Hormetic Effects of Reactive Oxygen Species by Exercise: A View from Animal Studies for Successful Aging in Human

Numerous anti-aging measures have been proposed to cope with age-associated decline of physiological functions and/or onset of diseases, mostly based on free radical (or oxidative stress) theory of aging, though no robust scientific data have been reported to extend human healthspan. This is due to dual (harmful as well as essential) roles of reactive oxygen species (ROS) to a body. Regular moderate exercise provides benefits upregulating defense against oxidative stress in good balance between the opposing dual roles. Sources of ROS in exercise appear to be not only mitochondria as often claimed but also enzymatic reactions catalyzed by NADPH oxidase and other oxidases. It may, therefore, be possible to mimic this aspect of exercise to promote the defense for healthspan extension by other means such as modest alcohol consumption that could upregulate activity of enzymes against oxidative stress.     

Exercise-Induced Hormesis May Help Healthy Aging

Hormesis plays a critical role in producing some major benefits derived from physical exercise. However whether these known cellular mechanisms are applicable to ameliorate age-related deterioration of muscle function is not entirely clear. The present communication proposes that antioxidant adaptation, the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α activated mitochondrial biogenesis, and eccentric contraction-induced, cytokine-propelled muscle inflammation could be important redox-sensitive pathways by which exercise-induced disturbance in oxidant-antioxidant hemeostasis may serve as a heretic stimulus to promote adaptations that help healthy aging and improve the quality of life.     

Mimetics of Hormetic Agents: Stress-Resistance Triggers

Mimetics of hormetic agents offer a novel approach to adjust dose to minimize the risk of toxic response, and maximize the benefit of induction of at least partial physiological conditioning. Nature selected and preserved those organisms and triggers that promote tolerance to stress. The induced tolerance can serve to resist that challenge and can repair previous age, disease, and trauma damage as well to provide a more youthful response to other stresses. The associated physiological conditioning may include youthful restoration of DNA repair, resistance to oxidizing pollutants, protein structure and function repair, improved immunity, tissue remodeling, adjustments in central and peripheral nervous systems, and altered metabolism. By elucidating common pathways activated by hormetic agent’s mimetics, new strategies for intervention in aging, disease, and trauma emerge. Intervention potential in cancer, diabetes, age-related diseases, infectious diseases, cardiovascular diseases, and Alzheimer’s disease are possible. Some hormetic mimetics exist in pathways in primitive organisms and are active or latent in humans. Peptides, oligonucleotides, and hormones are among the mimetics that activate latent resistance to radiation, physical endurance, strength, and immunity to physiological condition tolerance to stress. Co-activators may be required for expression of the desired physiological conditioning health and rejuvenation benefits.     

Interspecies Chemical Signals Released into the Environment May Create Xenohormetic, Hormetic and Cytostatic Selective Forces that Drive the Ecosystemic Evolution of Longevity Regulation Mechanisms

Various organisms (i.e., bacteria, fungi, plants and animals) within an ecosystem can synthesize and release into the environment certain longevity-extending small molecules. Here we hypothesize that these interspecies chemical signals can create xenohormetic, hormetic and cytostatic selective forces driving the ecosystemic evolution of longevity regulation mechanisms. In our hypothesis, following their release into the environment by one species of the organisms composing an ecosystem, such small molecules can activate anti-aging processes and/or inhibit pro-aging processes in other species within the ecosystem. The organisms that possess the most effective (as compared to their counterparts of the same species) mechanisms for sensing the chemical signals produced and released by other species and for responding to such signals by undergoing certain hormetic and/or cytostatic life-extending changes to their metabolism and physiology are expected to live longer then their counterparts within the ecosystem. Thus, the ability of a species of the organisms composing an ecosystem to undergo life-extending metabolic or physiological changes in response to hormetic or cytostatic chemical compounds released to the ecosystem by other species: 1) increases its chances of survival; 2) creates selective forces aimed at maintaining such ability; and 3) enables the evolution of longevity regulation mechanisms.     

Hormetic Responses in Neural Systems: Consideration,Contexts, and Caveats

Dr. Edward Calabrese asserts that hormetic responses occur in neural systems, and provides ample review of evidence to support this claim. In this essay, we survey Dr. Calabrese's findings, illustrate the somewhat provocative premise of hormesis, and posit that while evidence suggests that amplification of low-dose effects are operative in neural systems, it is equally important to consider observations and claims of hormesis in greater detail, and framed within the “cultural” and epistemic contexts of science. We offer specific caveats to avoid the overgeneralization of findings, oversimplification of putative effects or mechanisms, and the dogmatic adherence to a restrictive methodologic orientation. Finally, we assert that any meaningful discussion of hormesis must be grounded to methodologic rigor, yet openness, and must allow for a self-critical and self-revisionist epistemic approach. We attempt to show that the work presented by Calabrese takes a first and important step toward the initiation of dialectic, allows for the exchange of ideas, strives toward reconciliation of differences and the amelioration of error, and seeks intellectual synthesis.     

氧化应激诱导动脉粥样硬化的机制及相关治疗药物

综述氧化应激在动脉粥样硬化发生中的作用及其细胞和分子机制以及血管细胞中活性氧生成酶的作用,探讨相关治疗药物的药效学和作用机制。当血管细胞遭受不良刺激后,在各种活性氧生成酶的作用下,活性氧的生成速率大于清除速率,导致氧化应激,从而诱导内皮损伤和凋亡以及低密度脂蛋白的氧化修饰,促进动脉粥样硬化的发生、发展。因此,抗氧化治疗是防治动脉粥样硬化最有效、最有希望的策略。     

Low Doses of Camptothecin Induced Hormetic and Neuroprotective Effects in PC12 Cells

Hormetic response is an adaptive mechanism for a cell or organism surviving in an unfavorable environment. It has been an intriguing subject of researches covering a broad range of biological and medical disciplines, in which the underlying significance and molecular mechanisms are under intensive investigation. In the present study, we demonstrated that topoisomerase I inhibitor camptothecin (CPT), a potent anticancer agent, induced an obvious hormetic response in rat pheochromocytoma PC12 cells. Camptothecin inhibited PC12 cell growth at relative high doses as generally acknowledged while stimulated the cell growth by as much as 39% at low doses. Moreover, low doses of CPT protected the cells from hydrogen peroxide (H₂O₂)-induced cell death. Phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathways were reported playing pivotal roles in protecting cells from oxidative stress. We observed that these 2 pathways were upregulated by low doses of CPT, as evidenced by increased levels of phosphorylated PI3K, phosphorylated Akt, phosphorylated mammalian target of rapamycin, Nrf2, and HO-1; and abolishment of the growth-promoting and neuroprotective effects of CPT by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, a PI3K inhibitor. These results suggest that the hormetic and neuroprotective effects of CPT at low doses on PC12 cells were attributable, at least partially, to upregulated PI3K/Akt and Nrf2/HO-1 pathways.     

Mechanisms of potentiation of Angiotensin II-induced contractile response of isolated rat aorta by hydrogen peroxide and tert-butyryl hydroperoxide

Objective:

To study the mechanism involved in hydrogen peroxide (H₂O₂) or tert-butyl hydroperoxide (t-BHP)-induced potentiation of the Ang II-mediated contraction of isolated rat thoracic aorta.

Materials and Methods:

Thoracic aorta was isolated from the Sprauge dawley rats (300–320 gm), cut spirally and response to Ang II (5 × 10⁻⁸M) was taken in the absence and presence of H₂O₂ (10⁻⁶M) and t-BHP (10⁻⁵M). To explore the probable mechanism of H₂O₂ and t-BHP-induced potentiation of Ang II-mediated contractile response, different blockers such as losartan (AT₁ receptor blocker; 1 μM), catalase (H₂O₂ scavenger; 500 U/ml), lercanidipine (L-type calcium channel blocker; 1 μM), geinistein (tyrosine kinase inhibitor; 100 μM), and indomethacin (cyclo-oxygenase inhibitor; 10 μM) were used.

Results:

In spiral preparation of rat thoracic aorta, H₂O₂ (10⁻⁶M) and t-BHP (10⁻⁵M) did not produce the contraction as such. However, when they are added simultaneously with Ang II (5 × 10⁻⁸ M), they potentiated the contractile response of the Ang II. Catalase (500 U/ml) partially antagonized the Ang-II-induced contraction, as well as antagonized the potentiation induced by H₂O₂. Losartan (1 μM) and lercanidipine (1 μM) antagonized the Ang II-induced contractile response without affecting H₂O₂ (10⁻⁶M)-mediated potentiation. Geinistein (100 μM) antagonized H₂O₂ (10⁻⁶M)-mediated potentiation, but it slightly decreased the Ang II response. Losartan (1 μM) and lercanidipine (1 μM) and Geinistein (100 μM) antagonized the Ang II-induced contractile response but not t-BHP-mediated potentiation. Indomethacin antagonized t-BHP-mediated potentiation without affecting much of Ang II response.

Conclusion:

From the above-mentioned results, we can reasonably conclude that H₂O₂ and t-BHP potentiated the contraction induced by the Ang II. H₂O₂-induced potentiation of Ang II response may be mediated through tyrosine kinase activation and t-BHP through the activation of cyclo-oxygenase enzyme.     

Mechanisms of augmented vasoconstriction induced by 5-hydroxytryptamine in aortic rings from spontaneously hypertensive rats

Background and purpose:To test whether development of enhanced vasoconstriction to 5-hydroxytryptamine (5-HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O(2)(-)) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho-kinase and/or PKC.Experimental approach:We examined systolic blood pressure (SBP), vascular O(2)(-), and 5-HT-induced contractile responses of aortic segments from 4- and 8-week-old WKY and SHR.Key results:SBP was 35% higher in SHR than WKY at 4 weeks and 60% higher at 8 weeks. Contractile responses to 5-HT were similar in WKY and SHR at 4 weeks, but were markedly augmented in SHR at 8 weeks. The NO synthase inhibitor, L-NAME, enhanced contractile responses to 5-HT markedly in both strains at 4 weeks and in WKY at 8 weeks, but only very modestly in SHR at 8 weeks. These functional differences were associated with higher O(2)(-) levels in SHR versus WKY at 8 weeks, but not at 4 weeks. The rho-kinase inhibitor, Y-27632, and the PKC inhibitor, Ro 31-8220, each only modestly attenuated contractions in WKY and SHR in each age group, and their effects in each strain were more pronounced at 8 weeks. The cyclooxygenase inhibitor, indomethacin, had no effect on contractile responses.Conclusions and implications:Development of augmented vascular contractile responses to 5-HT in SHR is preceded by hypertension. It is associated with increased vascular O(2)(-) levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho-kinase, PKC or cyclooxygenase.British Journal of Pharmacology (2008) 155, 210-216; doi:10.1038/bjp.2008.247; published online 16 June 2008.     

Effects of silver nanoparticles on the interactions of neuron‐ and glia‐like cells: Toxicity,uptake mechanisms,and lysosomal tracking

Silver nanoparticles (AgNPs) are commonly used nanomaterials in consumer products. Previous studies focused on its effects on neurons; however, little is known about their effects and uptake mechanisms on glial cells under normal or activated states. Here, ALT astrocyte‐like, BV‐2 microglia and differentiated N2a neuroblastoma cells were directly or indirectly exposed to 10 nm AgNPs using mono‐ and co‐culture system. A lipopolysaccharide (LPS) was pretreated to activate glial cells before AgNP treatment for mimicking NP exposure under brain inflammation. From mono‐culture, ALT took up the most AgNPs and had the lowest cell viability within three cells. Moreover, AgNPs induced H₂O₂ and NO from ALT/activated ALT and BV‐2, respectively. However, AgNPs did not induce cytokines release (IL‐6, TNF‐α, MCP‐1). LPS‐activated BV‐2 took up more AgNPs than normal BV‐2, while the induction of ROS and cytokines from activated cells were diminished. Ca²⁺‐regulated clathrin‐ and caveolae‐independent endocytosis and phagocytosis were involved in the AgNP uptake in ALT, which caused more rapid NP translocation to lysosome than in macropinocytosis and clathrin‐dependent endocytosis‐involved BV‐2. AgNPs directly caused apoptosis and necrosis in N2a cells, while by indirect NP exposure to bottom chamber ALT or BV‐2 in Transwell, more apoptotic upper chamber N2a cells were observed. Cell viability of BV‐2 also decreased in an ALT–BV‐2 co‐culturing study. The damaged cells correlated to NP‐mediated H₂O₂ release from ALT or NO from BV‐2, which indicates that toxic response of AgNPs to neurons is not direct, but indirectly arises from AgNP‐induced soluble factors from other glial cells.     

Nanosilica-induced placental inflammation and pregnancy complications: Different roles of the inflammasome components NLRP3 and ASC

Abstract

Despite the increasing commercial use of nanoparticles, little is known about their effects on placental inflammation and pregnancy complications. In this study, nanosilica (NS) particles upregulated the inflammasome component nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) and induced placental inflammation and reactive oxygen species (ROS) generation, resulting in pregnancy complications. Furthermore, NS-induced pregnancy complications were markedly improved in Nlrp3^?/? mice but not in component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-deficient (Asc^?/?) mice, indicating the independence of NLRP3 inflammasomes. Pregnancy complications in Nlrp3^?/? and Asc^?/? mice phenotypes were dependent on the balance between interleukin (IL)-1α and IL-10. NS-induced pregnancy complications were completely prevented by either inhibition of ROS generation or forced expression of IL-10. Our findings provide important information about NS-induced placental inflammation and pregnancy complications and the novel pathophysiological roles of NLRP3 and ASC in pregnancy.     

Nonlinear Effects of Nanoparticles: Biological Variability From Hormetic Doses,Small Particle Sizes,and Dynamic Adaptive Interactions

Researchers are increasingly focused on the nanoscale level of organization where biological processes take place in living systems. Nanoparticles (NPs, e.g., 1–100 nm diameter) are small forms of natural or manufactured source material whose properties differ markedly from those of the respective bulk forms of the “same” material. Certain NPs have diagnostic and therapeutic uses; some NPs exhibit low-dose toxicity; other NPs show ability to stimulate low-dose adaptive responses (hormesis). Beyond dose, size, shape, and surface charge variations of NPs evoke nonlinear responses in complex adaptive systems. NPs acquire unique size-dependent biological, chemical, thermal, optical, electromagnetic, and atom-like quantum properties. Nanoparticles exhibit high surface adsorptive capacity for other substances, enhanced bioavailability, and ability to cross otherwise impermeable cell membranes including the blood-brain barrier. With super-potent effects, nano-forms can evoke cellular stress responses or therapeutic effects not only at lower doses than their bulk forms, but also for longer periods of time. Interactions of initial effects and compensatory systemic responses can alter the impact of NPs over time. Taken together, the data suggest the need to downshift the dose-response curve of NPs from that for bulk forms in order to identify the necessarily decreased no-observed-adverse-effect-level and hormetic dose range for nanoparticles.     

Mechanisms of nanotoxicity: Generation of reactive oxygen species

Nanotechnology is a rapidly developing field in the 21^st century, and the commercial use of nanomaterials for novel applications is increasing exponentially. To date, the scientific basis for the cytotoxicity and genotoxicity of most manufactured nanomaterials are not understood. The mechanisms underlying the toxicity of nanomaterials have recently been studied intensively. An important mechanism of nanotoxicity is the generation of reactive oxygen species (ROS). Overproduction of ROS can induce oxidative stress, resulting in cells failing to maintain normal physiological redox-regulated functions. This in turn leads to DNA damage, unregulated cell signaling, change in cell motility, cytotoxicity, apoptosis, and cancer initiation. There are critical determinants that can affect the generation of ROS. These critical determinants, discussed briefly here, include: size, shape, particle surface, surface positive charges, surface-containing groups, particle dissolution, metal ion release from nanometals and nanometal oxides, UV light activation, aggregation, mode of interaction with cells, inflammation, and pH of the medium.     

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Titanium dioxide nanoparticles (TiO₂ NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO₂ NPs but the underlying mechanisms are unclear at present. Data from genome‐wide analyses showed that TiO₂ NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO₂ NP‐induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO₂ NP‐induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO₂ NP‐induced ER stress occurred earlier than ROS generation. Upon treatment with 4‐phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO₂ NP increased ROS production was inhibited. These results suggest that TiO2 NP‐induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO₂ NPs on plasma glucose metabolism.     

铁死亡在非酒精性脂肪性肝炎发生发展中作用的研究进展

铁死亡是铁依赖性的脂质过氧化物致死性堆积诱发的细胞死亡。胞内铁超载以及大量活性氧（ROS）积蓄催化细胞膜上高表达的不饱和脂肪酸过氧化,从而诱导细胞死亡。自噬、凋亡等细胞程序化死亡在非酒精性脂肪性肝炎（NASH)的发生发展中发挥关键作用。有研究发现铁死亡直接参与单纯性脂肪肝发展到NASH的进程,抑制铁死亡,几乎可以完全抑制NASH发生。通过对铁死亡是否参与NASH的进展进行综述,以期为NASH机制研究与临床治疗提供新的参考。     

Superoxide dismutase: an emerging target for cancer therapeutics

Superoxide dismutase (SOD) is a critical enzyme responsible for the elimination of superoxide radicals and is considered to be a key anti-oxidant in aerobic cells. Cellular consumption of oxygen is essential for oxidative phosphorylation during ATP generation in the mitochondria, yet this cellular metabolism also leads to the production of reactive oxygen species (ROS), including the superoxide radical (O₂ ^{? -}) and hydrogen peroxide (H₂O₂). Accumulation of ROS results in cellular oxidative stress and, if not corrected, can lead to the damage of important biomolecules such as membrane lipids, proteins and DNA. Prolonged accumulation of high levels of free radicals in cells may cause irreversible cellular injury and ultimately result in cell death. Since SOD is the key enzyme in the first metabolic step of superoxide elimination, deficiency in SOD or inhibition of the enzyme activity may cause severe accumulation of O₂ ^{? -} in cells and lead to cell death. Thus, inhibition of SOD may provide a novel way to kill cancer cells. Due to dysfunction in the regulation of cell growth, cancer cells are active in energy metabolism, and thus produce high levels of O₂ ^{? -} and other ROS and are under constant oxidative stress. This may render the malignant cells more dependent on SOD to eliminate the toxic superoxide radicals and thus potentially more sensitive to SOD inhibitors. It is a plausible hypothesis that inhibition of SOD may preferentially kill malignant cells through a free radical-mediated mechanism. This article will review evidence that suggests SOD as an emerging therapeutic target for cancer treatment. The relevant clinical implications and potential risk will also be discussed.     

The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells

Summary Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been reported to have potent inflammatory properties but appears to be a weaker tumor promoter than PMA. While the effect of PMA on the function and metabolism of human blood cells has been extensively studied, there is little similar information concerning mezerein. Therefore, in these studies, we have compared the capacities of mezerein and PMA to activate the cytotoxic capacity and oxidative metabolism of human granulocyte (PMNs), monocyte, lymphocyte, and mononuclear cell (lymphocytes and monocytes) cultures in vitro. Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H₂O₂, hydroxyl radical and stable oxidants. Mezerein also stimulated the release of thromboxane B₂ from PMNs. Both compounds activated the oxidative metabolism of monocytes but not the oxidative metabolism of lymphocytes. The enhanced oxidative metabolism of the phagocytic cells was associated with an increased cytotoxicity against human red cells which are sensitive to oxidant damage but not against the NK resistant Raji lymphoblast cell line or the SW1116 colon tumor cell line.Of interest is that mezerein did not augment significantly the minimal cytotoxic capacity (NK activity) of mononuclear cells, monocytes or freshly isolated lymphocyte cultures against the tumor cell targets used in our experiments. However, lymphocyte cultures preincubated for 15 hours with mezerein had a marked enhancement of cytotoxicity against the tumor targets. This activation was not observed in similarly treated mononuclear cell cultures suggesting a suppressor activity of the monocytes.Our data suggest that the potent inflammatory activity of mezerein similar to PMA, may be related to its capacity to activate the oxidative and arachidonic metabolism of phagocytic cells. In addition, the capacity of mezerein to activate the cytotoxic capacity of lymphocytes may relate to its reported in vivo antitumor activity.Dr. Barton is currently a resident in Medicine at the Unviersity of Chicago.     

Nonmonotonic dose-response relationships: mechanistic basis, kinetic modeling, and implications for risk assessment.

Dose-response curves for the first interaction of a chemical with a biochemical target molecule are usually monotonic; i.e., they increase or decrease over the entire dose range. However, for reactions of a complex biological system to a toxicant, nonmonotonic (biphasic) dose-effect relationships can be observed, showing a decrease at low dose followed by an increase at high dose, or vice versa. We present four examples to demonstrate that nonmonotonic dose-response relationships can result from superimposition of monotonic dose responses of component biological reactions. Examples include (i) a membrane-receptor model with receptor subtypes of different ligand affinity and opposing downstream effects (adenosine receptors A1 vs. A2), (ii) androgen receptor-mediated gene expression driven by homodimers, but not mixed-ligand dimers, (iii) repair of background DNA damage by enzymatic activity induced by adducts formed by a xenobiotic, (iv) rate of mutation as a consequence of DNA damage times rate of cell division, the latter being modulated by cell-cycle delay at low-level DNA damage, and cell-cycle acceleration due to regenerative hyperplasia at cytotoxic dose levels. Quantitative analyses based on biological models are shown, and factors that affect the degree of nonmonotonicity are identified. It is noted that threshold-type dose-response curves could in fact be nonmonotonic. Our analysis should promote a scientific discussion of biphasic dose responses and the concept termed "hormesis," and of default procedures for low-dose extrapolation in toxicological risk assessment.     

In vitro and in vivo evaluation of the neuroprotective activity of Uncaria hirsuta Haviland

The incidence of neurodegeneration leading to the conditions such as Alzheimer's and Parkinson's diseases are on the increase, they require the approaches that focus on protection prevention rather than treatment. Plants are rich sources of many compounds which possess medicinal properties. We sought to investigate the neuroprotective effects of Uncaria hirsuta and its compounds on d-galactose-induced stress in BALB/c mice as well as 6-hydroxydopamine (6-OHDA)-induced stress in mouse nerve growth factor (mNGF)-differentiated PC12 cells. Our results demonstrate that the 95% ethanol extract of U. hirsuta reversed the d-galactose-induced learning and memory dysfunctions and decreased the malodialdehyde levels. Furthermore, the isolated compounds, 5β-carboxystrictosidine (1) and chlorogenic acid (2), protected mNGF-differentiated PC12 cells against toxicity induced by 6-OHDA by acting as antiapoptotic agents. The 50% inhibitory concentration (IC₅₀) for intracellular reactive oxygen species (ROS) scavenging was found to be 24.5 (for 1) and 19.7 μM (for 2), and both 1 and 2 reduced intracellular calcium levels with respective IC₅₀ values of 46.9 and 27 μM. Interestingly, both compounds inhibited caspase 3 and 9 activities with respective IC₅₀ values of 25.6 and 24.5 μM for 1 and 19.4 and 16.3 μM for 2. Our results identify U. hirsuta and its active compounds as potential neuroprotective agents and deserve further evaluation for drug development for neuroprotection in the future.     

Addiction and Dose Response: The Psychomotor Stimulant Theory of Addiction Reveals That Hormetic Dose Responses Are Dominant

In 1987 Wise and Bozarth proposed a psychomotor stimulant theory of addiction whose most consistent feature was enhanced forward (horizontal) locomotion. While controversial, the theory of Wise and Bozarth has had substantial impact on addiction behavior theory over the past two decades, being cited over 1,400 times. The present assessment places the theoretical formulation of within a dose-response framework. This analysis demonstrates that the psychomotor stimulant effects of addictive drugs routinely display biphasic dose-response relationships that are consistent with the quantitative features of the hormetic dose-response model. This is the case, regardless of addictive agent, animal model, and experimental protocol employed. Not only do these findings suggest an important role for the hormetic dose response model in the assessment of addictive behaviors, they also further extend the generalizability of the hormesis dose-response model concept within the biomedical sciences.