Special Issue on “Pharmacodynamics Modeling of Anti-Inflammatory Drugs”

Immuno-inflammatory responses are essential for defending the host against pathogenic infections. However, unregulated inflammatory reactions are sometimes dangerous and pose risks to life. For example, the hyperinflammation caused by respiratory infections (e.g., cytokine storm) exacerbates lung damage and is associated with acute respiratory distress syndrome. Cancer incidence and deterioration are accompanied by inflammatory phenomena such as leukocyte infiltration, increases in cytokine levels (including chemokines and growth factors), tissue remodeling, and angiogenesis. In addition to cancer development, unregulated inflammatory reactions contribute to chronic inflammatory diseases such as lupus, atherosclerosis, rheumatoid arthritis, osteoarthritis, psoriasis, vasculitis, and irritable bowel disease. Therefore, in the treatment of intractable diseases, the removal of invading pathogens, the removal of enlarged cancer masses, and the control of excessive inflammatory reactions are important goals. Recently, various natural products have been reported to have anti-inflammatory, antioxidant, and analgesic effects. Obtaining a more detailed understanding of the mechanisms of action of natural products with anti-inflammatory and analgesic effects and identifying specific related inflammatory mediators will improve the possibility of treating acute or chronic inflammatory diseases using natural products. These natural products include coffee, Andrographis paniculata, diospyrin, Gardeniae Fructus, Perillae Folium, etc. This Special Issue also presents unique pathways, such as p38 mitogen-activated protein kinase (p38 MAPK) signaling, associated with the modulation of inflammatory mediators in some natural products. The proposed signaling pathways include endoplasmic reticulum (ER)-stress-induced C/EBP homologous protein (CHOP) signaling and eicosanoid metabolism. The characteristic inflammatory mediators associated with these mechanisms include interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nitric oxide (NO), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), monokine induced by gamma interferon (MIG), prostaglandins, leukotrienes, etc. The Special Issue is available online at: https://www.mdpi.com/journal/processes/special_issues/anti-inflammatory_activity_natural_product.

As the demand coffee continues to increase worldwide, how coffee intake affects human health is a hot topic. For most coffee consumers, coffee is a favorite and a natural product that is easy to habitually consume. Studies show that coffee ingredients contain flavonoids, which have positive physiological effects on human health, and antioxidant polyphenols. However, controversy continues over the harmful effects and benefits of caffeine, the main ingredient in coffee, on the human body. Further investigating the relationship between coffee consumption and cardiovascular disease would also be meaningful. In this Special Issue, Lim et al. [1] report that coffee, one of the most popular beverages in the world, is generally regarded as beneficial in many studies, but concerns are growing about the adverse effect of coffee consumption on cardiovascular disease due to the potential aggravating impact on the cardiovascular system attributed to various compounds within coffee. Patients with risk factors of cardiovascular diseases should prudently avoid heavy coffee consumption because it may exacerbate hypertension, dyslipidemia, and atherosclerosis and increase the odds of cardiovascular events. The authors drew meaningful conclusions from their study on the effect of coffee consumption on cardiovascular disease, but they stated that more detailed and convincing reasoning will need to be obtained through additional epidemiological studies considering the population’s characteristics. In addition, the findings should motivate interest in studying the effectiveness and suitability of coffee consumption.

Osteoarthritis is a degenerative disease, with pain and immobility caused by swelling of the synovial membrane, erosion of cartilage, and disturbance of cartilage cell metabolism. Osteoarthritis is mainly found in the elderly.

Because the erosion of cartilage in osteoarthritis is caused by synovial inflammation in the joints, the suppression of synovial inflammation and reduction in inflammatory cytokines in synovial fluid are notable in the osteoarthritis treatment. Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, which can suppress synovial inflammation, have been used to treat osteoarthritis. However, because NSAIDs and steroids have side effects including gastrointestinal disorders, urological diseases, and cardiovascular diseases, interest continues in natural products that have fewer or no side effects and are effective in treating osteoarthritis. The anti-inflammatory and analgesic efficacies of Andrographis paniculata, which is distributed in India and southeast Asia and contains diterpenes, polyphenols, and flavonoids, are well known [2]. Lee et al. induced experimental osteoarthritis in rats via a knee injection of monosodium iodoacetate, which represented the pathological characteristics of osteoarthritis in humans. The administration of Andrographis paniculata extract (APE) substantially reversed the loss of hind-limb weight-bearing, and the cartilage damage resulted from the osteoarthritis induction in rats. Additionally, the levels of serum pr-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, as well as the concentration of matrix metalloproteinases (MMPs), including MMP-1, MMP-3, MMP-8, and MMP-13, were decreased by APE administration. The acetic-acid-induced writhing responses in mice, which quantitatively indicates pain, were significantly reduced by APE administered. APE inhibited the generation of NO and downregulated the expressions of IL-1β, IL-6, COX-2, and iNOS in lipopolysaccharide-stimulated RAW 264.7 mouse macrophages. These results indicate the suitability of the use APE as a therapeutic agent against osteoarthritis [2]. However, more research is needed to identify a detailed signaling pathway related to the inhibitory effect of Andrographis paniculata in osteoarthritis.

Reproducing the inflammatory process caused by a viral infection is challenging, but artificially synthesized double-stranded RNA such as polyinosinic-polycytidylic acid (poly I:C) activates macrophages, similar to double-stranded RNA, which can increase in number during viral infection, enabling the establishment of an experimental model similar to the inflammatory response associated with viral infection. Diospyrin, a plant-derived bisnaphthoquinonoid, inhibits the macrophage activation caused by lipopolysaccharides [3], investigations are needed of the effect of diospyrin on the inflammatory responses in macrophages activated by poly I:C. Kim et al. reported that diospyrin has anticancer activity; diospyrin treatment significantly reduced NO production, granulocyte-macrophage colony-stimulating factor production, and intracellular calcium release in poly I:C-induced RAW 264.7. the phosphorylation of p38 MAPK and ERK1/2 was also significantly suppressed. Diospyrin also inhibited mRNA levels of iNOS, CHOP, calcium/calmodulin dependent protein kinase II alpha (Camk2α), signal transducers and activators of transcription 1 (STAT1), STAT3, STAT4, Janus kinase 2 (Jak2), first apoptosis signal receptor (Fas), c-Jun, and c-Fos in poly I:C-induced RAW 264.7 cells. Diospyrin might have the inhibitory activity against viral inflammation processes such as the excessive production of inflammatory mediators in poly I:C-induced RAW 264.7 cells via ER stress-induced calcium-CHOP pathway. Diospyrin might inhibit TNF-α-converting enzyme [3]. This is the first report that the inhibitory effect of diospyrin on viral infectious inflammation occurs through calcium signaling related to ER stress [3].

In general, the use of natural products for human health often relies on medical experiences handed down between generations or the medical records of traditional medical books published in countries where traditional medicine has been developed, such as Korea, China, and Japan. Among the topics of the papers in this Special Issue, Gardeniae Fructus and Perilla Folium are also described in detail in Donguibogam, a famous classic of traditional Korean medicine, as a treatment for inflammatory diseases [4]. In addition, because previous studies have already described the antioxidant activity of Gardeniae Fructus and the anti-inflammatory effect of Perilla Folium, a mixture of Gardeniae Fructus and Perilla Folium could potentially exhibit anti-inflammatory action. Park found that an extract combining Gardeniae Fructus and Perillae Folium (GP) significantly reduced the lipopolysaccharide-induced productions of MIP-1α and MIG and the release of intracellular calcium in lipopolysaccharide-activated RAW 264.7 cells. GP significantly inhibited p38 MAPK phosphorylation and mRNA levels of CHOP, Camk2α, STAT1, STAT3, Jak2, Fas, iNos, and Ptgs2 in lipopolysaccharide-activated RAW 264.7 cells. Moreover, GP exerted anti-inflammatory effects on lipopolysaccharide-activated RAW 264.7 cells via the ER-stress-induced CHOP pathway [4]. In line with the focus of this Special Issue, the author reports that GP inhibited the excess production of proinflammatory mediators (e.g., NO, cytokines, etc.) in lipopolysaccharide-induced macrophages and that the mechanism of activity is related to ER stress signaling through p38 MAPK phosphorylation. This study demonstrates the possibility that GP may be applied to various diseases related to ER stress, such as endotoxemia or atherosclerosis in relation to macrophage activation.

In respiratory infectious diseases such as COVID-19, cytokine overproduction, called ‘cytokine storms’, is a problem, but the detailed mechanism of cytokine storms has not yet been fully identified. As a result, appropriate treatments for controlling excessive production of cytokines in infectious diseases have not been sufficiently developed. Moreover, research is lacking on the causal relationship between the eicosanoid and cytokine production processes. Aboulmouna et al. report that the cellular response to inflammatory stimuli leads to the production of eicosanoids such as prostanoids (PRs) and leukotrienes (LTs) and signaling molecules (cytokines, chemokines, etc.) by macrophages; they developed a cybernetic model to study arachidonic acid (AA) metabolism, which included two branches, PRs and LTs. They utilized a priori biological knowledge to define the branch-specific cybernetic goals for PR and LT branches as the maximization of TNF-α and MCP-1, respectively. The dominant metabolites are PGD2 (a PR) and LTB4 (an LT), aligning with their corresponding known prominent biological roles during inflammation. Using heuristic arguments, the authors inferred that eicosanoid overproduction can lead to the increased secretion of cytokines/chemokines. This novel model integrates mechanistic knowledge, known biological understanding of signaling pathways, and data-driven methods to study the dynamics of eicosanoid metabolism [5]. This study is valuable as the researchers developed a cybernetic framework model that can quantitatively identify the causal relationship between eicosanoid and cytokine production by combining mathematical research methodologies with existing biomedical experimental studies for studying the mechanism of the inflammatory process. It also showed that AA metabolism could be involved in the development of cytokine storms. This cybernetic model developed by these researchers can be used not only to better understand eicosanoid metabolism but also to predict the causal relationship between AA and other cytokines (such as IL-6) and between TNF-α and other inflammatory mediators such as NO.

The above papers demonstrate the methodological diversity and the importance of research details in constructing pharmacodynamics modeling of anti-inflammatory drugs based on natural products, ranging from the cybernetic framework model to in vitro ER-stress-related signaling model. For example, regarding coffee consumption, people with risk factors should be careful to avoid excessive coffee consumption because it can worsen hypertension, although the population could not be compared in specific groups based on the characteristics of coffee consumers. In addition, although animal experiments have not provided confirmation, ER stress signaling is modulated by the inhibition of intracellular calcium release through the regulation of p38 MAPK phosphorylation and the expression of the transcription factor CHOP. Consequently, these studies provide useful guidance in identifying signaling mechanisms and setting important targets in the development of anti-inflammatory drugs using natural products in the future.

We thank all the contributors and the Editor-in-Chief, Giancarlo Cravotto, for their enthusiastic support of the Special Issue, as well as the editorial staff of Processes for their efforts.