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AIMS: Transactivation of insulin-growth-factor-receptor (IGF-1R) by angiotensin-II-type-1-receptor (AT-1R) was only demonstrated in vascular-smooth-muscle cells and has never been tested in breast-cancer (BC). This investigation addressed the impact of chronic AT-1R blockade by valsartan (Val) on possible concurrent AT-1R/IGF-1R signaling inhibition, regressing BC-tumor-microenvironment (TME) cellular components activation, and hindering BC development. MAIN METHODS: The effect of different Val doses (10, 20, 40 & 80 mg/kg/day for 490 days) was tested on dimethylbenz(a)anthracene (DMBA)-induced progesterone-promoted-BC in rats. The influence on intratumoral/circulating angiotensin-II (ANG-II) levels and AT-1R/Mas-R immunofluorescent-expression were assessed. The potential AT-1R/IGF-1R crosstalk within TME-BC-stem-cells (BCSCs) and cancer-associated-fibroblasts (CAFs) was evaluated by fluorescently marking these cells and locating the immunofluorescently-stained AT-1R/IGF-1R in them using confocal-laser-microscopy and further quantified by flow cytometry. In addition, the molecular alterations following blocking AT-1R were inspected including determining Src; crucial for IGF-1R transactivation by AT-1R, Notch-1; IGF-IR transcriptional-regulator, and PI3K/Akt &IL-6/STAT expression. Further, the suppression of CSCs' capabilities to maintain pluripotency, stemness features, epithelial-to-mesenchymal-transition (EMT), and angiogenesis was evaluated by assessing NANOG gene, aldehyde-dehydrogenase (ALDH), N-cadherin and vascular-endothelial-growth-factor (VEGF), respectively. Furthermore, the proliferative marker; Ki-67, was detected by immunostaining, and tumors were histologically graded using Elston-Ellis-modified-Scarff-Bloom-Richardson method. KEY FINDINGS: Prophylactic Val significantly reduced tumor size, prolonged latency, reduced tumor histopathologic grade, decreased circulating/intratumoral-ANG-II levels, increased Mas-R, and decreased AT1R expression. AT-1R/IGF-1R were co-expressed with a high correlation coefficient on CAFs/BCSCs. Moreover, Val significantly attenuated IGF-1R transactivation and transcriptional regulation via Src and Notch-1 genes' downregulation and reduced Src/IGF-IR-associated PI3K/Akt and IL-6/STAT3 signaling. Further, Val significantly decreased intratumoral NANOG, ALDH, N-cadherin, VEGF, and Ki-67 levels. SIGNIFICANCE: Chronic Val administration carries a potential for repurposing as adjuvant or conjunct therapy for patients at high risk for BC.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II , Neoplasias de la Mama , Receptor de Angiotensina Tipo 1 , Receptor IGF Tipo 1 , Microambiente Tumoral , Valsartán , Animales , Femenino , Ratas , Valsartán/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Receptor IGF Tipo 1/metabolismo , Microambiente Tumoral/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
Rhipicephalus microplus, known as the hard tick, is a vector for the parasites Babesia spp. and Anaplasma marginale, both of which can cause significant financial losses to the livestock industry. There is currently no effective vaccine for R. microplus tick infestations, despite the identification of numerous prospective tick vaccine candidates. As a result, the current research set out to develop an immunoinformatics-based strategy using existing methods for designing a multi-epitope based vaccination that is not only effective but also safe and capable of eliciting cellular and humoral immune responses. First, R. microplus proteins Bm86, Subolesin, and Bm95 were used to anticipate and link B and T-cell epitopes (HTL and CTL) to one another. Antigenicity testing, allergenicity assessment, and toxicity screening were just a few of the many immunoinformatics techniques used to identify potent epitopes. Multi-epitope vaccine design was chosen based on the antigenic score 0.935 that is promising vaccine candidate. Molecular docking was used to determine the nature of the interaction between TLR2 and the vaccine construct. Finally, molecular dynamic simulation was used to assess the stability and compactness of the resulting vaccination based on docking scores. The developed vaccine was shown to be stable, have immunogenic qualities, be soluble, and to have high expression by in silico cloning. These findings suggest that experimental investigation of the multi-epitope based vaccine designed in the current study will produce achievable vaccine candidates against R. microplus ticks, enabling more effective control of infestations.
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Proteínas de Artrópodos , Biología Computacional , Epítopos de Linfocito B , Epítopos de Linfocito T , Rhipicephalus , Vacunas , Rhipicephalus/inmunología , Animales , Vacunas/inmunología , Proteínas de Artrópodos/inmunología , Proteínas de Artrópodos/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito B/inmunología , Simulación del Acoplamiento Molecular , Infestaciones por Garrapatas/prevención & control , Infestaciones por Garrapatas/veterinaria , Infestaciones por Garrapatas/inmunología , Simulación de Dinámica Molecular , Epítopos/inmunología , Inmunoinformática , Antígenos , Glicoproteínas de Membrana , Proteínas RecombinantesRESUMEN
Breast cancer, the most common cancer among women, caused over 500,000 deaths in 2020. Conventional treatments are expensive and have severe side effects. Drug repurposing is a novel approach aiming to reposition clinically approved non-cancer drugs into newer cancer treatments. Atorvastatin calcium (ATR Ca) which is used for the treatment of hypercholesterolemia has potential to modulate cell growth and apoptosis. The study aimed at utilizing gelucire-based solid lipid nanoparticles (SLNs) and lactoferrin (Lf) as targeting ligand to enhance tumor targeting of atorvastatin calcium for effective management of breast cancer. Lf-decorated-ATR Ca-SLNs showed acceptable particle size and PDI values <200 nm and 0.35 respectively, entrapment efficiency >90% and sustained drug release profile with 78.97 ± 12.3% released after 24 h. In vitro cytotoxicity study on breast cancer cell lines (MCF-7) showed that Lf-decorated-ATR Ca-SLNs obviously improved anti-tumor activity by 2 to 2.5 folds compared to undecorated ATR Ca-SLNs and free drug. Further, In vivo study was also carried out using Ehrlich breast cancer model in mice. Caspase-3 apoptotic marker revealed superior antineoplastic and apoptosis-inducing activity in the groups treated with ATR Ca-SLNs either decorated/ undecorated with Lf in dosage 10 mg/kg/day p < 0.001 with superior activity for lactoferrin-decorated formulation.
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The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety.
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Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment.
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This article's main objective is to maximize solar radiations (SRs) through the use of the gorilla troop algorithm (GTA) for identifying the optimal tilt angle (OTA) for photovoltaic (PV) panels. This is done in conjunction with an experimental work that consists of three 100 W PV panels tilted at three different tilt angles (TAs). The 28°, 30°, and 50° are the three TAs. The experimental data are collected every day for 181-day and revealed that the TA of 28° is superior to those of 50° and 30°. The GTA calculated the OTA to be 28.445°, which agrees with the experimental results, which show a TA of 28°. The SR of the 28o TA is 59.3% greater than that of the 50° TA and 4.5% higher than that of the 30° TA. Recent methods are used to compare the GTA with the other nine metaheuristics (MHTs)-the genetic algorithm, particle swarm, harmony search, ant colony, cuckoo search, bee colony, fire fly, grey wolf, and coronavirus disease optimizers-in order to figure out the optimal OTA. The OTA is calculated by the majority of the nine MHTs to be 28.445°, which is the same as the GTA and confirms the experimental effort. In only 181-day, the by experimentation it may be documented SR difference between the TAs of 28° and 50° TA is 159.3%. Numerous performance metrics are used to demonstrate the GTA's viability, and it is contrasted with other recent optimizers that are in competition.
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PURPOSE: To examine the 6-month visual outcomes and complications following cataract surgery in patients with persumed trematode induced granulomatous anterior uveitis. SETTING: Assiut university hospital, Assiut, Egypt. DESIGN: This is a retrospective non comparative case series study. METHODS: Patients presenting with significant cataract secondary to uveitis caused by trematode induced anterior chamber granuloma were included in this study. Cases with active anterior uveitis, within the last 3 months preceding surgery, and those with a history of trauma, were excluded from this study. Data collected included demographic characteristics, history of the condition including when uveitis started, treatment received and history of other health conditions that may be relevant to uveitis.Complete opthalmologic examination including assessment of best corrected visual acuity (BCVA) and OCT macula, if possible, were done. These was repeated 1 week, 1 month, 3 months and 6 months after surgery. Specular microscopy was performed preoperatively and 3 months after surgery. Patients underwent cataract surgery with posterior chamber intra ocular lens and statistical analysis was performed to compare preoperative and postoperative BCVA and corneal endothelial cell counts. Postoperative complications were recorded. RESULTS: Five eyes of 5 patients were included in the study. All study eyes showed improvement in the post-operative visual acuity. A statistically significant improvement was observed in VA in the sixth postoperative month compared to the baseline measurements (p = 0.004). No statistically significant difference was observed between the preoperative and postoperative endothelial cell counts (p = 0.696). Cystoid macular edema did not occur as a postoperative complication. CONCLUSION: Visual outcomes of cataract surgery in eyes with persumed trematode induced granulametous anterior uveitis are favorable. No sight threatening complication was observed in our series.
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Catarata , Facoemulsificación , Trematodos , Uveítis Anterior , Uveítis , Niño , Animales , Humanos , Estudios Retrospectivos , Uveítis/complicaciones , Uveítis Anterior/complicaciones , Uveítis Anterior/cirugía , Catarata/complicaciones , Complicaciones Posoperatorias/cirugía , Resultado del Tratamiento , Facoemulsificación/efectos adversosRESUMEN
@#Rhipicephalus microplus, known as the hard tick, is a vector for the parasites Babesia spp. and Anaplasma marginale, both of which can cause significant financial losses to the livestock industry. There is currently no effective vaccine for R. microplus tick infestations, despite the identification of numerous prospective tick vaccine candidates. As a result, the current research set out to develop an immunoinformatics-based strategy using existing methods for designing a multi-epitope based vaccination that is not only effective but also safe and capable of eliciting cellular and humoral immune responses. First, R. microplus proteins Bm86, Subolesin, and Bm95 were used to anticipate and link B and T-cell epitopes (HTL and CTL) to one another. Antigenicity testing, allergenicity assessment, and toxicity screening were just a few of the many immunoinformatics techniques used to identify potent epitopes. Multi-epitope vaccine design was chosen based on the antigenic score 0.935 that is promising vaccine candidate. Molecular docking was used to determine the nature of the interaction between TLR2 and the vaccine construct. Finally, molecular dynamic simulation was used to assess the stability and compactness of the resulting vaccination based on docking scores. The developed vaccine was shown to be stable, have immunogenic qualities, be soluble, and to have high expression by in silico cloning. These findings suggest that experimental investigation of the multi-epitope based vaccine designed in the current study will produce achievable vaccine candidates against R. microplus ticks, enabling more effective control of infestations.
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Babesiosis is a parasitic disease caused by intraerythrocytic parasites of the genus Babesia, which infect both wild and domestic animals. Merozoite surface antigens (MSAs) have been identified as efficient immunogens in Babesia-infected animals. MSAs play a key role in the invasion process and have been proposed as potential targets for vaccine development. Epitope-based vaccines offer several advantages over whole protein vaccines as the immunogenic proteins are small and can induce both Th1 and Th2 immune responses, which are desirable for protection. However, the MSA, particularly gp45, is polymorphic in Babesia bigemina, posing a challenge to vaccine development. The purpose of this study was to develop a recombinant gpME (gp45-multi-epitope) for a vaccine against Babesia bigemina. B-cell, T-cell, and HLA epitope predictions were used to synthesize the gpME sequence from the consensus sequence of gp45. The gpME sequence was synthesized and cloned in the pET28α vector through the commercial biotechnology company to get pET28-gpME. The plasmid cloned with the gpME sequence comprising 1068 bp was expressed in a bacterial expression system. A band of 39 kDa of rec-gpME was obtained via SDS-PAGE and Western blotting. Rec-gpME @200ng was injected in calves 3 times at 2 weeks interval. The humoral response was evaluated through the indirect ELISA method. The ELISA with rec-gp45 protein showed a significant value of optical density. The recombinant protein containing multiple epitopes from the MSA gp45 may represent a promising candidate for a vaccine against Babesia bigemina.
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Babesia , Babesiosis , Enfermedades de los Bovinos , Animales , Bovinos , Antígenos de Superficie , Epítopos , Merozoítos , Babesiosis/prevención & control , Enfermedades de los Bovinos/prevención & controlRESUMEN
BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.
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Indazoles , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Indazoles/farmacología , Resistencia a Antineoplásicos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Benzamidas/farmacología , Línea Celular Tumoral , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Mutación , Proliferación Celular , ApoptosisRESUMEN
A new series of 3,4,5-trimethoxyphenyl thiazole pyrimidines has been synthesized and biologically evaluated for its in vitro anticancer activity. Compounds 4a, 4b, and 4h with substituted piperazine showed the best antiproliferative activity. In the NCI-60 cell line screening, compound 4b showed promising cytostatic activity against multiple cell lines. Notably, it elicited a GI value of 86.28% against the NSCL cancer cell line HOP-92 at a 10 µM dose. Compounds 4a and 4h at 10 µM showed promising GI values of 40.87% and 46.14% against HCT-116 colorectal carcinoma and SK-BR-3 breast cancer cell lines, respectively. ADME-Tox prediction of compounds 4a, 4b, and 4h revealed their acceptable drug-likeness properties. In addition, compounds 4a, 4b, and 4h showed a high probability of targeting kinase receptors via Molinspiration and Swiss TargetPrediction.
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Antineoplásicos , Tiazoles , Humanos , Relación Estructura-Actividad , Tiazoles/farmacología , Tiazoles/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Relación Dosis-Respuesta a DrogaRESUMEN
Anaplasma marginale is the most prevalent tick-borne haemoparasite of cattle and causes huge economic losses to the dairy industry worldwide. This study aimed to determine the occurrence of A. marginale infection in blood and tick samples collected from livestock animals in the districts located in Khyber Pakhtunkhwa (KPK), Pakistan. A total of 184 blood and 370 tick samples were included in this study. It has never been reported that sheep, goats, and cattle in Tank, Ghulam Khan, Birmil and Miran Shah areas were infected with A. marginale. All samples of blood and ticks were collected through random sampling from March 2021 to January 2022 from cattle, sheep and goats and screened through PCR for anaplasmosis by using primer pairs of Anaplasma spp. Three hundred and seventy ticks were collected from infested hosts (120/184, 64.21%). Among the four morphologically identified tick species, the highest occurrence was recorded for Rhipicephalus sanguineus (n=138, 37.29%), followed by Rhipicephalus microplus (n=131, 35.4%), Rhipicephalus annulatus (n=40, 10.81%), Hyalomma anatolicum (n=31, 8.37%), and Hyalomma marginatum (n=30, 8.1%). The occurrence of female tick was highest (n=160, 43.24%), followed by nymphs (n=140, 37.38%) and males ticks (n=70, 18.9%). Among these ticks, A. marginale was detected in female ticks of R. microplus, and R. sanguineus. Molecular identification of A. marginale was confirmed in 120 out of 184 blood samples and 6 out of 74 tick samples. Overall, occurrence of A. marginale in blood and tick samples was found to be 65.21% and 8.1% respectively. Species-wise occurrence in blood samples of goats were 71.11% followed by sheep 68.31% and cattle 50%. Specie-wise occurrence of A. marginale in tick samples of cattle were 12.5% followed by goats 6.89%. The obtained sequence showed similarity with A. marginale reported from Kenya and USA. We report the first PCR based detection of A. marginale infection in blood samples and in R. sanguineus ticks of goats simultaneously.
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Anaplasma marginale , Anaplasmosis , Enfermedades de los Bovinos , Rhipicephalus , Masculino , Bovinos , Animales , Femenino , Ovinos , Anaplasma marginale/genética , Prevalencia , Pakistán/epidemiología , Rumiantes/parasitología , Anaplasmosis/epidemiología , Anaplasma , Cabras/parasitología , Enfermedades de los Bovinos/epidemiología , Enfermedades de los Bovinos/parasitologíaRESUMEN
Fisetin (FS) is an anticancer drug having potential role in oral tumors management. However, its clinical application is limited due to its hydrophobicity and instability. Bioactive polymers-based nanosystems have a great potential in cancer therapy. Herein, different biopolymers were selected for their anticancer activity and targeting ability for nanoparticles preparation namely; fucoidan (FU), zein (Zn) and hyaluronic acid (HA). The selected FS-loaded cross-linked Zn nanoparticles (ZFH) which contains HA& FU for Zn nanoparticles stabilization showed the most suitable particle size (196 ± 6.53 nm), mean surface net charge (-38.8 ± 1.47 mV) and entrapment efficiency (98 ± 1.2 %). This is the first study to utilize both HA &FU not only for stabilization but also for dual targeting effect due to their targeting ability to multiple tumor targets. In-vitro anticancer activity of ZHF revealed remarkable uptake by SCC-4 cells with significant cytotoxic action. Further, ZHF was appraised using 4-nitroquinoline 1-oxide (4-NQO)-induced oral cancer in-vivo; ZHF significantly reduced OSCC-specific serum biomarkers levels, histologic tumor grade and increased caspase-3 level. Moreover, potential of destroying two key tumor regulatory cells; TECs and CSCs, was evaluated using their specific markers. The elaborated ZFH nanoparticles could be considered as promising targeted nanotherapy for oral cancer treatment with enhanced efficacy and survival rate.
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Antineoplásicos , Neoplasias de la Boca , Nanopartículas , Zeína , Humanos , Ácido Hialurónico , Antineoplásicos/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Tamaño de la Partícula , Portadores de Fármacos , Línea Celular TumoralRESUMEN
Powder metallurgy (PM) is a technique that involves the manufacturing of metal powders and their consolidation into finished products or components. This process involves the mixing of metal powders with other materials such as ceramics or polymers, followed by the application of heat and pressure to produce a solid, dense material. The use of PM has several advantages over traditional manufacturing techniques, including the ability to create complex shapes and the production of materials with improved properties. Cu-TiO2 composite materials are of great interest due to their unique properties, such as high electrical conductivity, improved mechanical strength, and enhanced catalytic activity. The synthesis of Cu-TiO2 composites using the PM technique has been gaining popularity in recent years due to its simplicity, cost-effectiveness, and ability to produce materials with excellent homogeneity. The novelty of using the PM technique for the preparation of Cu-TiO2 composite lies in the fact that it enables the production of materials with controlled microstructures and optical properties. The microstructure of the composite can be fine-tuned by controlling the particle size and distribution of the starting powders, as well as the processing parameters such as temperature, pressure, and sintering time. The optical properties of the composite can also be tailored by adjusting the size and distribution of the TiO2 particles, which can be used to control the absorption and scattering of light. This makes Cu-TiO2 composites particularly useful for applications such as photocatalysis and solar energy conversion. In summary, the use of Powder Metallurgy for the preparation of Cu-TiO2 composite is a novel and effective technique for producing materials with controlled microstructures and optical properties. The unique properties of Cu-TiO2 composites make them attractive for a wide range of applications in various fields, including energy, catalysis, and electronics.
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The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2a-f was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABLT315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o-methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC50 values of 2.0 and 0.65 nM against BCR-ABLT315I, respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer.
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Proteínas de Fusión bcr-abl , Pirimidinas , Mesilato de Imatinib/farmacología , Proteínas de Fusión bcr-abl/genética , Pirimidinas/farmacología , Piperazinas/farmacología , Benzamidas/farmacología , ApoptosisRESUMEN
A series of 6-ureido/amidocoumarins (5a-p and 7a-c) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase hCA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against hCA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms hCA IX (KIs: 14.7-82.4 nM) and hCA XII (KIs: 5.9-95.1 nM), whereas the cytosolic off-target hCA I and II isoforms have not inhibited by all tested coumarins up to 100 µM. These findings granted the target coumarins an excellent selectivity profile towards both hCA IX and hCA XII isoforms, supporting their development as promising anticancer candidates. Moreover, all target molecules were evaluated for their anticancer activities against HCT-116 and MCF-7 cancer cells. The 3,5-bis-trifluoromethylphenyl ureidocoumarin 5i, exerted the best anticancer activity. Overall, ureidocoumarins, particularly compound 5i, could serve as a promising prototype for the development of potent anticancer CAIs.
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Anhidrasas Carbónicas , Humanos , Anhidrasas Carbónicas/metabolismo , Relación Estructura-Actividad , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasa Carbónica IX , Antígenos de Neoplasias , Células MCF-7 , Cumarinas/farmacología , Estructura MolecularRESUMEN
The principal target of this work is to compute the optimal tilt angle (OTA) for Photovoltaic (PV) panels. To perform this task, comprehensive simulations are done starting from altering the tilt angle (TA) daily, to use one fixed TA for all the year. The mathematical models for extra-terrestrial radiation (ETR) of both horizontal and inclined surfaces are presented firstly. At a later stage, the optimization formulation for the maximizing the solar radiation (SR) is adapted, and then the daily, monthly, seasonally, half-yearly and optimal fixed TAs are obtained. Although, the daily OTA produces the maximum SR, it is costly and impractical. It is found that altering the TA twice a year at optimal values that are computed as 5° and 50° for Suez city, gives the best results that are very near to the daily altering of the OTA. The difference between the two methods is 1.56% which is very small. Also, the two OTAs has SR better than that of the fixed OTA which is 28° by 7.77%. Also, it is found that the yearly fixed OTA (28°) is nearly equal to the latitude angle of Suez city which is 30°. The two OTAs method of this paper is different from the commonly used method that suggests two TAs. The first TA is used for winter months which is obtained by adding 15° to the latitude angle while the second TA is obtained by subtracting 15° from the latitude angle for the summer months. This commonly used method produces lesser SR than the two OTAs method of this paper. The theoretical work has been proved by an experimental work on two PV systems constructed at 25° and 30° TAs. The results of the experimental work agree with the theoretical results.
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Chronic hepatitis C is a major health concern with high morbidity and mortality rates. The introduction of direct acting antivirals (DAAs) as a first-line treatment for hepatitis C virus (HCV) has significantly enhanced HCV eradication. However, DAA therapy is facing rising concerns regarding long-term safety, viral resistance, and reinfection. HCV is associated with different immune alteration mechanisms that can evade immunity and establish persistent infection. One of these suggested mechanisms is the accumulation of myeloid-derived suppressor cells (MDSCs), which is known to accumulate in chronic inflammatory conditions. Moreover, the role of DAA in restoring immunity after successful viral eradication is still unclear and needs further investigations. Thus, we aimed to investigate the role of MDSCs in chronic HCV Egyptian patients and its response to DAA in treated compared with untreated patients. Fifty untreated chronic hepatitis C (CHC) patients, 50 DAA-treated CHC patients, and 30 healthy individuals were recruited. We used flow cytometer analysis to measure MDSCs frequency and enzyme-linked immunosorbent assay analysis to evaluate the serum level of interferon (IFN)-γ. We found a significant elevation in MDSC% among the untreated group (34.5 ± 12.4%) compared with the DAA-treated group (18.3 ± 6.7%), while the control group had a mean of (3.8 ± 1.6%). IFN-γ concentration was higher in treated patients compared with untreated. We also found a significant negative correlation (rs -0.662) (p < 0.001) between MDSC% and IFN-γ concentration among treated HCV patients. Our results revealed important evidence of MDSCs accumulation in CHC patients and partial retrieval of the immune system regulatory function after DAA therapy.
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Hepatitis C Crónica , Hepatitis C , Células Supresoras de Origen Mieloide , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , Egipto , Hepatitis C/tratamiento farmacológico , HepacivirusRESUMEN
The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines 17b and 18a stood out as the most potent members, with IC50 values of 0.128 µM, 0.114 µM against B-RAFV600E, and 0.0653 µM, 0.0676 µM against C-RAF. Most importantly, 17b elicited remarkable inhibitory potency against the clinically resistant B-RAFV600K mutant with an IC50 value of 0.0616 µM. The putative binding mode of 17b and 18a were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline VII against all cell lines at a 10 µM dose. Notably, both 17b and 18b showed highly potent antiproliferative activity against melanoma cell lines with growth percent under -90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while 17b maintained potency with GI50 values of 1.60-1.89 µM against melanoma cell lines. Taken together, 17b, a promising B-RAFV600E/V600K and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics.
Asunto(s)
Antineoplásicos , Melanoma , Quinolonas , Humanos , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Melanoma/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/metabolismo , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer's disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 µM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 µM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 µM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 µM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19-3.87 µM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (-11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood-brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.