The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and ...δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.
Background Asthma is related to airway inflammation and oxidative stress. High levels of reactive oxygen and nitrogen species can induce cytotoxic DNA damage. Nevertheless, little is known about the ...possible role of allergen-induced DNA damage and DNA repair as modulators of asthma-associated pathology. Objective We sought to study DNA damage and DNA damage responses induced by house dust mite (HDM) in vivo and in vitro. Methods We measured DNA double-strand breaks (DSBs), DNA repair proteins, and apoptosis in an HDM-induced allergic asthma model and in lung samples from asthmatic patients. To study DNA repair, we treated mice with the DSB repair inhibitor NU7441. To study the direct DNA-damaging effect of HDM on human bronchial epithelial cells, we exposed BEAS-2B cells to HDM and measured DNA damage and reactive oxygen species levels. Results HDM challenge increased lung levels of oxidative damage to proteins (3-nitrotyrosine), lipids (8-isoprostane), and nucleic acid (8-oxoguanine). Immunohistochemical evidence for HDM-induced DNA DSBs was revealed by increased levels of the DSB marker γ Histone 2AX (H2AX) foci in bronchial epithelium. BEAS-2B cells exposed to HDM showed enhanced DNA damage, as measured by using the comet assay and γH2AX staining. In lung tissue from human patients with asthma, we observed increased levels of DNA repair proteins and apoptosis, as shown by caspase-3 cleavage, caspase-activated DNase levels, and terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling staining. Notably, NU7441 augmented DNA damage and cytokine production in the bronchial epithelium and apoptosis in the allergic airway, implicating DSBs as an underlying driver of asthma pathophysiology. Conclusion This work calls attention to reactive oxygen and nitrogen species and HDM-induced cytotoxicity and to a potential role for DNA repair as a modulator of asthma-associated pathophysiology.
Artemisinins are a family of sesquiterpene trioxane lactone anti-malarial agents originally derived from Artemisia annua L. The anti-malarial action of artemisinins involves the formation of free ...radicals via cleavage of the endoperoxide bond in its structure, which mediate eradication of the Plasmodium species. With its established safety record in millions of malarial patients, artemisinins are also being investigated in diseases like infections, cancers and inflammation. Artemisinins have been reported to possess robust inhibitory effects against viruses (e.g. Human cytomegalovirus), protozoa (e.g. Toxoplasma gondii), helminths (e.g. Schistosoma species and Fasciola hepatica) and fungi (e.g. Cryptococcus neoformans). Artemisinins have demonstrated cytotoxic effects against a variety of cancer cells by inducing cell cycle arrest, promoting apoptosis, preventing angiogenesis, and abrogating cancer invasion and metastasis. Artemisinins have been evaluated in animal models of autoimmune diseases, allergic disorders and septic inflammation. The anti-inflammatory effects of artemisinins have been attributed to the inhibition of Toll-like receptors, Syk tyrosine kinase, phospholipase Cγ, PI3K/Akt, MAPK, STAT-1/3/5, NF-κB, Sp1 and Nrf2/ARE signaling pathways. This review provides a comprehensive update on non-malarial use of artemisinins, modes of action of artemisinins in different disease conditions, and drug development of artemisinins beyond anti-malarial. With the concerted efforts in the novel synthesis of artemisinin analogs and clinical pharmacology of artemisinins, it is likely that artemisinin drugs will become a major armamentarium combating a variety of human diseases beyond malaria.
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Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. ...paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.
Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their ...antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin‐induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin‐induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents.
Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and ...functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (
) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78
AMs are expanded in
mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78
AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78
AMs in both
and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.
Summary
1. Andrographis paniculata (Burm. f) Nees, commonly known as ‘king of bitters’, is a herbaceous plant belonging to the Family Acanthaceae. It has been widely used for centuries in Asian ...countries like China, India, Thailand and Malaysia for the treatment of sore throat, flu and upper respiratory tract infections.
2. Andrographolide, 14‐deoxy‐11,12‐didehydroandrographolide and neoandrographolide are examples of the major labdane diterpenoids isolated from A. paniculata. These bioactive molecules have exhibited varying degrees of anti‐inflammatory and anticancer activities in both in vitro and in vivo experimental models of inflammation and cancer.
3. Extensive libraries of andrographolide analogues have been synthesised mainly by modifying the α,β‐unsaturated γ‐butyrolactone moiety, the two double bonds Δ8,(17) and Δ12,(13) and the three hydroxyls at C‐3 (secondary), C‐14 (allylic) and C‐19 (primary). Many of these synthetic analogues exhibit superior anticancer activity over the naturally occurring andrographolides.
4. Andrographolide and its derivatives have been shown to have anti‐inflammatory effects in experimental models of asthma, stroke and arthritis, as well as in patients with upper respiratory tract infections. Andrographolide reduces the production of cytokines, chemokines, adhesion molecules, nitric oxide and lipid mediators, probably via inhibition of the nuclear factor (NF)‐κB signalling pathway.
5. The anticancer mechanisms for andrographolide include inhibition of Janus tyrosine kinases–signal transducers and activators of transcription, phosphatidylinositol 3‐kinase and NF‐κB signalling pathways, suppression of heat shock protein 90, cyclins and cyclin‐dependent kinases, metalloproteinases and growth factors, and the induction of tumour suppressor proteins p53 and p21, leading to inhibition of cancer cell proliferation, survival, metastasis and angiogenesis.
6. Andrographolide drug discovery is a promising strategy for the development of a novel class of anti‐inflammatory and anticancer drugs.
Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining ...severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point
would reduce the severity of organ injury in this model.
We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation with persistent respiratory symptoms. Current therapeutics for COPD are largely borrowed from the drug ...armamentarium for the treatment of asthma, which has different pathophysiological mechanisms from COPD. COPD has been linked to dysregulated expression of mRNAs and noncoding (nc)RNAs including miRNAs, PIWI-interacting (pi)RNAs, long noncoding (lnc)RNAs, and circular (circ)RNAs. This review highlights and discusses some recent advances towards development of RNA therapeutics for COPD.
COPD is the third leading cause of death globally, and there is an urgent unmet medical need to develop novel therapeutics specifically for COPD.Numerous ncRNAs like miRNAs, lncRNAs, and circRNAs, have been linked to COPD. Few of these dysregulated ncRNAs have been functionally characterized. Some ncRNA targets including miR-195, miR-181c, and TUG1 have shown promise in mitigating COPD in vivo.Significant effort has been made to develop siRNA therapeutics targeting mRNAs critical for the pathogenesis of COPD. siRNAs targeting RIP2, RPS3, MAP3K19, and CHST3 mRNAs have been successfully validated in in vivo COPD models.Direct inhalation of RNA therapeutics to the lungs is the best route of administration for COPD. Innovative approaches to enhance RNA stability, tissue targeting, cell penetration and intracellular endosomal escape are critical to realize the full potentials of RNA drugs.
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Patients with severe asthma that remain uncontrolled incur significant medical burden and healthcare costs. Severe asthma is a heterogeneous airway disorder with complex ...pathophysiological mechanisms which can be broadly divided into type 2 (T2)-high and T2-low inflammatory pathways. Recent advances in asthma therapeutics with the advent of biologics have heralded an era of promising targeted therapy in this group of patients. The current available biologics, including anti-IgE mAb, anti-IL-5/IL-5R mAb and anti-IL-4Rα mAb, mainly target patients with an asthma endotype characterised by T2-high inflammation. While they have delivered positive outcomes in terms of reduction in exacerbations, improving lung function and quality of life, as well as reducing the dependence on oral corticosteroids, they have not functioned as the “panacea” as a significant proportion of patients do not respond completely to these targeted therapies. In addition, there is a lack of markers that can predict treatment response and clinicians are guided only by subjective asthma symptom scores. Suboptimal treatment response is common for individual patients. There has also been a dearth of effective targeted therapy for patients with T2-low asthma and treatment options remain limited for these patients. There is a pipeline of newer biologics targeting cytokines that operate at the interface between innate and adaptive immunity (e.g. IL-17A, thymic stromal lymphopoietin (TSLP), IL-25, IL-33, IL-32 and IL-36γ) with potential of modifying and reducing the severity of asthma. This commentary provides an overview of treatment with the current biologics and highlights the limitations, challenges and unmet needs in clinical management. We also summarise up-and-coming potential targets and therapeutic biologics for severe asthma.
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