Wedelolactone: Unveiling the Multifaceted Anti-Inflammatory Potential

Inhibition of ferroptosis by serine protease inhibitor attenuates acute respiratory distress syndrome.

Background: Prostate cancer cells continuously generate 5(S)-HETE series of metabolites via 5-lipoxygenase (5-Lox) activity, and inhibition of 5-Lox blocks production of metabolites and triggers apoptosis both in androgen-sensitive and androgen-independent prostate cancer cells. Apoptosis is prevented by 5(S)-HETE and 5-oxoETE, but not by leukotrienes or metabolites of 12-Lox or 15-Lox, which is consistent with the idea that the 5-HETE series of metabolites are essential survival factors for prostate cancer cells. Recently, we found that 5-Lox-regulated survival-signaling is mediated via protein kinase C-epsilon (PKCε), but not Akt, or ERK. Prostate tumor tissues express high levels of 5-Lox, but the expression of 5-Lox in normal prostate glands is undetectable. Thus, 5-Lox emerges as a novel molecular target for prostate cancer therapy. However, lack of suitable 5-Lox inhibitors for in vivo use is hampering progress towards clinical development. Several natural compounds possess 5-Lox inhibitory effects, raising the possibility that effective 5-Lox inhibitors may be found in natural products for use against prostate cancer. Wedelolactone (WDL), a medicinal plant-derived coumestan, is known to inhibit 5-Lox activity in neutrophils. However, its potential on apoptosis induction in prostate cancer cells is not known. Thus, we tested the effects of WDL on a range of human prostate cancer cells in vitro. Methods: Prostate cancer cells were treated with doses of WDL for varying periods of time. Apoptosis was measured by annexin-V binding, PARP-cleavage, and DNA-degradation. Role of caspase in apoptosis was tested by enzymatic assays and chemical inhibitors. Effects of WDL on PKC-epsilon and Akt were analyzed by Western blot and enzymatic assays. Results: We observed that WDL kills both androgen-sensitive as well as androgen-independent prostate cancer cells in a dose-dependent manner by dramatically inducing apoptosis. This apoptosis is dependent on c-Jun N-terminal Kinase (c-JNK) and caspase-3. Interestingly, WDL was observed to trigger apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon (PKCε), but without any inhibition of Akt. WDL does not affect the viability of normal prostate epithelial cells (PrEC) at doses that kill prostate cancer cells. Moreover, it was found that WDL-induced apoptosis is effectively prevented by 5-oxoETE, a metabolite of 5-Lox, confirming that WDL induces apoptosis in prostate cancer cells via inhibition of 5-Lox activity. Conclusion: Our findings indicate that WDL selectivity induces caspase-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of the oncogenic serine/threonine kinase PKCε without affecting Akt, and suggest that WDL may emerge as a novel therapeutic agent against clinical prostate cancer in human. Citation Format: Sivalokanathan Sarveswaran, Subhash Gautam, Jagadananda Ghosh. Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via down-regulation of PKC-epsilon without inhibiting Akt. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2253. doi:10.1158/1538-7445.AM2013-2253

Liver fibrosis is a commonly observed pathological phenomenon that occurs during the progression of various types of chronic liver diseases. The Hippo pathway is closely associated with the pathogenesis of liver fibrosis. Previous studies have shown that wedelolactone (WED) has a significant antihepatic fibrosis effect, whereas the target and mechanism underlying WED remain elusive. In this study, we found that WED significantly alleviated liver fibrosis and injury by inhibiting the expression of Yes-associated protein (YAP) and tafazzin (TAZ). In an in vitro model, WED suppressed the activation of hepatic stellate cells (HSCs) induced by transforming growth factor (TGF-β1), as well as the mRNA and protein expression of α-smooth muscle actin (α-SMA), YAP, and TAZ. The allosteric regulation of YAP by WED was confirmed using MD and cellular thermal shift assay. Moreover, specific knockdown or inhibition of YAP did not enhance the suppressive effect of WED on HSC activation or protein expression associated with fibrosis. These findings demonstrated that the administration of WED effectively alleviated liver fibrosis by suppressing the Hippo/YAP/TAZ pathways. In addition, YAP activity may be regulated by WED via allosteric regulation.

Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.

Background: Traditional Chinese Medicine (TCM) offers a comprehensive approach to cancer treatment, often complementing conventional therapies. Persimmon or Diospyros kaki has long been used in Traditional Chinese Medicine for its potential antioxidant and anti-inflammatory effects. Bioactive compounds found in this plant can be used for cancer treatment and therapy. Aim: The study aims to comprehensively review the pharmacological and anti-cancer properties of Diospyros kaki, emphasising its phytochemical composition, mechanism of action and its potential application in traditional medicine and modern oncology. Methods: Relevant literature published till 2024 was retrieved from various databases including Google Scholar, PubMed, SciSpace, ScienceDirect, IMMPAT 2.0 and PubChem. Keywords such as Diospyros kaki, anti-cancer, pharmacological activity, and phytochemicals were chosen for screening. Studies reporting pharmacological properties, particularly those exhibiting anti-cancer activity, were selected. Result: Diospyros kaki demonstrates significant pharmacological activity across multiple systems. Its fruit, leaves, roots, and calyx contain polyphenols, flavonoids, and triterpenes that exhibit antidiabetic, cardioprotective, neuroprotective, antimicrobial, and anti-inflammatory effects. From an anticancer perspective, compounds such as quercetin, kaempferol, diospyrin, and plumbagin contribute to apoptosis, oxidative stress modulation, and inhibition of tumour proliferation and angiogenesis. Therapeutically, its phytoconstituents support immune modulation, cellular redox balance, and enzyme inhibition, enhancing its potential as a supportive agent in chemotherapy and radiotherapy. Conclusion: The broad therapeutic profile of Diospyros kaki underlines its role in managing chronic diseases and cancer. Further research should focus on standardising extraction, improving bioavailability, and conducting clinical trials to translate these benefits into clinical use. Major Findings: Diospyros kaki exhibits potent anticancer and pharmacological activities, primarily through apoptosis induction, ROS modulation, and inflammation suppression, validating its traditional medicinal use and modern therapeutic relevance.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions that involve severe lung inflammation leading to respiratory failure. Tanshinone IIA (TIIA) and Matrine (MAT), two herbal medicinal compounds, have been reported to exhibit several similar pharmacological properties including anti-inflammatory, antioxidant, and anticancer effects. Although previous studies have reported the combined therapeutic efficacy of using two drugs in treating ALI, it remains unknown whether TIIA and MAT have any synergistic effect in alleviating ALI/ARDS. Therefore, this study investigated whether a combined therapy of TIIA and MAT has protective effects against lipopolysaccharide (LPS)-induced ALI and its mechanism of action using mouse and cell models. The results showed that the TIIA + MAT combination ameliorated ALI by reducing edema, tissue injury, and proinflammatory cytokine secretion. This therapy enhanced antioxidant defences, as indicated by upregulated GPX4 and SLC7A11 levels, decreased 4-HNE and ROS levels, and ferroptosis inhibition. Furthermore, TIIA + MAT promoted Nrf2 nuclear translocation, leading to increased HO-1 expression and an anti-oxidative response. These findings suggest that the combination of TIIA and MAT alleviates LPS-induced ALI by inhibiting ferroptosis via activation of the Nrf2/HO-1 pathway. Thus, the co-administration of TIIA and MAT may be an effective therapeutic strategy for ALI, potentially offering a novel clinical approach to mitigate ferroptosis and inflammation.

Wedelia calendulacea has a long history of use in the Indian Ayurvedic System of Medicine for the treatment, prevention, and cure of a diverse range of human diseases such as diabetes obesity, and other metabolic diseases. A wide range of chemical constituents, such as triterpenoid saponin, kauren diterpene, and coumestans, has been isolated from the plant. Conversely, no published literature is available in relation to the isolation of wedelolactone (WEL) for its anti-diabetic effect. The aim of the present study was to isolate the bioactive phyto-constituent from Wedelia calendulacea and to scrutinize the antidiabetic effect with its possible mechanism of action. The structure of the isolated compound was elucidated by different spectroscopy techniques. Proteins, such as dipeptidyl peptidase-4 (DPPIV), glucose transporter 1 (GLUT1), and peroxisome proliferator-activated receptors-γ (PPARγ), were also subjected to in silico docking. Later, this isolated compound was scrutinized against α-glucosidase and α-amylase enzyme activity along with an oral glucose tolerance test (OGTT) for estimation of glucose utilization. Streptozotocin (STZ) was used for the induction of type II diabetes mellitus (DM) in Wistar rats. The rats were divided into different groups and received the WEL (5, 10, and 20 mg kg−1, b.w.) and glibenclamide (2.5 mg kg−1, b.w.) for 28 days. The blood glucose level (BGL), plasma insulin, and body weight were determined at regular time intervals. The serum lipid profile hypolipidemic effect for the different antioxidant markers and hepatic tissue markers were scrutinized along with an inflammatory mediator to deduce the possible mechanism. With the help of spectroscopy techniques, the isolated compound was identified as wedelolactone. In the docking study, WEL showed docking scores of −6.17, −9.43, and −7.66 against DPP4, GLUTI, and PRARY, respectively. WEL showed the inhibition of α-glucosidase (80.65%) and α-amylase (93.83%) and suggested an effect on postprandial hyperglycemia. In the OGTT, WEL significantly (P < 0.001) downregulated the BGL, a marker for better utilization of drugs. In the diabetes model, WEL reduced the BGL and enhanced the plasma insulin and body weight. It also significantly (P < 0.001) modulated the lipid profile; this suggested an anti-hyperlipidemia effect. WEL significantly (P < 0.001) distorted the hepatic tissue, acting as an antioxidant marker in a dose-dependent manner. WEL significantly (P < 0.001) downregulated the C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) level. On the basis of the available results, we can conclude that WEL can be an alternative drug for the treatment of type II DM either by inhibiting the production of inflammatory mediator or by the downregulation of oxidative stress.

Wedelolactone inhibits human cytomegalovirus replication by targeting distinct steps of the viral replication cycle

Psoriasis is a chronic inflammatory disorder for which phosphodiesterase-4 (PDE4) inhibitors have emerged as promising therapeutic agents due to an ability to regulate inflammatory signaling pathways. In this study 1200 methanolic extracts from Chinese medicinal plants were screened and Eclipta prostrata (L.) Linn. (E. prostrata) was shown to have potent PDE4 inhibitory activity. Bioassay-guided fractionation further demonstrated that the ethyl acetate (EA) fraction exhibited the highest inhibitory activity, leading to the isolation of wedelolactone (WDL) as the principal bioactive compound (IC50 = 2.8 μM). Molecular dynamics simulations revealed that WDL forms stable interactions with PDE4D through hydrogen bonding and hydrophobic contacts. E. prostrata-EA and WDL significantly suppressed pro-inflammatory cytokines in keratinocytes in vitro. Topical application of WDL demonstrated superior anti-psoriatic efficacy compared to calcipotriol in vivo, as evidenced by reduced Psoriasis Area and Severity Index scores, normalized epidermal thickness, and improved inflammatory cytokine profiles. WDL exhibited favorable metabolic stability in liver microsomes and demonstrated a good safety profile in subacute toxicity assessments with no systemic toxicity. These findings established WDL as a potent and safe topical PDE4 inhibitor, highlighting the potential of WDL as a novel therapeutic candidate for psoriasis and warranting further clinical development.

A RARE TRIGGER OF ASTHMA EXACERBATION: THE SCOTCH MARIGOLD

Clinical application of traditional herbal medicine in five countries and regions: Japan; South Korea; Mainland China; Hong Kong, China; Taiwan, China

1-Nitropyrene (1-NP) is harmful to the respiratory system and can evoke acute lung injury (ALI). Pyroptosis and apoptosis, two important types of programmed cell death, are involved in the pathological process of ALI. However, the roles and mechanisms of pyroptosis and apoptosis on 1-NP-incurred ALI remain unclear. All the mice were exposed to a single dose of 1-NP (20 μg/mouse, dissolved in saline) or normal saline via intratracheal instillation. At different times after 1-NP exposure, the mice were sacrificed. Mouse lung epithelial (MLE-12) cells were incubated with 1-NP (5 μM), the indicators of pyroptosis and apoptosis were detected. Pulmonary pathological injury and inflammatory cell infiltration was observed in 1-NP-exposed mice. Additionally, the indicators of apoptosis, Bcl-2 was downregulated, Bad and Caspase-3, and apoptotic cells were increased in 1-NP-exposed mouse lungs and mouse lung epithelial (MLE-12) cells. Meanwhile, the proteins of GSDMD and Pro- and Cleaved Caspase-11 and the mRNAs of Il-1β and Il-18, which are markers of pyroptosis, were increased after 1-NP treatment. Moreover, pretreatment with wedelolactone (WED), an antagonist of Caspase-11, alleviated 1-NP-induced ALI. As expected, pharmacological inhibition or genetic deletion of Caspase-11 abolished 1-NP-induced apoptosis and pyroptosis. Interestingly, 1-NP attenuated Caspase-11 proteasome degradation. Mechanistically, 1-NP downregulated the expression of SYVN1, an E3 ubiquitin ligase of Caspase-11. 1-NP promoted the interaction between SYVN1 and Caspase-11 and inhibited Caspase-11 ubiquitination and subsequent proteasome degradation. Transfection with SYVN1 overexpression plasmids abolished 1-NP-mediated the reduction of Caspase-11 ubiquitination-dependent degradation, apoptosis, and pyroptosis. These results revealed that acute 1-NP may induce ALI via Caspase-11-mediated apoptosis and pyroptosis by downregulating SYVN1.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure. Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption. This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release. ROS-induced lipid and protein peroxidation, endothelial dysfunction, and programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, exacerbate lung injury. In COVID-19-related ARDS, SARS-CoV-2 spike protein amplifies mitochondrial ROS, worsening outcomes. Antioxidant therapies falter due to non-specific ROS suppression, patient heterogeneity (e.g., GSTP1 polymorphisms), and poor bioavailability. We propose a model where oxidative stress drives ARDS stages—early alveolar injury and late systemic dysfunction—suggesting targeted therapies like endothelial-specific nanoparticles or ferroptosis inhibitors. Precision medicine using biomarkers (e.g., mtDNA) and gender-specific approaches (e.g., estrogen-Nrf2 regulation) could enhance outcomes. This review bridges mechanistic gaps, critiques therapeutic failures, and advocates novel strategies like mitochondrial-targeted therapies to improve ARDS management.

Celastrol attenuates ferroptosis-mediated intestinal ischemia/reperfusion-induced acute lung injury via Hippo-YAP signaling.

Identification of phytochemical compounds of Fagopyrum dibotrys and their targets by metabolomics, network pharmacology and molecular docking studies