The landscape of potential health benefits of carotenoids as natural supportive therapeutics in protecting against Coronavirus infection.

The Coronavirus Disease-2019 (COVID-19) pandemic urges researching possibilities for prevention and management of the effects of the virus. Carotenoids are natural phytochemicals of anti-oxidant, anti-inflammatory and immunomodulatory properties and may exert potential in aiding in combatting the pandemic. This review presents the direct and indirect evidence of the health benefits of carotenoids and derivatives based on in vitro and in vivo studies, human clinical trials and epidemiological studies and proposes possible mechanisms of action via which carotenoids may have the capacity to protect against COVID-19 effects. The current evidence provides a rationale for considering carotenoids as natural supportive nutrients via antioxidant activities, including scavenging lipid-soluble radicals, reducing hypoxia-associated superoxide by activating antioxidant enzymes, or suppressing enzymes that produce reactive oxygen species (ROS). Carotenoids may regulate COVID-19 induced over-production of pro-inflammatory cytokines, chemokines, pro-inflammatory enzymes and adhesion molecules by nuclear factor kappa B (NF-κB), renin-angiotensin-aldosterone system (RAS) and interleukins-6- Janus kinase-signal transducer and activator of transcription (IL-6-JAK/STAT) pathways and suppress the polarization of pro-inflammatory M1 macrophage. Moreover, carotenoids may modulate the peroxisome proliferator-activated receptors γ by acting as agonists to alleviate COVID-19 symptoms. They also may potentially block the cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human angiotensin-converting enzyme 2 (ACE2). These activities may reduce the severity of COVID-19 and flu-like diseases. Thus, carotenoid supplementation may aid in combatting the pandemic, as well as seasonal flu. However, further in vitro, in vivo and in particular long-term clinical trials in COVID-19 patients are needed to evaluate this hypothesis.

Bioavailability of Orally Administered Active Lipid Compounds from four Different Greenshell™ Mussel Formats.

Greenshell™ mussel (GSM, Perna canaliculus) is New Zealand's most important aquaculture species. They are a good source of long chain-polyunsaturated fatty acids (n-3 LC PUFA). Beyond a traditional food product, GSMs are also sold as mussel powders and oil extract formats in the nutraceutical markets. In this study, a four-sequence, single dose, randomized crossover human trial with eight evaluable healthy male participants was undertaken to determine the bioavailability of the n-3 LC PUFA in four different GSM formats (oil, powder, food ingredient and half-shell unprocessed whole mussel) by measuring area under the curve (AUC) and maximal concentration (CMax). Blood samples were collected at baseline and up to 48 h after initiation of product consumption in each administration period. There were minor differences between the bioavailability of FA (fatty acid) between the different GSM formats. Eicosapentaenoic acid (EPA) peak concentrations and plasma exposures were significantly lower with GSM oil compared to GSM half-shell and GSM powder formats, which resulted in AUC0-48 for the intake of GSM half-shell mussel and GSM powder being significantly higher than that for GSM oil (p = 0.013, f= 4.84). This equated to a 20.6% and 24.3% increase in the amount of EPA present in the plasma after consumption of half-shell mussels and mussel powder respectively compared to GSM oil. GSM oil produced the shortest median time to maximal plasma n-3 LC PUFA concentration of all evaluated products demonstrated by a shorter maximum measured plasma concentration (TMax = 5 h). Docosahexaenoic acid (DHA) and n-3 LC PUFA plasma exposure parameters were statistically comparable across the four GSM products evaluated.

Greenshell™ Mussels: A Review of Veterinary Trials and Future Research Directions.

The therapeutic benefits of Greenshell™ mussel (GSM; Perna canaliculus) preparations have been studied using in vitro test systems, animal models, and human clinical trials focusing mainly on anti-inflammatory and anti-arthritic effects. Activity is thought to be linked to key active ingredients that include omega-3 polyunsaturated fatty acids, a variety of carotenoids and other bioactive compounds. In this paper, we review the studies that have been undertaken in dogs, cats, and horses, and outline new research directions in shellfish breeding and high-value nutrition research programmes targeted at enhancing the efficacy of mussel and algal extracts. The addition of GSM to animal diets has alleviated feline degenerative joint disease and arthritis symptoms, and chronic orthopaedic pain in dogs. In horses, GSM extracts decreased the severity of lameness and joint pain and provided improved joint flexion in limbs with lameness attributed to osteoarthritis. Future research in this area should focus on elucidating the key active ingredients in order to link concentrations of these active ingredients with their pharmacokinetics and therapeutic effects. This would enable consistent and improved efficacy from GSM-based products for the purpose of improved animal health.

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.

Bridging disciplines, knowledge systems and cultures in pest management.

The success of research in integrated environmental and natural resource management relies on the participation and involvement of different disciplines and stakeholders. This can be difficult to achieve in practice because many initiatives fail to address the underlying social processes required for successful engagement and social learning. We used an action research approach to support a research-based group with a range of disciplinary and stakeholder expertise to critically reflect on their engagement practice and identify lessons around how to collaborate more effectively. This approach is provided here as a guide that can be used to support reflective research practice for engagement in other integration-based initiatives. This paper is set in the context of an integrated wildlife management research case study in New Zealand. We illustrate how multi-, inter- and trans-disciplinary approaches can provide a framework for considering the different conversations that need to occur in an integrated research program. We then outline rubrics that list the criteria required in inter- and trans-disciplinary collaborations, along with examples of effective engagement processes that directly support integration through such efforts. Finally, we discuss the implications of these experiences for other researchers and managers seeking to improve engagement and collaboration in integrated science, management and policy initiatives. Our experiences reaffirm the need for those involved in integrative initiatives to attend to the processes of engagement in both formal and informal settings, to provide opportunities for critical reflective practice, and to look for measures of success that acknowledge the importance of effective social process.

Innovative developments for long-term mammalian pest control.

BACKGROUND: Invasive mammalian pests have inflicted substantial environmental and economic damage on a worldwide scale. RESULTS: Over the last 30 years there has been minimal innovation in the development of new control tools. The development of new vertebrate pesticides, for example, has been largely restricted due to the costly and time-consuming processes associated with testing and registration. CONCLUSION: In this article we discuss recent progress and trends in a number of areas of research aimed to achieve long-term population suppression or eradication of mammalian pest species. The examples discussed here are emerging from research being conducted in New Zealand, where invasive mammalian pests are one of the greatest threats facing the national environment and economy.

Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.

A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.

Development of a new humane toxin for predator control in New Zealand.

The endemic fauna of New Zealand evolved in the absence of mammalian predators and their introduction has been responsible for many extinctions and declines. Introduced species including possums (Trichosurus vulpecula Kerr), ship rats (Rattus rattus L.) and stoats (Mustela erminea L.) are targeted to protect native birds. Control methodologies currently rely largely on labor-intensive trapping or the use of increasingly unpopular poisons, or poisons that are linked with low welfare standards. Hence, the development of safer humane predator toxins and delivery systems is highly desirable. Para-aminopropiophenone (PAPP) is being developed as a toxin for feral cats (Felis catus L.) and stoats. Carnivores appear to be much more susceptible to PAPP than birds, so it potentially has high target specificity, at least in New Zealand. Pen trials with 20 feral cats and 15 stoats have been undertaken using meat baits containing a proprietary formulation of PAPP. A PAPP dose of 20-34 mg kg(-1) was lethal for feral cats and 37-95 mg kg(-1) was lethal for stoats. Our assessments suggest that PAPP, for the control of feral cats and stoats, is a humane and effective toxin. PAPP causes methaemoglobinaemia, resulting in central nervous system anoxia, lethargy and death.

Vertebrate pesticide risk assessment by indigenous communities in New Zealand.

In New Zealand, the vertebrate pesticide sodium fluoroacetate (Compound 1080) is aerially applied in baits for control of the brush-tailed possum Trichosurus vulpecula (Kerr, 1792). Maori, the indigenous people of New Zealand, have raised concerns about 1080 impacts on culturally-important species. Here, we outline two steps taken to help Maori assess 1080 risk. First, field research was undertaken to determine if naturally-occurring plants utilized by a Maori community for food and medicine would take up 1080 from baits. Single baits were placed at the base of individual plants of two species, pikopiko (Asplenium bulbiferum) and karamuramu (Coprosma robusta). Plants were sampled at various times up to 56 days, and samples were analyzed for 1080 content. No 1080 was detected in any of the pikopiko samples, whereas 1080 was detected in karamuramu, at a maximum concentration of 5 ppb after seven days, and 2.5 ppb after 14 days. This concentration decreased to 0 at 28 days, indicating that 1080 was not persistent. The results of the present study suggest there is negligible risk of humans being poisoned by consuming plants that have taken up 1080 from baits. To allay community concerns that minute concentrations of 1080 might influence the medicinal properties of plants, it is suggested that a withholding period of 30 days after 1080 control operations could be adopted. Second, after further consultation we undertook a review of the scientific literature relating to 1080 impacts on additional non-target species of cultural importance to Maori. The information was presented on an interactive foodweb database that allowed the collection and presentation of a large volume of complex information about 1080 in a holistic and pictorial fashion. This database was presented to many Maori communities throughout New Zealand, and feedback was overwhelmingly positive. The database is likely to play a key role in informing these communities about 1080, and is seen as an important new tool to help these communities make their own risk assessments.

Sodium fluoroacetate (1080): assessment of occupational exposures and selection of a provisional biological exposure index.

AIM: Sodium fluoroacetate (1080) is used for control of vertebrate pests in New Zealand. Little is known about chronic effects in humans, but animal studies demonstrate potential for adverse fetal, male fertility, and cardiac effects. We aimed to employ analyses of 1080 to help assess the degree of exposure of bait formulators and distributors, and identify specific tasks where exposure reduction appeared most indicated. We also aimed to utilise the (limited) 1080 toxicity data to assess the significance of the analytical results. METHOD: Exposures during various activities were assessed by monitoring air levels and blood and urine concentrations. To help evaluate the results, a provisional "biological exposure index" (BEI) was later derived, by extrapolating from experimental data. RESULTS: Early monitoring indicated exposures were highest in relation to (cereal) bait manufacturing and aerial carrot baiting procedures. A provisional BEI of 15 microg/L for 1080 in urine was proposed. CONCLUSION: Further protective measures and ongoing workplace monitoring are required, particularly in the above situations. Compliance with the current BEI cannot guarantee complete safety. Any information regarding chronic adverse effects in humans, along with the associated urine levels, would assist risk assessment. Further investigation of the human kinetics of fluoroacetate would be helpful.

Biomarkers in toxicology versus ecological risk assessment.

Toxicity testing of drugs, pesticides, and hazardous compounds has evolved into a battery of standardized tests conducted in a range of surrogate test organisms. The toxicity of these xenobiotics in terms of their LD(50) and LC(50) (Dose or concentration lethal to 50% of the test population), ED(50) and EC(50) (Dose or concentration producing a specified response in 50% of the test population), MATC (Maximum acceptable toxicant concentration), LOEL (Lowest observable effects level), LOEC (Lowest observable effects concentration), NOEL (No observable effects level) or NOEC (No observable effects concentration) is extrapolated to humans and wildlife. Historical failures in the risk assessment process have been largely due to over reliance on regulatory toxicology and an 'assembly line' mentality to toxicology. The importance of toxicokinetics, receptor studies and biomarkers are reviewed, firstly, with reference to toxicological incidences in drug development programmes, and secondly, with reference to improved environmental risk assessment of pesticides and other contaminants. Ecological risk assessments also require multidisciplinary skills to study the entry, distribution, and biological effect and fate of chemicals to fully characterise and understand the potential adverse implications of contamination. Optimum integration of chemical measurements and biomarker responses is a challenge that will lead to an improved understanding of adverse effects and their significance in both human and ecological risk assessment.

Sodium monofluoroacetate (1080) risk assessment and risk communication.

Sodium monofluoroacetate (1080) is a vertebrate pesticide widely used for possum control in New Zealand. Fluoroacetate is also a toxic component of poisonous plants found in Australia, South Africa, South America, and India. Because of its importance and effectiveness in pest control and the highly toxic nature of this compound, its acute sub-lethal and target organ toxicity have been extensively studied. In relation to its use as a pesticide its environmental fate, persistence, non-target impacts and general toxicology have been and continue to be extensively studied. Toxic baits must be prepared and used with extreme care, otherwise humans, livestock, and non-target wildlife will be put at risk. The high risk of secondary poisoning of dogs is a cause for concern. 1080 acts by interfering with cellular energy production. Possums die from heart failure, usually within 6-18 h of eating baits. Long-term exposure to sub-lethal doses can have harmful effects and strict safety precautions are enforced to protect contractors and workers in the bait manufacturing industry. Considerable care is taken when using 1080 to ensure that the risks of using it are outweighed by the ecological benefits achieved from its use. When its use is controversial, risk communicators must take care not to trivialise the toxicity of the compound. The benefits of 1080 use in conservation, pest control, and disease control should be weighed up alongside the risks of using 1080 and other techniques for pest control.

A 90-day toxicological evaluation of Compound 1080 (sodium monofluoroacetate) in Sprague-Dawley rats.

Groups of Sprague-Dawley rats received sodium monofluoroacetate (Compound 1080) at 0.025, 0.075, and 0.25 mg/kg by oral gavage once daily for 90 days and were then euthanized. The control and 0.25 mg/kg/day groups included additional rats of each sex that were treated for 90 days, then maintained without treatment for a further 56-day recovery period. Microscopic changes were restricted to the testes and the heart, and were seen only in males dosed with 1080 at 0.25 mg/kg/day and included severe hypospermia in the epididymides, severe degeneration of the seminiferous tubules of the testes, and cardiomyopathy. Sperm evaluation indicated severe decreases in all three sperm parameters evaluated (concentration, % motile, and % abnormal) at 0.25 mg/kg/day. There were no microscopic changes or 1080-related effects on sperm parameters at 0.025 and 0.075 mg/kg/day. The no observable effects level (NOEL) for rats administered 1080 via oral gavage for 90 days was 0.075 mg/kg/day. The lowest observable effects level (LOEL) dose was 0.25 mg/kg/day. After dosing with the LOEL dose of 0.25 mg/kg/day, mean concentrations of 1080 in rat plasma were 0.26 micro g/ml at 1 h and 0.076 microg/ml at 12 h. Rat urine collected from the same animals contained 0.059 microg/ml.

Assessment of risks of brodifacoum to non-target birds and mammals in New Zealand.

The risks to non-target birds and other wildlife from the use of vertebrate pesticides, including anticoagulant rodenticides, are determined to a significant extent by species' intrinsic susceptibility, and the toxicokinetics of the compounds used. Brodifacoum is highly toxic to birds and mammals. The acute toxicity of brodifacoum to birds in New Zealand varies from <1 mg/kg in pukeko (Porphyrio p. melanotus), the native swamp hen, to >20 mg/kg in the paradise shelduck (Tadorna variegata). Like other second-generation anticoagulants brodifacoum is strongly bound to vitamin K epoxide reductase and will persist, apparently for at least 6 months, in organs and tissue containing this enzyme, e.g., liver, kidney, and pancreas. The unique toxicokinetics of this class of compound exacerbates the risk of primary and secondary poisoning of non-target species. Vertebrate pest control programmes in New Zealand using bait containing brodifacoum have resulted in the primary and secondary poisoning and sub-lethal contamination of non-target species. These include native raptors, such as the Australasian harrier (Circus approximans) and morepork (Ninox novaeseelandiae), other native birds such as the pukeko, weka (Gallirallus australis), southern black-backed gull (Larus dominicanus), and kiwi (Apteryx spp.), and introduced mammals, including game animals. There are increasing numbers of reports worldwide of wildlife contamination and toxicosis after the use of second-generation anticoagulants. All pest control activities require careful risk-benefit assessment in view of their potential to cause adverse environmental impact. Monitoring of wildlife for pesticide residues will provide data that can be used to reduce the risk of anticoagulant bioaccumulation and mortality in non-target species.