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Reactive oxygen species (ROS) in biological systems are transient but essential molecules that are generated and eliminated by a complex set of delicately balanced molecular machineries. Disruption of redox homeostasis has been associated with various human diseases, especially cancer, in which increased ROS levels are thought to have a major role in tumour development and progression. As such, modulation of cellular redox status by targeting ROS and their regulatory machineries is considered a promising therapeutic strategy for cancer treatment. Recently, there has been major progress in this field, including the discovery of novel redox signalling pathways that affect the metabolism of tumour cells as well as immune cells in the tumour microenvironment, and the intriguing ROS regulation of biomolecular phase separation. Progress has also been made in exploring redox regulation in cancer stem cells, the role of ROS in determining cell fate and new anticancer agents that target ROS. This Review discusses these research developments and their implications for cancer therapy and drug discovery, as well as emerging concepts, paradoxes and future perspectives.Reactive oxygen species are essential molecules that are generated and eliminated through complex balanced mechanisms. Increased reactive oxygen species levels have a role in tumour development, and targeting reactive oxygen species and their regulatory machineries is a promising therapeutic strategy. This Review discusses recent research developments in the field, their implications for cancer drug discovery, as well as emerging concepts and future perspectives.

Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.

Bergaptol (5-hydroxypsoralen or 5-hydroxyfuranocoumarin) is a naturally occurring furanocoumarin widely found in citrus fruits, which has multiple health benefits. Nonetheless, no specific review articles on bergaptol have been published. Compiling updated information on bergaptol is crucial in guiding future research direction and application. The present review focuses on the research evidence related to the pharmacological properties and toxicity of bergaptol. Bergaptol has anti-inflammatory, antioxidant, anti-cancer, anti-osteoporosis, anti-microbial, and anti-lipidemic effects. It can inhibit the activities of cytochrome P450s (CYP), especially CYP2C9 and CYP3A4, thereby affecting the metabolism and concentrations of some drugs and toxins. Compared with other coumarins, bergaptol has the least potency to inhibit CYP3A4 in cancer cells. Instead, it can suppress drug efflux transporters, such as P-glycoprotein, thereby overcoming chemotherapeutic drug resistance. Furthermore, bergaptol has antimicrobial effects with a high potential for inhibition of quorum sensing. In vivo, bergaptol can be retained in plasma for longer than other coumarins. Nevertheless, its toxicity has not been clearly reported. In vitro study suggests that, unlike most furocoumarins, bergaptol is not phototoxic or photomutagenic. Existing research on bergaptol has mostly been conducted in vitro. Further in vivo and clinical studies are warranted to identify the safe and effective doses of bergaptol for its multimodal application.

Key Points The effectiveness of current gene-targeting therapeutic strategies is limited by the drug resistance and the genomic instability that cancer cells acquire. Most cancer cells exhibit increased aerobic glycolysis and oxidative stress — features that could be important in the development new anticancer strategies. An increase in reactive oxygen species (ROS) is associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis, due either to an elevation of ROS production or to a decline of ROS-scavenging capacity. If the increase of ROS reaches a certain threshold level that is incompatible with cellular survival, ROS may exert a cytotoxic effect, leading to the death of malignant cells and thus limiting cancer progression. However, under persistent intrinsic oxidative stress, many cancer cells become well-adapted to such stress and develop an enhanced, endogenous antioxidant capacity. Abrogation of this adaptation mechanism with 'pro-oxidant' agents could be an attractive strategy to preferentially affect cancer cells and could have significant therapeutic implications. Because radiation and many conventional cytotoxic anticancer drugs can also directly or indirectly increase ROS levels in cancer cells, combination of radiotherapy or standard chemotherapy with agents that abrogate antioxidant systems in cancer cells should also be explored. Finally, the undefined, possibly unique, redox biology of cancer stem cells suggests that redox-modulating strategies could represent an effective strategy to combat this highly drug-resistant population of cells. Drug resistance and the genomic instability of cancer cells hamper current gene-targeting therapeutic strategies for cancer. As Huang and colleagues discuss, targeting the unique biochemical properties of cancer cells — in particular, increased oxidative stress — might represent an alternative approach for the development of selective, redox-modulating anticancer agents. Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

Green extraction is aimed at reducing energy consumption by using renewable plant sources and environmentally friendly bio-solvents. Lime (Citrus aurantifolia) is a rich source of flavonoids (e.g., hesperidin) and limonoids (e.g., limonin). Manufacturing of lime products (e.g., lime juice) yields a considerable amount of lime peel as food waste that should be comprehensively exploited. The aim of this study was to develop a green and simple extraction method to acquire the highest yield of both limonin and hesperidin from the lime peel. The study method included ethanolic-aqueous extraction and variable factors, i.e., ethanol concentrations, pH values of solvent, and extraction temperature. The response surface methodology was used to optimize extraction conditions. The concentrations of limonin and hesperidin were determined by using UHPLC-MS/MS. Results showed that the yields of limonin and hesperidin significantly depended on ethanol concentrations and extraction temperature, while pH value had the least effect. The optimal extraction condition with the highest amounts of limonin and hesperidin was 80% ethanol at pH 7, 50 °C, which yields 2.072 and 3.353 mg/g of limonin and hesperidin, respectively. This study illustrates a green extraction process using food waste, e.g., lime peel, as an energy-saving source and ethanol as a bio-solvent to achieve the highest amount of double bioactive compounds.

Lime peels are food waste from lime product manufacturing. We previously developed and optimized a green extraction method for hesperidin-limonin-rich lime peel extract. This study aimed to identify the metabolomics profile of phytochemicals and the anti-cancer effects of ethanolic extract of lime (Citrus aurantifolia) peel against liver cancer cells PLC/PRF/5. The extract’s metabolomics profile was analyzed by using LC-qTOF/MS and GC-HRMS. The anti-cancer effects were studied by using MTT assay, Annexin-PI assay, and Transwell-invasion assay. Results show that the average IC50(s) of hesperidin, limonin, and the extract on cancer cells’ viability were 165.615, 188.073, and 503.004 µg/mL, respectively. At the IC50 levels, the extract induced more apoptosis than those of pure compounds when incubating for 24 and 48 h (p < 0.0001). A combination of limonin and hesperidin showed a synergistic effect on apoptosis induction (p < 0.001), but the effect of the combination was still less than that of the extract at 48 h. Furthermore, the extract significantly inhibited cancer cell invasion better than limonin but equal to hesperidin. At the IC50 level, the extract contains many folds lower amounts of hesperidin and limonin than the IC50 doses of the pure compounds. Besides limonin and hesperidin, there were another 60 and 22 compounds detected from the LCMS and GCMS analyses, respectively. Taken altogether, the superior effect of the ethanolic extract against liver cancer cells compared to pure compound likely results from the combinatorial effects of limonin, hesperidin, and other phytochemical components in the extract.

Alzheimer’s disease (AD), one type of dementia, is a complex disease affecting people globally with limited drug treatment. Thus, natural products are currently of interest as promising candidates because of their cost-effectiveness and multi-target abilities. Diplazium esculentum (Retz.) Sw., an edible fern, inhibited acetylcholinesterase in vitro , inferring that it might be a promising candidate for AD treatment by supporting cholinergic neurons. However, evidence demonstrating anti-AD properties of this edible plant via inhibiting of neurotoxic peptides production, amyloid beta (Aβ), both in vitro and in vivo is lacking. Thus, the anti-AD properties of D. esculentum extract both in vitro and in Drosophila models of Aβ-mediated toxicity were elucidated. Findings showed that an ethanolic extract exhibited high phenolics and flavonoids, contributing to antioxidant and inhibitory activities against AD-related enzymes. Notably, the extract acted as a BACE-1 blocker and reduced amyloid beta 42 (Aβ42) peptides in Drosophila models, resulting in improved locomotor behaviors. Information gained from this study suggested that D. esculentum showed potential for AD amelioration and prevention. Further investigations in vertebrates or humans are required to determine the effective doses of D. esculentum against AD, particularly via amyloidogenic pathway.

Purpose The aim of this study is to investigate the effect of an edible saliva substitute, oral moisturizing jelly (OMJ), and a topical saliva gel (GC) on dry mouth, swallowing ability, and nutritional status in post-radiotherapy head and neck cancer patients. Methods Sixty-two post-radiation head and neck cancer patients with xerostomia completed a blinded randomized controlled trial. They were advised to swallow OMJ ( n = 31) or apply GC orally ( n = 31) for 2 months. Outcome measures were assessed at baseline, 1, and 2 months, including subjective and objective dry mouth (Challcombe) scores, subjective swallowing problem scores (EAT-10), water swallowing time, clinical nutritional status (PG-SGA), body weight, and dietary intake. Results After 1 and 2 months of interventions, subjective and objective dry mouth scores, subjective swallowing problem scores, swallowing times, and clinical nutritional status in both groups were significantly improved ( p < 0.0001). Compared to GC, OMJ group had higher percent improvement in all outcome measures ( p < 0.001) except swallowing time and clinical nutritional status. Interestingly, subjective dry mouth scores were significantly correlated with subjective swallowing problem scores ( r = 0.5321, p < 0.0001). Conclusions Continuous uses of saliva substitutes (OMJ or GC) for at least a month improved signs and symptoms of dry mouth and enhanced swallowing ability. An edible saliva substitute was superior to a topical saliva gel for alleviating dry mouth and swallow problems. These lead to improved clinical nutritional status. Thus, palliation of dry mouth may be critical to support nutrition of post-radiotherapy head and neck cancer patients. Clinical trial registry Clinicaltrials.gov NCT03035825

Objective To evaluate the efficacy of an edible artificial saliva gel, oral moisturizing jelly (OMJ), and a topical commercial gel (GC dry mouth gel) on Candida colonization and saliva properties. Materials and methods This study was a secondary analysis of a single-blinded randomized controlled trial conducted in xerostomic post-radiotherapy head and neck cancer patients. Candida colonization, stimulated salivary flow rate (SSFR), saliva pH, and buffering capacity (BC) were measured at 0, 1, and 2 months after each intervention. Candida colonization was quantified by colony counts and species identified by Candida Chromagar, polymerase chain reaction, and API 20C AUX system. Statistical significance level was 0.05. Results A total of 56 participants in OMJ ( N  = 30) and GC ( N  = 26) groups completed the study. OMJ significantly increased saliva pH ( p  = 0.042) and BC ( p  = 0.013) after 1-month use, while GC only improved saliva pH ( p  = 0.027). Both interventions tended to increase SSFR but only GC had a significant increase at 2 months ( p  = 0.015). GC and OMJ significantly decreased the number of Candida species at 1 and 2 months, respectively. Both groups tended to reduce Candida counts but not significant. Conclusions Both OMJ and GC saliva gels could improve saliva pH and decrease the number of Candida species. OMJ is superior to GC in its buffering capacity, while GC may better improve salivary flow rate. Long-term and large-scale study is warranted to test the efficacy of artificial saliva in oral health improvement. Clinical relevance OMJ and GC gel could decrease the number of Candida species and improve saliva properties in post-radiation xerostomic patients. Trial registration number Clinicaltrials.gov NCT03035825. Date of registration: 25th January 2017.

Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-ras G12V causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-ras G12V expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo . Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-ras G12V causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.