In vitro investigation on synergistic anticancer effects between vitamin E isomers, pure compounds and crude alkaloid plant extracts on human cancerous cells

Anticancer chemotherapeutic treatment using single dose has been limited due to drug resistance and potential metabolic degradation. For instance, high-dose tocotrienols undergo metabolic degradation that limits the availability of therapeutic dose thereby limiting the potency in vivo. Combined treatment of tocotrienols at low dosage has been suggested as alternative to circumventing this limitation. This study was designed to investigate the cytotoxic effects and subsequently the apoptotic mechanisms of individual doses and combined treatments at lower dosages of tocotrienols (delta and gamma), jerantinines (A and B) and extracts (ethanol and alkaloid crude) from leaves and bark of Ficus hispida, Ficus fistulosa and Ficus schwarzii on lung (A549), brain (U87MG) and colon (HT-29) cancer cell lines. Neutral red uptake assay was conducted to evaluate the antiproliferative effect of individual and combined treatments. Staining techniques (histochemical and fluorescence), COMET assay flow cytometric analysis and immunofluorescence were conducted to evaluate cell morphology, DNA damage, cell cycle arrest pattern and antimicrotubule effects. Finally cell and molecular based assays were conducted to investigate the pathways for induction of apoptosis. Cell viability study revealed that alkaloid crude extracts of leaves and bark of F. fistulosa demonstrated the highest potency with IC50 range of 0.96 – 46.81 µg/ml compared to F. schwarzii (8.79 – 107.9 µg/ml) and F. hispida (15.14 – 49.58 µg/ml) on A549, U87MG and HT-29 cells. Both delta- and gamma-tocotrienols induced antiproliferative effects on A549, U87MG and HT-29 cells with IC50 values of 3.12 - 12.40 µg/ml and 3.17 – 16.36 µg/ml, respectively. Potent antiproliferative effects were also evident for jerantinine A (IC50 0.62 – 1.74 µg/ml), jerantinine B (IC50 0.58 – 1.48 µg/ml) and vinblastine (IC50 0.03 – 0.71 µg/ml). However, similar toxic effects on these three compounds were also evident on non-cancerous lung fibroblast (MRC5) cells. The leaf and bark alkaloid crude extracts of F. fistulosa and F. schwarzii were selected for combined treatments. The combined treatment of IC20 doses of F. fistulosa with both delta- and gamma-tocotrienols induced synergistic antiproliferative effects (combination index (CI) 1) were observed for IC20 doses of F. schwarzii extracts combined with delta- and gamma-tocotrienols on HT-29 cells. On the other hand, combined treatments of tocotrienols (delta and gamma) with IC20 doses of jerantinines (A and B) induced synergistic effects (CI < 1) on A549, U87MG and HT-29 cells causing up to 4.48-fold dose reduction of tocotrienols thus reducing toxicity towards MRC5 cells compared to cancer cells. Further morphological and DNA damage assessment focusing on tocotrienols (delta and gamma), jerantinines (A and B) and combined low-dose treatments revealed anticancer features including cell shrinkage, nuclear chromatin condensation and fragmentation, membrane blebbing, apoptotic bodies and induction of predominantly double stranded DNA breaks. Cell cycle analysis demonstrated the induction of G0/G1 and G2/M cell cycle arrests by tocotrienols (delta and gamma) and jerantinines (A and B), respectively on U87MG, A549 and HT-29 cells. Meanwhile, G2/M (A549) and G0/G1 (U87MG and HT-29) cell cycle arrests were evident for combined low-dose treatments of tocotrienols (delta and gamma) with IC20 doses of jerantinines (A and B). Jerantinines A and B and combined low-dose treatments with tocotrienols (delta and gamma) caused disruption of microtubule networks and induction of caspase 8-, 9- and 3-mediated apoptosis with caspase-independent growth inhibition evidenced in the presence of caspase inhibitors on U87MG, A549 and HT-29 cells. In contrast, although treatments of tocotrienols (delta and gamma) alone caused similar apoptotic features as those of combined, disruption of microtubule networks were not characterized on these three cancer cell lines. Further mechanistic study on U87MG cells revealed that the apoptosis triggered by individual doses of tocotrienols (delta and gamma) involved the activation of TRAIL and Bid as well as the release of cytochrome C, thus confirming the recruitment of the death receptor and mitochondria-mediated pathways. On the other hand, individual doses of jerantinines (A and B) and combined low-dose treatments with tocotrienols resulted in the activation of TRAIL, FAS, p53 and Bid, as well as the release of cytochrome C. The activation of both death receptors, p53 and microtubule disruption by combined low-dose treatments demonstrates an improved mechanism of action comparing to individual doses of tocotrienols and jerantinines. In addition, the combined low-dose treatments also caused a reduction of required potent doses thereby minimizing the toxicity of jerantinines (A and B) towards the non-cancerous MRC5 cells. In conclusion, this research has presented valuable combined treatment candidates which are warranted for further investigations as future chemotherapeutic agents against cancers

In vitro investigation on synergistic anticancer effects between vitamin E isomers, pure compounds and crude alkaloid plant extracts on human cancerous cells

Anticancer chemotherapeutic treatment using single dose has been limited due to drug resistance and potential metabolic degradation. For instance, high-dose tocotrienols undergo metabolic degradation that limits the availability of therapeutic dose thereby limiting the potency in vivo. Combined treatment of tocotrienols at low dosage has been suggested as alternative to circumventing this limitation. This study was designed to investigate the cytotoxic effects and subsequently the apoptotic mechanisms of individual doses and combined treatments at lower dosages of tocotrienols (delta and gamma), jerantinines (A and B) and extracts (ethanol and alkaloid crude) from leaves and bark of Ficus hispida, Ficus fistulosa and Ficus schwarzii on lung (A549), brain (U87MG) and colon (HT-29) cancer cell lines. Neutral red uptake assay was conducted to evaluate the antiproliferative effect of individual and combined treatments. Staining techniques (histochemical and fluorescence), COMET assay flow cytometric analysis and immunofluorescence were conducted to evaluate cell morphology, DNA damage, cell cycle arrest pattern and antimicrotubule effects. Finally cell and molecular based assays were conducted to investigate the pathways for induction of apoptosis. Cell viability study revealed that alkaloid crude extracts of leaves and bark of F. fistulosa demonstrated the highest potency with IC50 range of 0.96 – 46.81 µg/ml compared to F. schwarzii (8.79 – 107.9 µg/ml) and F. hispida (15.14 – 49.58 µg/ml) on A549, U87MG and HT-29 cells. Both delta- and gamma-tocotrienols induced antiproliferative effects on A549, U87MG and HT-29 cells with IC50 values of 3.12 - 12.40 µg/ml and 3.17 – 16.36 µg/ml, respectively. Potent antiproliferative effects were also evident for jerantinine A (IC50 0.62 – 1.74 µg/ml), jerantinine B (IC50 0.58 – 1.48 µg/ml) and vinblastine (IC50 0.03 – 0.71 µg/ml). However, similar toxic effects on these three compounds were also evident on non-cancerous lung fibroblast (MRC5) cells. The leaf and bark alkaloid crude extracts of F. fistulosa and F. schwarzii were selected for combined treatments. The combined treatment of IC20 doses of F. fistulosa with both delta- and gamma-tocotrienols induced synergistic antiproliferative effects (combination index (CI) 1) were observed for IC20 doses of F. schwarzii extracts combined with delta- and gamma-tocotrienols on HT-29 cells. On the other hand, combined treatments of tocotrienols (delta and gamma) with IC20 doses of jerantinines (A and B) induced synergistic effects (CI < 1) on A549, U87MG and HT-29 cells causing up to 4.48-fold dose reduction of tocotrienols thus reducing toxicity towards MRC5 cells compared to cancer cells. Further morphological and DNA damage assessment focusing on tocotrienols (delta and gamma), jerantinines (A and B) and combined low-dose treatments revealed anticancer features including cell shrinkage, nuclear chromatin condensation and fragmentation, membrane blebbing, apoptotic bodies and induction of predominantly double stranded DNA breaks. Cell cycle analysis demonstrated the induction of G0/G1 and G2/M cell cycle arrests by tocotrienols (delta and gamma) and jerantinines (A and B), respectively on U87MG, A549 and HT-29 cells. Meanwhile, G2/M (A549) and G0/G1 (U87MG and HT-29) cell cycle arrests were evident for combined low-dose treatments of tocotrienols (delta and gamma) with IC20 doses of jerantinines (A and B). Jerantinines A and B and combined low-dose treatments with tocotrienols (delta and gamma) caused disruption of microtubule networks and induction of caspase 8-, 9- and 3-mediated apoptosis with caspase-independent growth inhibition evidenced in the presence of caspase inhibitors on U87MG, A549 and HT-29 cells. In contrast, although treatments of tocotrienols (delta and gamma) alone caused similar apoptotic features as those of combined, disruption of microtubule networks were not characterized on these three cancer cell lines. Further mechanistic study on U87MG cells revealed that the apoptosis triggered by individual doses of tocotrienols (delta and gamma) involved the activation of TRAIL and Bid as well as the release of cytochrome C, thus confirming the recruitment of the death receptor and mitochondria-mediated pathways. On the other hand, individual doses of jerantinines (A and B) and combined low-dose treatments with tocotrienols resulted in the activation of TRAIL, FAS, p53 and Bid, as well as the release of cytochrome C. The activation of both death receptors, p53 and microtubule disruption by combined low-dose treatments demonstrates an improved mechanism of action comparing to individual doses of tocotrienols and jerantinines. In addition, the combined low-dose treatments also caused a reduction of required potent doses thereby minimizing the toxicity of jerantinines (A and B) towards the non-cancerous MRC5 cells. In conclusion, this research has presented valuable combined treatment candidates which are warranted for further investigations as future chemotherapeutic agents against cancers

Knowledge and Perception of Alcohol Abuse as a Risk Factor of Non-Communicable Diseases among Undergraduate Students in Lead City University

Low- and middle-income countries are experiencing a transition from a preponderance of infectious to Non-Communicable Diseases (NCDs). Many of the behaviour’s that produce these risks often commence in late adolescence. The study assessed knowledge and perception of alcohol abuse as a risk factor for NCDs among undergraduate students in Lead City University Ibadan, Oyo state. This was a cross-sectional study using a systematic random sampling technique. Data were collected using the semi-structured interviewer-administered questionnaire and were entered and analysed using SPSS version 21. Data were analysed with descriptive statistics such as frequency tables and percentages, and a Chi-square test at p &lt;0.05 were used to determine the level of association between two different variables. Of 216 undergraduates, 132 (61.1%) were male and 103 (47.7%) were aged 26 years and above; the mean age was 22.4 (+/-8.437) years; 139 (64.4%) were singles. Only 69.9% of the respondents were current drink containing alcohol with 84.4 % classified as having excess alcohol use. Moreover, 79.6% were classified as having good knowledge toward NCDs. The most prominent influence sources of alcohol intake reported by the students were friends. it was revealed in this study that knowledge of alcohol as a risk factor for NCDs was found to be statistically significant with perception of alcohol abuse of the respondents. These findings highlight the need of developing school-based health awareness and promotion programs in Lead city University. The findings of this study will serve as the baseline data to develop new programs and to evaluate existing programs (if any), as limited data are available related to the implementation of NCDs prevention efforts in Lead city University

Potentiation of in vitro apoptotic effects of δ-Tocotrienol and Jerantinine A on human lung adenocarcinoma cells

Introduction: The apoptotic effects of single-compound and combined sub-effective concentrations of δ-tocotrienol and jerantinine A on human lung adenocarcinoma (A549) cells were investigated. Methods: Assays including cell viability, histochemical and immunofluorescence staining techniques, flow cytometry and enzyme activity were used. Results: The combination of δ-tocotrienol with jerantinine A at sub-effective concentrations induced a synergistic effect and improved selective toxicity towards cancerous A549 cells over normal lung fibroblast (MRC5) cells compared to the single-compound jerantinine. Morphological features of apoptosis were evident on treated A549 cells. Combined sub-effective concentrations of δ-tocotrienol with jerantinine A induced a predominantly G2/M cell cycle arrest and characterised by a disruption of microtubular networks mediated via caspase 8, 9 and 3 enzymatic activities. Conclusion: These findings demonstrated improved potency in vitro and reduced dose-related toxicity of jerantinine A to normal cells through prospective combined treatment between low-concentration δ-tocotrienol and jerantinine A for lung cancer

Product Innovation and Sales Growth; A Study of Monas Table Water Company Gombe

&lt;p&gt;This paper assessed the effect of product innovation on sales growth of Monas table water company Gombe. The study utilized different related literatures sourced from current journal articles, text books, and previous researches of scholars that are related to the study. The finding revealed the positive effect. The study draw it conclusion based on the comprehensive overview of the phenomenon and consider the implications of logistics of reviewed related literatures, The study recommend that Companies should always innovate their products in order to attract more customers which will bring about increase in sales. Relaying on olden means of advertisement may also decrease the rate of sales in the company, because some customers are digital in nature.&nbsp;&lt;br&gt;&nbsp;&lt;/p&gt

Alkaloid extracts of <i>Ficus</i> species and palm oil-derived tocotrienols synergistically inhibit proliferation of human cancer cells

<div><p>Tocotrienols have been reported to possess anticancer effects other than anti-inflammatory and antioxidant activities. This study explored the potential synergism of antiproliferative effects induced by individual alkaloid extracts of <i>Ficus fistulosa</i>, <i>Ficus hispida</i> and <i>Ficus schwarzii</i> combined with δ- and γ-tocotrienols against human brain glioblastoma (U87MG), lung adenocarcinoma (A549) and colorectal adenocarcinoma (HT-29) cells. Cell viability and morphological results demonstrated that extracts containing a mixture of alkaloids from the leaves and bark of <i>F. schwarzii</i> inhibited the proliferation of HT-29 cells, whereas the alkaloid extracts of <i>F. fistulosa</i> inhibited the proliferation of both U87MG and HT-29 cells and showed synergism in combined treatments with either δ- or γ-tocotrienol resulting in 2.2–34.7 fold of reduction in IC₅₀ values of tocotrienols. The observed apoptotic cell characteristics in conjunction with the synergistic antiproliferative effects of <i>Ficus</i> species-derived alkaloids and tocotrienols assuredly warrant future investigations towards the development of a value-added chemotherapeutic regimen against cancers.</p></div

Jerantinine B Enhances the Mitochondria-Mediated Apoptosis by p53 Activation in Human Glioblastoma Cells via a Combination with δ-Tocotrienol

Combined treatment using tocotrienols at low dosage with chemotherapeutic agents has been suggested as an alternative to circumvent the single high-dose associated metabolic degradation and non-selective toxicity of the bioactive compounds. A synergism of combined δ-tocotrienol and jerantinine B in killing brain cancer (U87MG) cells that could potentially be mediated via mitochondrial and death receptor pathways has been demonstrated previously. Therefore, the present study was conducted to explore the mitochondrial pathway for the apoptosis induction in U87MG cells via the combination of δ-tocotrienol and jerantinine B at low concentrations. Individual δ-tocotrienol and combined (δ-tocotrienol and jerantinine B) treatments induced G0/G1, whereas, IC 50 of jerantinine B induced G2/M cell cycle arrests in U87MG cells. This was mediated via the activation of Bid, Bax and cytochrome c activities. Interestingly, only the individual jerantinine B and combined treatments induced p53 activation. These findings suggest that the combined treatment mediates an apoptosis via the mitochondrial pathway potentiated by p53 activation and may rationalize a better treatment for brain cancer in the future

Potential benefits and challenges on the use of phytochemicals for obese COVID-19 patients: A review

Background: COVID-19 produces a great burden on obese individuals. Due to the age-long use of medicinal herbs in the management of obesity, their potential against the COVID-19 pandemic is increasingly investigated. This study aims to review phytochemicals or bioactive compounds with the potential of being useful for obese COVID-19 patients. Methods: Using search terms that include pairwise combinations of either COVID-19 or obesity with each of nine selected phytochemicals (epigallocatechin gallate, rutin, astaxanthin, resveratrol, genistein, curcumin, quercetin, ellagic acid, and hesperidin). Relevant articles published from January 2009 to August 2023 were retrieved from PubMed. Results: A total of 43 papers (17 clinical trials, 12 preclinical studies, 3 systemic reviews of randomized controlled trials, and 11 other review papers) met the inclusion criteria and were discussed in this review. These include research articles reporting the anti-COVID-19 properties of the selected phytochemicals, which have previous or recent “clinical evidence” against overweight or obesity Conclusion: Phenolic compounds make up to eight out of the nine selected bioactive compounds and are, therefore, concluded to be the best class of phytochemicals for managing obese COVID-19 patients