METHODS: In this study, twenty Egyptian cases with neck-AN were enrolled, where each case was exposed to four sessions with 2 weeks apart of both fractional CO2  laser on the right half of the neck and retinoic acid peel on the left half of the neck. Cases were assessed by a scoring system: Acanthosis Nigricans Area and Severity Index (ANASI) score, two blinded dermatologists, and dermoscopically before and one month after treatment. RESULTS: We found a highly statistically significant improvement among both treated groups regarding (ANASI) score and dermatologist's assessments. Bedside, the degree of sulci cutis, cristae cutis, brown-to-dark brown dots, and milia-like cysts, dermoscopic sign improvement was evident in both treated groups. However, fractional CO2 laser shows the superior result to retinoic acid peel in the treatment. CONCLUSION: Fractional CO2 laser and retinoic acid peel are considered effective modalities for neck-AN treatment. However, fractional CO2 laser was more effective.


Subject(s)
Acanthosis Nigricans , Chemexfoliation , Lasers, Gas , Acanthosis Nigricans/drug therapy , Carbon Dioxide , Humans , Lasers, Gas/adverse effects , Treatment Outcome , Tretinoin/therapeutic use
12.
JMIR Infodemiology ; 1(1): e30979, 2021.
Article in English | MEDLINE | ID: mdl-34604708

ABSTRACT

BACKGROUND: An infodemic is an overflow of information of varying quality that surges across digital and physical environments during an acute public health event. It leads to confusion, risk-taking, and behaviors that can harm health and lead to erosion of trust in health authorities and public health responses. Owing to the global scale and high stakes of the health emergency, responding to the infodemic related to the pandemic is particularly urgent. Building on diverse research disciplines and expanding the discipline of infodemiology, more evidence-based interventions are needed to design infodemic management interventions and tools and implement them by health emergency responders. OBJECTIVE: The World Health Organization organized the first global infodemiology conference, entirely online, during June and July 2020, with a follow-up process from August to October 2020, to review current multidisciplinary evidence, interventions, and practices that can be applied to the COVID-19 infodemic response. This resulted in the creation of a public health research agenda for managing infodemics. METHODS: As part of the conference, a structured expert judgment synthesis method was used to formulate a public health research agenda. A total of 110 participants represented diverse scientific disciplines from over 35 countries and global public health implementing partners. The conference used a laddered discussion sprint methodology by rotating participant teams, and a managed follow-up process was used to assemble a research agenda based on the discussion and structured expert feedback. This resulted in a five-workstream frame of the research agenda for infodemic management and 166 suggested research questions. The participants then ranked the questions for feasibility and expected public health impact. The expert consensus was summarized in a public health research agenda that included a list of priority research questions. RESULTS: The public health research agenda for infodemic management has five workstreams: (1) measuring and continuously monitoring the impact of infodemics during health emergencies; (2) detecting signals and understanding the spread and risk of infodemics; (3) responding and deploying interventions that mitigate and protect against infodemics and their harmful effects; (4) evaluating infodemic interventions and strengthening the resilience of individuals and communities to infodemics; and (5) promoting the development, adaptation, and application of interventions and toolkits for infodemic management. Each workstream identifies research questions and highlights 49 high priority research questions. CONCLUSIONS: Public health authorities need to develop, validate, implement, and adapt tools and interventions for managing infodemics in acute public health events in ways that are appropriate for their countries and contexts. Infodemiology provides a scientific foundation to make this possible. This research agenda proposes a structured framework for targeted investment for the scientific community, policy makers, implementing organizations, and other stakeholders to consider.

13.
Life Sci ; 283: 119865, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34358549

ABSTRACT

AIMS: Stroke has risen to the fifth and third most common causes of death in the United States and the rest of the world, respectively. Vortioxetine (VTX) is a multimodal antidepressant agent that balances 5-HT receptors and represses the serotonin transporter. Our study aimed to examine the neuroprotective impacts of VTX against cerebral ischemia caused by occluding the middle cerebral artery (MCA). MAIN METHODS: Until the middle cerebral artery occlusion (MCAO) induction, VTX (10 mg/kg/day) was taken orally for 14 days. Behavioral assessments were carried out 24 h after the MCAO technique. The hippocampal and cortical tissues of the brain were isolated to assess the histological changes and the levels of the biochemical parameters. KEY FINDINGS: MCAO damage led to severe neurological deficits and histopathological damage. However, VTX improved MCAO-induced neurological deficits and ameliorated histopathological changes in both hippocampal and cortical tissues of MCAO rats. Western blot analysis showed increments of p-PERK, CHOP, ASK-1, NICD, HES-1, HES-5, and p-eIF2α expression levels in MCAO rats. Moreover, ELISA revealed an increase in the levels of ATF4, IRE1, Apaf-1, and HIF-1α, while VTX administration ameliorated most of these perturbations induced after MCAO injury. SIGNIFICANCE: This research suggests that VTX could be a potent neuroprotective agent against ischemic stroke by inhibiting a variety of oxidative, apoptotic, inflammatory, and endoplasmic reticulum stress pathways.


Subject(s)
Activating Transcription Factor 4/metabolism , Cerebrovascular Disorders/drug therapy , Eukaryotic Initiation Factor-2/metabolism , Neurons/metabolism , Reperfusion Injury/drug therapy , Signal Transduction/drug effects , Transcription Factor CHOP/metabolism , Vortioxetine/pharmacology , eIF-2 Kinase/metabolism , Animals , Cerebrovascular Disorders/metabolism , Cerebrovascular Disorders/pathology , Male , Neurons/pathology , Rats , Rats, Wistar , Reperfusion Injury/metabolism , Reperfusion Injury/pathology
14.
Biomolecules ; 11(5)2021 05 14.
Article in English | MEDLINE | ID: mdl-34069089

ABSTRACT

BACKGROUND: Polymorphisms of long noncoding RNAs are lately documented as hazardous factors for the development of numerous tumors. Furthermore, the evaluation of noncoding RNAs has emerged as a novel detector of breast cancer patients. We aimed to genotype the HOXA transcript at the distal tip (HOTTIP) rs1859168 and assess its relationship with the levels of the serum HOTTIP and its target miR-615-3p in patients with breast cancer (BC). METHODS: One hundred and fifty-one patients with BC, 139 patients with fibroadenoma (FA), and 143 healthy participants were incorporated into the current study. The genotyping of rs1859168 and the measurements of the HOTTIP and miR-615-3p levels were assessed using quantitative real-time PCR. RESULTS: We revealed a significant association between each of the CC genotypes, C allele, dominant and recessive models, and the increased risk of BC (p = 0.013, p < 0.001, p < 0.001, and p < 0.001, respectively) relative to the healthy controls. Similarly, the CC genotype, C allele, and recessive model were observed to be related to the increased incidence of BC with respect to FA (p < 0.001 for all). A significant upregulation of HOTTIP and a marked decrease of miR-615-3p were verified in patients with BC compared to each of the healthy individuals, patients with FA, and the non-BC group (healthy subjects + FA) (p < 0.001 for all). A significant negative correlation was demonstrated between the expression of HOTTIP and miR-615-3p in the serum of patients with BC. The HOTTIP expression was upregulated, while that of miR-615-3p was downregulated in patients with BC who carried the CC genotype with respect to those who carried the AA or AC genotypes (p < 0.05 for all). CONCLUSIONS: The genetic variants of rs1859168 are linked to an increased susceptibility to BC. Moreover, HOTTIP and miR-615-3p may be used as novel indicators and targets for the treatment of patients with BC.


Subject(s)
Breast Neoplasms/pathology , MicroRNAs/blood , RNA, Long Noncoding/blood , RNA, Long Noncoding/genetics , Alleles , Breast Neoplasms/blood , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Case-Control Studies , Egypt , Female , Humans , MicroRNAs/genetics , Middle Aged , Polymorphism, Single Nucleotide , ROC Curve
15.
Molecules ; 26(7)2021 Mar 25.
Article in English | MEDLINE | ID: mdl-33805918

ABSTRACT

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1-4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 µM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53-79%) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.


Subject(s)
Antineoplastic Agents , Models, Molecular , Neoplasm Proteins , Neoplasms/drug therapy , Pyrimidines , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , HCT116 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Mice , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Xenograft Model Antitumor Assays
16.
Front Mol Biosci ; 8: 758742, 2021.
Article in English | MEDLINE | ID: mdl-35237654

ABSTRACT

Background: Ischemic stroke is one of the serious complications of diabetes. Non-coding RNAs are established as promising biomarkers for diabetes and its complications. The present research investigated the expression profiles of serum TUG1, LINC00657, miR-9, and miR-106a in diabetic patients with and without stroke. Methods: A total of 75 diabetic patients without stroke, 77 patients with stroke, and 71 healthy controls were recruited in the current study. The serum expression levels of TUG1, LINC00657, miR-9, and miR-106a were assessed using quantitative real-time polymerase chain reaction assays. Results: We observed significant high expression levels of LINC00657 and miR-9 in the serum of diabetic patients without stroke compared to control participants. At the same time, we found marked increases of serum TUG1, LINC00657, and miR-9 and a marked decrease of serum miR-106a in diabetic patients who had stroke relative to those without stroke. Also, we revealed positive correlations between each of TUG1, LINC00657, and miR-9 and the National Institutes of Health Stroke Scale (NIHSS). However, there was a negative correlation between miR-106a and NIHSS. Finally, we demonstrated a negative correlation between LINC00657 and miR-106a in diabetic patients with stroke. Conclusion: Serum non-coding RNAs, TUG1, LINC00657, miR-9, and miR-106a displayed potential as novel molecular biomarkers for diabetes complicated with stroke, suggesting that they might be new therapeutic targets for the treatment of diabetic patients with stroke.

17.
Pol J Pathol ; 72(3): 200-210, 2021.
Article in English | MEDLINE | ID: mdl-35048632

ABSTRACT

The combined immunohistochemical evaluation of EZH2 (enhancer of zeste homolog 2) and ERRα (estrogen-related receptor α), in relation to clinicopathological prognostic factors and patients' outcome, has not been performed yet in colorectal carcinoma (CRC). In order to achieve this aim, 120 samples were extracted; 60 cases of CRC; and 60 samples from normal colonic tissue. Our study showed that 63.3% and 38.3% of CRC cases reveal high EZH2 and high ERRα nuclear expression, respectively. 6.6% and 8.3% of normal colonic mucosa samples express low EZH2 and low ERRα nuclear expression, respectively. High EZH2 and high ERRα expression correlate with late tumor stages (p = 0.001 each), high grade (p = 0.001, p = 0.009 respectively), positive lymph node involvement (p = 0.001, p = 0.002 respectively) and larger tumor size (p = 0.001 each). There is a moderate highly statistically significant agreement (κ = 0.467, p = 0.001) between EZH2 and ERRα immunohistochemical expression. By Kaplan Meier analysis, high EZH2 and high ERRα show statistically significant shorter overall survival, and progression free survival than cases with low EZH2 and low ERRα immunohistochemical expression, respectively. Thus, EZH2 and ERRα might serve as potential promising prognostic markers in CRC.


Subject(s)
Colorectal Neoplasms , Enhancer of Zeste Homolog 2 Protein , Biomarkers, Tumor , Humans , Prognosis , Receptors, Estrogen , ERRalpha Estrogen-Related Receptor
18.
Front Public Health ; 8: 581373, 2020.
Article in English | MEDLINE | ID: mdl-33324599

ABSTRACT

Introduction: Work is a social double edged weapon activity that may have positive and negative effects on individual's quality of life and health. Objectives: To estimate workaholism prevalence and to determine its effects on quality of life, mental health, and burnout among healthcare workers (HCWs). Methods: Using a cross-sectional study, 1,080 Egyptian participants distributed as HCWs and non-HCWs were recruited. The study included 4 questionnaires to assess workaholism, quality of life (QoL), Psychological capital questionnaire (PCQ), and General health questionnaire (GHQ). Maslach Burnout Inventory (MBI) was applied to critical specialty HCWs in addition to pro-inflammatory markers including Il6, TNFα, and CoQ10. Results: This study revealed that 24.4 and 24.8% of HCWs were workaholic and hardworking, respectively, in comparison to 5.9 and 28.1% among non-HCWs (P < 0.001). Somatic symptoms and anxiety/ insomnia domains of GHQ were higher among HCWs than non-HCWs (P < 0.001 and 0.002, respectively). QoL was significantly lower among HCWs than non-HCWs (P < 0.001). Workaholism was reported among 43.2% of HCWs with critical specialty (P < 0.001). Components of PCQ components were significantly higher among HCWs with critical specialty than non-critical HCWs while QoL showed the reverse (P < 0.05). Working excessively was a predictor to burnout [Emotional exhaustion (ß = -0.23) and depersonalization (ß = -0.25)] and TNFα (ß = 0.41). Emotional exhaustion was a predictor to Il6 (ß = 0.66), TNFα (ß = 0.73), and CoQ10 (ß = -0.78). Conclusion: There is a significant association between workaholism and psychologically poor-health and poor quality of life among HCWs. Critical specialty healthcare workers showed association between workaholism, burnout and pro-inflammatory markers. Addressing of personal characteristics, supporting factors in the work environment and periodic examination of the healthcare workers and responding accordingly is required.


Subject(s)
Mental Health , Quality of Life , Cross-Sectional Studies , Egypt/epidemiology , Health Personnel , Humans , Prevalence
19.
IUBMB Life ; 72(9): 1941-1950, 2020 09.
Article in English | MEDLINE | ID: mdl-32563217

ABSTRACT

BACKGROUND/AIMS: Pediatric immune thrombocytopenia (ITP) is an autoimmune disease; whose etiology is not exactly understood and seems to be highly multifactorial. Long non-coding RNAs (lncRNAs) are key regulators of different actions, which contribute to the development of many autoimmune diseases. To gain a further understanding, we estimated the relative expression of lncRNAs Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and tumor necrosis factor-α (TNF-α) and heterogeneous nuclear ribonucleoprotein L (hnRNPL) immune-regulatory lncRNA (THRIL) in pediatric ITP. METHODS: In this case-control study, analysis of the expression profiles of these lncRNAs in blood samples from children with ITP and healthy controls (HCs) using quantitative real-time PCR was done. The association of MALAT1 and THRIL with ITP clinical features and their potential usage as non-invasive circulating biomarkers for ITP diagnosis was also evaluated. The receiver operating characteristic curve was constructed, and an area under the curve was analyzed. RESULTS: Both lncRNAs MALAT1 and THRIL were significantly upregulated in ITP patients in comparison to HCs ( p < .0001 and = .001 respectively). In addition, there was a positive significant correlation between the expression level of both biomarkers among patients (r = 0.745, p < .0001). At cutoff points of 1.17 and 1.27 for lncRNAs MALAT1and THRIL, respectively, both biomarkers had an excellent specificity (100% for both) and fair sensitivity (63.6 and 73.3% for lncRNAs MALAT1and THRIL, respectively). Improvement of biomarkers specificity was obtained by evaluation of the combined expression of both biomarkers. Serum lncRNAs MALAT1 and THRIL could be used as potential biomarkers in differentiating childhood ITP patients and HCs.


Subject(s)
Biomarkers/blood , Purpura, Thrombocytopenic, Idiopathic/diagnosis , RNA, Long Noncoding/genetics , Case-Control Studies , Child , Child, Preschool , Female , Humans , Male , Prognosis , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/genetics , RNA, Long Noncoding/blood , ROC Curve
20.
J Enzyme Inhib Med Chem ; 35(1): 847-863, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32216479

ABSTRACT

Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety. Chalcones 2a-e were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline 3a-e, phenylpyrazoline 4a-e, isoxazoline 5a-e and pyrazoline carbothioamide derivatives 6a-e were synthesized and screened for in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide radical scavenging assay as well as 15-lipoxygenase (15-LOX) inhibition activity. Compounds 3a, 4e, 5b, 5c, 6a, 6c, and 6e showed excellent radical scavenging activity in all three methods in comparison with ascorbic acid and 15-LOX inhibition potency using quercetin as standard then were subjected to in vivo study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds 5b, 5c, and 6e showed significant in vivo antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound 6a endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.


Subject(s)
Antioxidants/pharmacology , Arachidonate 15-Lipoxygenase/metabolism , Drug Design , Lipoxygenase Inhibitors/pharmacology , Pyrazoles/pharmacology , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Biphenyl Compounds/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Male , Models, Molecular , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Picrates/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Superoxides/antagonists & inhibitors
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