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Mangiferin (MF) is a natural C-glucosylxantone compound that has many substantial curative potentials against numerous illnesses including cancers. The present study's goal is to appraise the chemo preventive possessions of MF on azoxymethane (AOM)-mediated colonic aberrant crypt foci (ACF) in rats. Rats clustered into 5 groups, negative control (A), inoculated subcutaneously with normal saline twice and nourished on 0.5% CMC; groups B-E injected twice with 15 mg/kg azoxymethane followed by ingestion of 0.5% CMC (B, cancer control); intraperitoneal inoculation of 35 mg/kg 5-fluorouracil (C, reference rats) or nourished on 30 mg/kg (D) and 60 mg/kg (E) of MF. Results of gross morphology of colorectal specimens showed significantly lower total colonic ACF incidence in MF-treated rats than that of cancer controls. The colon tissue examination of cancer control rats showed increased ACF availability with bizarrely elongated nuclei, stratified cells, and higher depletion of the submucosal glands compared to MF-treated rats. Mangiferin treatment caused increased regulation of pro-apoptotic (increased Bax) proteins and reduced the ß-catenin) proteins expression. Moreover, rats fed on MF had significantly higher glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and lower malondialdehyde (MDA) concentrations in their colonic tissue homogenates. Mangiferin supplementation significantly down-shifted pro-inflammatory cytokines (transforming growth factor-α and interleukine-6) and up-shifted anti-inflammatory cytokines (interleukine-10) based on serum analysis. The chemo-protective mechanistic of MF against AOM-induced ACF, shown by lower ACF values and colon tissue penetration, could be correlated with its positive modulation of apoptotic cascade, antioxidant enzymes, and inflammatory cytokines originating from AOM oxidative stress insults.
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Focos de Criptas Aberrantes , Neoplasias Colorretais , Mangifera , Animais , Ratos , Antioxidantes/farmacologia , Citocinas , Focos de Criptas Aberrantes/induzido quimicamente , Focos de Criptas Aberrantes/tratamento farmacológico , Azoximetano/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológicoRESUMO
Weight loss is a significant health problem among patients with head and neck cancer (HNC) that is attributable primarily to the tumor or tumor therapy. Critical weight loss (CWL) is defined as the unintentional loss of ≥5% of weight. Therefore, this study's goal was to investigate and determine the possible factors influencing CWL among patients with HNC who have received radiotherapy or concurrent chemoradiotherapy (CCRT). We conducted a retrospective analysis of 175 patients who received radiotherapy or CCRT as either their primary, adjuvant, or combined treatment at the Oncology Center in King Abdullah Medical City. All patients were ≥18 years of age and diagnosed with HNC with no metastasis. The study results showed that 107 patients (61%) had CWL, while 68 (39%) did not. The following factors were significantly predictive of CWL with a multivariate regression analysis: pretreatment BMI (AOR = 1.1, 95% CI = 1.02-1.17), oral cavity cancer (AOR = 10.36, 95% CI = 1.13-94.55), and male sex (AOR = 3.15, 95% CI = 1.39-7.11). In conclusion, weight loss is highly prevalent among HNC patients during treatment. Accordingly, pretreatment BMI, cancer in the oral cavity, and being male can be considered predictive factors for CWL.
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Herbal medicine is one of the most common fields explored for combating colon cancers, and Pimpinella anisum L. seeds (PAS) have been utilized widely as medicinal agents because of their increased essential oil (trans-anethole) contents. In this essence, our study investigates the toxic effect and chemoprotective potentials of PAS against azoxymethane (AOM)-induced colon cancer in rats. The toxicity trial for PAS conducted by clustering fifteen rats into three groups (five rats each): A, normal control had 10% Tween 20; B, ingested with 2 g/kg PAS; and C, supplemented with 4 g/kg PAS. The in vivo cancer trial was performed by using 30 rats (Sprague-Dawley) that were randomly adapted in five steel cages (six rats each): group A, normal controls received two subcutaneous injections of normal saline 0.09% and ingested orally 10% Tween 20; groups B-E, rats received two injections of 15 mg/kg of azoxymethane (AOM) subcutaneously in 2 weeks and treated orally with 10% Tween 20 (group B) or intraperitoneal injection of 5-fluorouracil (35 mg/kg) (group C), or orally given 200 mg/kg PAS (group D) and 400 mg/kg PAS (group E) for 8 weeks. After the scarification of rats, the colon tissues were dissected for gross and histopathological evaluations. The acute toxicity trial showed the absence of any toxic signs in rats even after 14 days of ingesting 4 g/kg of PAS. The chemoprotective experiment revealed significant inhibitory potentials (65.93%) of PAS (400 mg/kg) against aberrant crypto foci incidence that could be correlated with its positive modulation of the immunohistochemically proteins represented by a significant up-regulation of the Bax protein and a decrease of the Bcl-2 protein expressions in colon tissues. Furthermore, PAS-treated rats had notably lower oxidative stress in colon tissues evidenced by decreased MDA levels and increased antiradical defense enzymes (SOD, CAT, and GPx). The outcomes suggest 400 mg/kg PAS as a viable additive for the development of potential pharmaceuticals against colorectal cancer.
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Neoplasias do Colo , Pimpinella , Ratos , Animais , Antioxidantes/metabolismo , Azoximetano/toxicidade , Azoximetano/uso terapêutico , Pimpinella/química , Ratos Sprague-Dawley , Polissorbatos , Neoplasias do Colo/induzido quimicamente , Anti-InflamatóriosRESUMO
Objectives: Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The present study investigates the chemo-preventive potentials of PN on azoxymethane-mediated colonic aberrant crypt foci in rats. Methods: Sprague Dawley rats clustered into five groups, normal control (A) and cancer controls were subcutaneously injected with normal saline and 15 mg/kg azoxymethane, respectively, and nourished on 10% tween 20 and fed on 10% tween 20; reference control (C), injected with 15 mg/kg azoxymethane and injected (intraperitoneal) with 35 mg/kg 5-fluorouracil (5-FU); D and E rat groups received a subcutaneous injection of 15 mg/kg azoxymethane and nourished on 30 and 60 mg/kg of PN, respectively. Results: The acute toxicity trial showed a lack of any abnormal signs or mortality in rats ingested with 250 and 500 mg/kg of PN. The gross morphology of colon tissues revealed significantly lower total colonic aberrant crypt foci incidence in PN-treated rats than that of cancer controls. Histological examination of colon tissues showed increased aberrant crypt foci availability with bizarrely elongated nuclei, stratified cells and higher depletion of the submucosal glands in cancer controls. PN treatment caused positive modulation of apoptotic (Bax and Bcl-2) proteins and inflammatory cytokines (TNF-α, IL-6 and IL-10). Moreover, rats fed on PN had significantly higher antioxidants (superoxide dismutase) and lower malondialdehyde concentrations in their colon tissue homogenates. Conclusion: The chemoprotective efficiency of PN against azoxymethane-induced aberrant crypt foci is shown by lower aberrant crypt foci values and higher aberrant crypt foci inhibition percentage, possibly through augmentation of genes responsible for apoptotic cascade and inflammations originating from azoxymethane oxidative stress insults.
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Breast cancer is a global health concern, with increasing disease burden and disparities in access to healthcare. Late diagnosis and limited treatment options in underserved areas contribute to poor outcomes. In response to this challenge, we developed a novel family of 2-substituted-quinoxaline analogues, combining coumarin and quinoxaline scaffolds known for their anticancer properties. Through a versatile synthetic approach, we designed, synthesized, and characterized a set of 2-substituted quinoxaline derivatives. The antiproliferative activity of the synthesized compounds was assessed toward the MCF-7 breast cancer cells. Our investigations showed that the synthesized compounds exhibit considerable antiproliferative activity toward MCF-7 cells. Notably, compound 3b, among examined compounds, displayed a superior inhibitory effect (IC50 = 1.85 ± 0.11 µM) toward the growth of MCF-7 cells compared to the conventional anticancer drug staurosporine (IC50 = 6.77 ± 0.41 µM) and showed minimal impact on normal cells (MCF-10A cell lines, IC50 = 33.7 ± 2.04 µM). Mechanistic studies revealed that compound 3b induced cell cycle arrest at the G1 transition and triggered apoptosis in MCF-7 cells, as evidenced by increasing the percentage of cells arrested in the G2/M and pre-G1 phases utilizing flow cytometric analysis and Annexin V-FITC/PI analysis. Moreover, compound 3b was found to substantially suppress topoisomerase enzyme activity in MCF-7 cells. Molecular modeling studies further supported the potential of compound 3b as a therapeutic candidate by demonstrating significant binding affinity to the active sites of both topoisomerase II and EGFR proteins. Taken together, the presented 2-substituted-quinoxaline analogues, especially compound 3b, show promise as potential candidates for the development of effective anti-breast cancer drugs.
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Boric acid (BA) is a naturally occurring weak Lewis acid containing boron, oxygen, and hydrogen elements that can be found in water, soil, and plants. Because of its numerous biological potentials including anti-proliferation actions, the present investigates the chemopreventive possessions of BA on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Thirty laboratory rats were divided into 5 groups: negative control (A) received two subcutaneous inoculations of normal saline and nourished on 10% Tween 20; groups B-E had two injections of 15 mg/kg azoxymethane followed by ingestion of 10% Tween 20 (B, cancer control), inoculation with intraperitoneal 35 mg/kg 5-fluorouracil injection (C, reference group), or ingested with boric acid 30 mg/kg (D) and 60 mg/kg (E). The gross morphology results showed significantly increased total colonic ACF in cancer controls, while BA treatment caused a significant reduction of ACF values. Histopathological evaluation of colons from cancer controls showed bizarrely elongated nuclei, stratified cells, and higher depletion of the submucosal glands than that of BA-treated groups. Boric acid treatment up-surged the pro-apoptotic (Bax) expression and reduced anti-apoptotic (Bcl-2) protein expressions. Moreover, BA ingestion caused upregulation of antioxidant enzymes (GPx, SOD, CAT), and lowered MDA contents in colon tissue homogenates. Boric acid-treated rats had significantly lower pro-inflammatory cytokines (TNF-α and IL-6) and higher anti-inflammatory cytokines (IL-10) based on serum analysis. The colorectal cancer attenuation by BA is shown by the reduced ACF numbers, anticipated by its regulatory potentials on the apoptotic proteins, antioxidants, and inflammatory cytokines originating from AOM-induced oxidative damage.
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BACKGROUND: The Biarum species (Kardeh) has been consumed as a traditional functional food and medicine for decades. The current study investigates the phytochemistry, in-vitro and in-vivo bioactivities of methanol extracts of B. bovei. METHODS: The Gas-chromatography mass spectrophotometer (GS/GS-MS) was used to analyze the phytochemical profile of the methanol extracts of B. bovei leaves and corms. The B. bovei extracts (BBE) were also investigated for in-vitro antioxidant, anticancer, and in-vivo acute toxicity (2000 mg/kg) activities. RESULTS: The chemical profiling of BBE revealed mainly fatty acids, phytosterol, alcohols, and hydrocarbon compounds. Namely, Linoleic acid, eliadic acid, palmitic acid, 22,23-dihydro-stigmasterol, and campesterol. The antioxidant activity of BBE ranged between 0.24-3.85 µg TE/mL based on different assays. The extracts also exhibited significant anticancer activity against DU-145 (prostate cancer cells), MCF-7 (human breast adenocarcinoma), and HeLa (human cervical cancer) cell lines with IC50 values ranging between 22.73-44.24 µg/mL. Rats fed on 2000 mg/kg dosage of BBE showed absence of any toxicological sign or serum biochemical changes. CONCLUSION: The detected phytochemicals and bioactivities of BBE scientifically backup the folkloric usage as an important source of nutraceuticals and alternative medicine for oxidative stress-related diseases and carcinogenesis inhibition.
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Antioxidantes , Extratos Vegetais , Masculino , Ratos , Humanos , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Extratos Vegetais/toxicidade , Extratos Vegetais/química , Metanol , Células HeLa , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/análiseRESUMO
BACKGROUND: Cadmium (Cd) is a major environmental pollutant and chronic toxicity could induce nephropathy by increasing renal oxidative stress and inflammation. Although vitamin D (VD) and calcium (Ca) prophylactic treatments attenuated Cd-induced cell injury, none of the prior studies measure their renoprotective effects against pre-established Cd-nephropathy. AIMS: To measure the alleviating effects of VD and/or Ca single and dual therapies against pre-established nephrotoxicity induced by chronic Cd toxicity prior to treatment initiation. METHODS: Forty male adult rats were allocated into: negative controls (NC), positive controls (PC), Ca, VD and VC groups. The study lasted for eight weeks and all animals, except the NC, received CdCl2 in drinking water (44 mg/L) throughout the study. Ca (100 mg/kg) and/or VD (350 IU/kg) were given (five times/week) during the last four weeks to the designated groups. Subsequently, the expression of transforming growth factor-ß (TGF-ß1), inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), VD synthesising (Cyp27b1) and catabolizing (Cyp24a1) enzymes with VD receptor (VDR) and binding protein (VDBP) was measured in renal tissues. Similarly, renal expression of Ca voltage-dependent channels (CaV1.1/CaV3.1), store-operated channels (RyR1/ITPR1), and binding proteins (CAM/CAMKIIA/S100A1/S100B) were measured. Serum markers of renal function alongside several markers of oxidative stress (MDA/H2O2/GSH/GPx/CAT) and inflammation (IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 were also measured. RESULTS: The PC group exhibited hypovitaminosis D, hypocalcaemia, hypercalciuria, proteinuria, reduced creatinine clearance, and increased renal apoptosis/necrosis with higher caspase-3 expression. Markers of renal tissue damage (TGF-ß1/iNOS/NGAL/KIM-1), oxidative stress (MDA/H2O2), and inflammation (TNF-α/IL-1ß/IL-6) increased, whilst the antioxidants (GSH/GPx/CAT) and IL-10 decreased, in the PC group. The PC renal tissues also showed abnormal expression of Cyp27b1, Cyp24a1, VDR, and VDBP, alongside Ca-membranous (CaV1.1/CaV3.1) and store-operated channels (RyR1/ITPR1) and cytosolic Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B). Although VD was superior to Ca monotherapy, their combination revealed the best mitigation effects by attenuating serum and renal tissue Cd concentrations, inflammation and oxidative stress, alongside modulating the expression of VD/Ca-molecules. CONCLUSIONS: This study is the first to show improved alleviations against Cd-nephropathy by co-supplementing VD and Ca, possibly by better regulation of Ca-dependent anti-oxidative and anti-inflammatory actions.
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Nefropatias , Vitamina D , Ratos , Masculino , Animais , Vitamina D/farmacologia , Vitamina D/metabolismo , Cádmio/metabolismo , Cálcio/metabolismo , Interleucina-10/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/farmacologia , Caspase 3/metabolismo , Lipocalina-2/metabolismo , Lipocalina-2/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/farmacologia , Vitamina D3 24-Hidroxilase/metabolismo , Peróxido de Hidrogênio/metabolismo , Interleucina-6/metabolismo , Rim , Nefropatias/metabolismo , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismoRESUMO
This study investigated the chemotherapeutic effects of 5-fluorouracil (5-FU), metformin (Met), and/or thymoquinone (TQ) single/dual/triple therapies in the HT29, SW480 and SW620 colon cancer (CRC) cell lines. Cell cycle/apoptosis were measured by flow cytometry. The gene and protein expression of apoptosis (PCNA/survivin/BAX/Cytochrome-C/Caspase-3) and cell cycle (CCND1/CCND3/p21/p27) molecules, the PI3K/mTOR/HIF1α oncogenic pathway, and glycolysis regulatory enzymes were measured by quantitative-PCR and Western blot. Markers of oxidative stress were also measured by colorimetric assays. Although all treatments induced anti-cancer effects related to cell cycle arrest and apoptosis, the triple therapy showed the highest pro-apoptotic actions that coincided with the lowest expression of CCND1/CCND3/PCNA/survivin and the maximal increases in p21/p27/BAX/Cytochrome-C/Caspase-3 in all cell lines. The triple therapy also revealed the best suppression of the PI3K/mTOR/HIF1α pathway by increasing its endogenous inhibitors (PTEN/AMPKα) in all cell lines. Moreover, the lowest expression of lactate dehydrogenase and pyruvate dehydrogenase kinase-1 with the highest expression of pyruvate dehydrogenase were seen with the triple therapy, which also showed the highest increases in oxidative stress markers (ROS/RNS/MDA/protein carbonyl groups) alongside the lowest antioxidant levels (GSH/CAT) in all cell lines. In conclusion, this is the first study to reveal enhanced anti-cancer effects for metformin/thymoquinone in CRC that were superior to all monotherapies and the other dual therapies. However, the triple therapy approach showed the best tumoricidal actions related to cell cycle arrest and apoptosis in all cell lines, possibly by enhancing oxidative glycolysis and augmenting oxidative stress through stronger modulation of the PI3K/mTOR/HIF1α oncogenic network.
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Neoplasias do Colo , Fluoruracila , Metformina , Humanos , Apoptose , Proteína X Associada a bcl-2/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Citocromos/metabolismo , Citocromos/farmacologia , Fluoruracila/farmacologia , Metformina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Survivina/metabolismo , Survivina/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
BACKGROUND: Chronic iron overload could induce nephropathy via oxidative stress and inflammation, and chelating therapy has limited efficacy in removing excess intracellular iron. Although vitamin D (VD) has shown potent antioxidant and anti-inflammatory effects, as well contribute to iron homeostasis, none of the previous studies measured its potential remedial effects against chronic iron toxicity. AIMS: To measure the alleviating effects of deferasirox (DFX) and/or vitamin D (VD) single and combined therapies against nephrotoxicity induced by chronic iron overload. METHODS: Forty male rats were divided into negative (NC) and positive (PC) controls, DFX, VD, and DFX/VD groups. The designated groups received iron for six weeks followed by DFX and/or VD for another six weeks. Then, the expression pattern of renal genes and proteins including hepcidin, ferroportin (FPN), megalin, transferrin receptor 1 (TfR1), ferritin heavy and light chains, VD receptor (VDR), VD synthesizing (Cyp27b1) and catabolizing (Cyp24a1) enzymes were measured alongside serum markers of renal function and iron biochemical parameters. Additionally, several markers of oxidative stress (MDA/H2O2/GSH/SOD1/CAT/GPx4) and inflammation (IL-1ß/IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 (Casp-3) were measured. RESULTS: The PC rats showed pathological iron and renal biochemical markers, hypovitaminosis D, increased renal tissue iron contents with increased Cyp24a1/Megalin/ferritin-chains/hepcidin, and decreased Cyp27b1/VDR/TfR1/FPN expression than the NC group. The PC renal tissues also showed abnormal histology, increased inflammatory (IL-1ß/IL-6/TNF-α), oxidative stress (MDA/H2O2), and apoptosis markers with decreased IL-10/GSH/SOD1/CAT/GPx4. Although DFX monotherapy reduced serum iron levels, it was comparable to the PC group in renal iron concentrations, VD and iron-homeostatic molecules, alongside markers of oxidative stress, inflammation, and apoptosis. On the other hand, VD monotherapy markedly modulated renal iron and VD-related molecules, reduced renal tissue iron concentrations, and preserved renal tissue relative to the PC and DFX groups. However, serum iron levels were equal in the VD and PC groups. In contrast, the best significant improvements in serum and renal iron levels, expression of renal iron-homeostatic molecules, oxidative stress, inflammation, and apoptosis were seen in the co-therapy group. CONCLUSIONS: iron-induced nephrotoxicity was associated with dysregulations in renal VD-system together with renal oxidative stress, inflammation, and apoptosis. While DFX reduced systemic iron, VD monotherapy showed better attenuation of renal iron concentrations and tissue damage. Nonetheless, the co-therapy approach exhibited the maximal remedial effects, possibly by enhanced modulation of renal iron-homeostatic molecules alongside reducing systemic iron levels. AVAILABILITY OF DATA AND MATERIALS: All data generated or analysed during this study are included in this published article [and its Supplementary information files].
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Colecalciferol , Sobrecarga de Ferro , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Caspase 3/metabolismo , Deferasirox/farmacologia , Ferritinas/metabolismo , Hepcidinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Rim , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Estresse Oxidativo , Ratos , Receptores da Transferrina/metabolismo , Superóxido Dismutase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitamina D3 24-Hidroxilase/metabolismoRESUMO
Background: Breast cancer is one of the leading causes of death worldwide, it affects both men and women. In Saudi Arabia, breast cancer has been the most prevalent type of cancer in women, for the past few years. Dietary habits and cultural beliefs vary according to region, and further studies are required to demonstrate the relationship between these dietary habits and cultural beliefs and the risk of developing breast cancer. This study is aimed to discover the relationship between preventive dietary factors of the Mediterranean diet and rates of breast cancer among postmenopausal women in the Makkah region of Saudi Arabia. Methods: A case-control study was conducted in King Abdulla Medical City Hospital, Makkah, Saudi Arabia and included 432 Saudi female participants: 218 in the control group and 214 breast cancer patients. All participants were postmenopausal, around the same age, and all were ethnically Arab Saudis. Data were obtained using a self-administered validated questionnaire. Results: Study results showed that a diet that includes 1-2 servings of legumes weekly, 1-5 servings of fish weekly, 1-5 servings of dairy products daily, 3-5 servings of fruits and vegetables daily, and more than one cup of black tea and coffee per day significantly (p < 0.05) reduces the risk of breast cancer. Conclusion: This study demonstrates that consuming a Mediterranean diet, which includes legumes, fish, fruits and vegetables, black tea, coffee, and low intake of dairy products, works as a preventive factor against breast cancer in postmenopausal females from the Makkah region.
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[This corrects the article DOI: 10.3389/fnut.2022.863029.].
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Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D3 (VD3), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) controls, and 5-FU, VD3, Met, 5-FU/VD3, 5-FU/Met, VD3/Met, and 5-FU/VD3/Met groups. Treatments lasted four weeks following CRC induction by azoxymethane. Similar regimens were also applied in the SW480 and SW620 CRC cell lines. The PC mice had abundant tumours, markedly elevated proliferation markers (survivin/CCND1) and PI3K/Akt/mTOR, and reduced p21/PTEN/cytochrome C/caspase-3 and apoptosis. All therapies reduced tumour numbers, with 5-FU/VD3/Met being the most efficacious regimen. All protocols decreased cell proliferation markers, inhibited PI3K/Akt/mTOR molecules, and increased proapoptotic molecules with an apoptosis index, and 5-FU/VD3/Met revealed the strongest effects. In vitro, all therapies equally induced G1 phase arrest in SW480 cells, whereas metformin-alone showed maximal SW620 cell numbers in the G0/G1 phase. 5-FU/Met co-therapy also showed the highest apoptotic SW480 cell numbers (13%), whilst 5-FU/VD3/Met disclosed the lowest viable SW620 cell percentages (81%). Moreover, 5-FU/VD3/Met revealed maximal inhibitions of cell cycle inducers (CCND1/CCND3), cell survival (BCL2), and the PI3K/Akt/mTOR molecules alongside the highest expression of cell cycle inhibitors (p21/p27), proapoptotic markers (BAX/cytochrome C/caspase-3), and PTEN in both cell lines. In conclusion, metformin monotherapy was superior to VD3, whereas the 5-FU/Met protocol showed better anticancer effects relative to the other dual therapies. However, the 5-FU/VD3/Met approach displayed the best in vivo and in vitro tumoricidal effects related to cell cycle arrest and apoptosis, justifiably by enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway.
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In the past decade, the use of marine mussels as seafood is being more popular. They considered being a rich source of various nutritional bioactive compounds that aroused the scientific community's interest. This study investigated the antioxidant and the antithrombotic consequences on Sprague-Dawley male rats after adding dried New Zealand mussel Perna canaliculus in their diet. The biochemical, hematological and histopathological changes were also observed. Forty rats were divided into four groups according to the amount of dried mussels in their diet, in addition to a control group that consumed a basal diet only. Group 1 consumed 25% dried mussels in its basal diet; Group 2 consumed 35% dried mussels in its basal diet, and Group 3 was consumed 45% dried mussels in its basal diet. The biochemical parameters showed improvements in liver function. Interestingly, the lipid profile decreased, especially the low-density lipoprotein cholesterol (LDL-C) levels which were reduced significantly in Group 3 (p < .01). These observations were accompanied by a decrease in iron levels significantly as the amount of dried mussels increased (p < .01). Furthermore, the noticed changes in the hematological profile prove that there is an increase in antithrombotic activity. Dried mussels had potent antioxidant effects in the liver as shown by increased lipid peroxide (p < .05), reduced glutathione (p < .05), and glutathione peroxidase (GSH-Px; p < .05). Additionally, antioxidant activity in the kidney was shown to increase through GSH-Px activity (p < .01). In conclusion, these results indicate that consuming dried mussels resulted in improved biochemical and antioxidants activities and could be used as an antithrombotic agent.
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Perna (Organismo) , Animais , Antioxidantes/farmacologia , Fibrinolíticos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Alimentos MarinhosRESUMO
Colorectal cancer (CRC) is one of the most common types of cancers. It is associated with a poor prognosis and high mortality. The role of mucins (MUCs) in colon tumorigenesis is unclear, but it might be significant in the progression of malignancy. Some mucins, such as MUC1 and MUC13, act as oncogenes, whereas others, such as MUC2 and MUC6, are tumor suppressors. However, there are still mucins with unidentified roles in CRC. In this review, we discuss the reported roles of mucins in CRC. Moreover, we review the capability of the mucin family to serve as a sensitive and specific histopathological marker for the early diagnosis of CRC. Lastly, the role of mucin genes clustered on chromosome 7q22 in CRC and other cancers is also discussed.
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Cervical cancer is the most important female genital cancer that develops from the cervix, a lower part of uterus. Houttuynia cordata is ubiquitously present in Asian countries, and traditionally prescribed to treat infections and oedema. Our study emphasizes on biological synthesis route for developing copper nanocomplex using Houttuynia cordata (Hc-CuONPs) plant extract. The UV-visible spectroscopy study of Hc-CuONPs revealed the maximum peak at 350 nm, which proved the formation of Hc-CuONPs and FT-IR absorption peaks revealed the existence of different functional groups. The results of high-resolution TEM and X-ray diffraction studies revealed that the Hc-CuONPs have face centred cubic structure along with 40-45 nm in size. The temperature conditions of the synthesized Hc-CuONPs were spherical and circular morphologies. Furthermore, the Hc-CuONPs (IC50=5 µg/ml) exhibited toxicity on cervical cancer cells (HeLa). The intracellular reactive oxygen species (ROS) level in the control and Hc-CuONPs-treated HeLa cells was monitored by DCFH-DA staining and the apoptotic cell death was detected by using the dual (AO/EtBr) staining, propidium iodide and DAPI staining assays. Our results from the fluorescent staining analysis evidenced that the Hc-CuONPs have inhibited the cell proliferation and promoted the apoptotic cell death in HeLa cells. The Hc-CuONPs promoted the apoptosis by targeting the PI3K/Akt signalling pathways in HeLa cells. Our results explored that the Hc-CuONPs are effective against in vitro HeLa cancer cells.
Assuntos
Cobre/química , Cobre/farmacologia , Houttuynia/química , Nanopartículas , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.
Assuntos
Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos/métodos , Flavanonas/administração & dosagem , Glioblastoma , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/metabolismo , Feminino , Flavanonas/síntese química , Flavanonas/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Lipídeos , Masculino , Nanopartículas/química , Paclitaxel/síntese química , Paclitaxel/metabolismo , Tamanho da Partícula , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/síntese química , Ratos , Ratos WistarRESUMO
Although vitamin D (VD) and calcium (Ca) attenuate cadmium (Cd) metabolism, their combined antioxidant and anti-inflammatory actions against Cd toxicity have not been previously explored. Hence, this study measured the protective effects of VD ± Ca supplements against Cd hepatotoxicity. Forty adult male rats were distributed to: negative controls (NCs), positive controls (PCs), VD, Ca, and VD3 and Ca (VDC) groups. All groups, except NC, received CdCl2 in drinking water (44 mg/L) for 4 weeks individually or concurrently with intramuscular VD3 (600 IU/kg; three times per week) and/or oral Ca (100 mg/kg; five times per week). The PC group showed abnormal hepatic biochemical parameters and increase in cellular cytochrome C, caspase-9, and caspase-3 alongside the apoptotic/necrotic cell numbers by terminal deoxynucleotidyl transferase dUTP nick end labeling technique. The PC hepatic tissue also had substantially elevated pro-oxidants (malondialdehyde [MDA]/H2 O2 /protein carbonyls) and inflammatory cytokines (interleukin 1ß [IL-1ß]/IL-6/IL17A/tumor necrosis factor-α), whereas the anti-inflammatory (IL-10/IL-22) and antioxidants (glutathione [GSH]/GPx/catalase enzyme [CAT]) markers declined. Hypovitaminosis D, low hepatic tissue Ca, aberrant hepatic expression of VD-metabolizing enzymes (Cyp2R1/Cyp27a1/cyp24a1), receptor and binding protein alongside Ca-membrane (CaV 1.1/CaV 3.1), and store-operated (RyR1/ITPR1) channels, and Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B) were observed in the PC group. Both monotherapies decreased serum, but not tissue Cd levels, restored the targeted hepatic VD/Ca molecules' expression. However, these effects were more prominent in the VD group than the Ca group. The VDC group, contrariwise, disclosed the greatest alleviations on serum and tissue Cd, inflammatory and oxidative markers, the VD/Ca molecules and tissue integrity. In conclusion, this report is the first to reveal boosted protection for cosupplementing VD and Ca against Cd hepatotoxicity that could be due to enhanced antioxidative, anti-inflammatory, and modulation of the Ca pathways.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/farmacologia , Doença Hepática Induzida por Substâncias e Drogas , Colecalciferol/farmacologia , Fígado , Animais , Cádmio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: There are various factors that play a major role in influencing the overall health conditions of women diagnosed with breast cancer. The population of women in Makkah region are diverse, therefore it is significant to highlight the possible determinants of breast cancer in this population. This is a case-control study that assessed determinants of breast cancer including socioeconomic factors, health-related characteristics, menstrual histories and breastfeeding among postmenopausal women in Makkah region in Saudi Arabia. METHODS: A total of 432 female participants (214 cases and 218 controls) were recruited for this study. A validated questionnaire was completed by trained dietitians at King Abdullah Medical City Hospital in the Makkah region of Saudi Arabia. RESULTS: Results displayed that determinants of breast cancer were associated significantly (P < 0.05) with unemployment, large family size, lack of knowledge and awareness about breast cancer, obesity, sedentary lifestyle, smoking, starting menarche at an early age, as well as hormonal and non-hormonal contraceptive use. There was no effect of diabetes, hypertension, hyperlipidemia, and duration of breastfeeding on the incidence of breast cancer. CONCLUSION: In summary, the results of this study accentuate the possible effect of socioeconomic factors, health-related characteristics and menstrual history on the incidence of breast cancer in postmenopausal women in the Makkah region. Education programs should be applied to increase breast cancer awareness and possibly decrease its incidence.
Assuntos
Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Menarca , Pessoa de Meia-Idade , Fatores de Risco , Arábia Saudita/epidemiologia , Fatores SocioeconômicosRESUMO
The Thymus vulgaris (T. vulgaris) has been used in foods for the flavor, aroma, and preservation and in folk medicines. The objective of the present work was to determine the antioxidant and protective effects of T. vulgaris extract against lead (Pb)-intoxicated rats. A thirty-two male Sprague-Dawley were randomly assigned into 4 equal groups and treated for six weeks as follows: group I (GP-I), served as negative control; GP-II, -III, and -IV received either Pb acetate in drinking water (500 mg/L), T. vulgaris extract (500 mg/kg/day) by oral gavage or Pb acetate with T. vulgaris extract, respectively. Blood samples were collected at the end of the study week 6 to measure the hepatic and renal biochemical markers, complete blood count alongside the serum levels of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis (TNF)-α, and interferon (IFN)-γ. Additionally, liver and kidney tissue specimens were collected for histopathology as well as to measure the antioxidant-reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) alongside the lipid peroxidation marker, malonaldehyde (MDA). The results indicated that Pb toxicity increased the serum levels of IL-1ß, IL-6, and TNF-α, whereas IL-10 and IFN-γ were reduced. The results showed disturbed liver and renal functions; increased serum levels of ALT, AST, ALP, total bilirubin, creatinine, and urea; and decreased total protein, albumin, and calcium. The GSH, Gpx, and CAT levels were significantly decreased in the Pb-administrated group, while MDA was increased. However, regarding the hepatorenal markers, those animals treated with T. vulgaris alone did not induce any significant changes. Moreover, the combined treatment with T. vulgaris extract together with Pb showed significant improvement in Pb-induced toxicity in all the tested parameters compared to the negative control group. We investigated the potential protective effects of the medicinal plant T. vulgaris in vivo, since there are no publications that address the potential protective effect of this leaf extract against Pb-induced hepatorenal toxicity. Our studies concluded that the T. vulgaris extract reduces Pb overload in hepatorenal tissues, and that this has a potential immunomodulatory role, antioxidant activity, and a protective effect against Pb toxicity.