Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: A review

Inflammation is a classical host defence response to infection and injury that has many beneficial effects. However, inappropriate (in time, place and magnitude) inflammation is increasingly implicated in diverse disease states, now including cancer, diabetes, obesity, atherosclerosis, heart disease and, most relevant here, CNS disease. A growing literature shows strong correlations between inflammatory status and the risk of cerebral ischaemia (CI, most commonly stroke), as well as with outcome from an ischaemic event. Intervention studies to demonstrate a causal link between inflammation and CI (or its consequences) are limited but are beginning to emerge, while experimental studies of CI have provided direct evidence that key inflammatory mediators (cytokines, chemokines and inflammatory cells) contribute directly to ischaemic brain injury. However, it remains to be determined what the relative importance of systemic (largely peripheral) versus CNS inflammation is in CI. Animal models in which CI is driven by a CNS intervention may not accurately reflect the clinical condition; stroke being typically induced by atherosclerosis or cardiac dysfunction, and hence current experimental paradigms may underestimate the contribution of peripheral inflammation. Experimental studies have already identified a number of potential anti-inflammatory therapeutic interventions that may limit ischaemic brain damage, some of which have been tested in early clinical trials with potentially promising results. However, a greater understanding of the contribution of inflammation to CI is still required, and this review highlights some of the key mechanism that may offer future therapeutic targets.

Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation.

Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release.

The family Polygonaceae is known for its traditional use in the management of various neurological disorders including Alzheimer's disease (AD). In search of new anti-AD drugs, β-sitosterol isolated from Polygonum hydropiper was subjected to in vitro, in vivo, behavioral and molecular docking studies to confirm its possibility as a potential anti-Alzheimer's agent. The in vitro AChE, BChE inhibitory potentials of β-sitosterol were investigated following Ellman's assay. The antioxidant activity was tested using DPPH, ABTS and H2O2 assays. Behavioral studies were performed on a sub-strain of transgenic mice using shallow water maze (SWM), Y-maze and balance beam tests. β-sitosterol was tested for in vivo inhibitory potentials against cholinesterase's and free radicals in the frontal cortex (FC) and hippocampus (HC). The molecular docking study was performed to predict the binding mode of β-sitosterol in the active sites of AChE and BChE as inhibitor. Considerable in vitro and in vivo cholinesterase inhibitory effects were observed in the β-sitosterol treated groups. β-sitosterol exhibited an IC50 value of 55 and 50 μg/ml against AChE and BChE respectively. Whereas, the activity of these enzymes were significantly low in FC and HC homogenates of transgenic animals. Molecular docking studies also support the binding of β-sitosterol with the target enzyme and further support the in vitro and in vivo results. In the antioxidant assays, the IC50 values were observed as 140, 120, and 280 μg/ml in the DPPH, ABTS and H2O2 assays respectively. The free radicals load in the brain tissues was significantly declined in the β-sitosterol treated animals as compared to the transgenic-saline treated groups. In the memory assessment and coordination tasks including SWM, Y-maze and balance beam tests, β-sitosterol treated transgenic animals showed gradual improvement in working memory, spontaneous alternation behavior and motor coordination. These results conclude that β-sitosterol is a potential compound for the management of memory deficit disorders like AD.

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Anti-Alzheimer's Studies on β-Sitosterol Isolated from Polygonum hydropiper L.

Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.

https://www.mdpi.com/1422-0067/14/5/9126/pdf

Targeting the Redox Balance in Inflammatory Skin Conditions

https://www.jstage.jst.go.jp/article/jphs/99/3/99_3_294/_pdf

Reduction of Atherosclerosis in Cholesterol-Fed Rabbits and Decrease of Expressions of Intracellular Adhesion Molecule-1 and Vascular Endothelial Growth Factor in Foam Cells by a Water-Soluble Fraction of Polygonum multiflorum

Hemin modulates cytokine expressions in macrophage-derived foam cells via heme oxygenase-1 induction.

C-reactive protein induced expression of adhesion molecules in cultured cerebral microvascular endothelial cells.

The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.

Jing Zhang

Papers

Reduction of Atherosclerosis in Cholesterol-Fed Rabbits and Decrease of Expressions of Intracellular Adhesion Molecule-1 and Vascular Endothelial Growth Factor in Foam Cells by a Water-Soluble Fraction of Polygonum multiflorum

Hemin modulates cytokine expressions in macrophage-derived foam cells via heme oxygenase-1 induction.

C-reactive protein induced expression of adhesion molecules in cultured cerebral microvascular endothelial cells.

Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation.