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Herba Siegesbeckiae (HS) has been traditionally used for managing cardio- and cerebro-vascular diseases. Our previous study demonstrated that HS ameliorates myocardial ischemia/reperfusion (I/R) injury. Also, the differentially expressed proteins between HS and I/R groups were shown to be displayed as UCHL5 and were mainly enriched in the NLRP3 inflammasome pathway. However, further elucidation is required concerning the effective subfractions, constituents, and HS influence on the UCHL5/NLRP3 pathway. A co-immunoprecipitation assay and UCHL5 overexpression in cardiomyocyte explores were used to determine the interaction between UCHL5 and NLRP3 during myocardial I/R. The water extracts of HS were subjected to column chromatography using a macroporous adsorption resin. Four HS subfractions (HS-A [H 2 O elution], HS-B [20% ethanol elution], HS-C [50% ethanol elution], and HS-D [95% ethanol elution]) were obtained in this study. HS-C exhibited the most significant protective effect against myocardial I/R and improved I/R injury in vivo . HS-C markedly restrained the expression of UCHL5 and NLRP3 and resisted the role of UCHL5/NLRP3 in the pathogenesis of I/R. Eleven main constituents of HS-C were identified, among which kirenol best displayed anti-I/R injury activity and binding energy. Kirenol accounted for 62.4% of HS-C. Thus, HS-C effectively protected against myocardial I/R injury, which was attributed to mitigation of the UCHL5/NLRP3 pathway and kirenol was identified as the core active constituent.

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The diterpene kirenol has notable biological activity. In this study, molecular docking software (Discovery Studio) was adopted to investigate the anti‐inflammatory and antioxidant properties of kirenol. Twenty‐nine kirenol derivatives were synthesized based on the molecular docking outcomes. Cytotoxicity analyses of the kirenol derivatives were performed in Raw264.7 macrophages using the CCK‐8 assay, and nitric oxide (NO) concentrations were determined using the Griess assay. The DCFH‐DA approach identified the general pattern of reactive oxygen species (ROS) fluctuations. The mitochondrial mass and morphology were detected using the Mito‐Tracker Red fluorescent probe. Preliminary bioassay tests indicated that the concentration of NO was substantially reduced by certain derivatives. Moreover, these derivatives inhibited LPS‐induced ROS generation, and one of them exhibited a further reducing ROS generation and pro‐inflammatory response by suppressing excessive mitochondrial fission. These findings suggest that this particular derivative may be a promising natural compound for combating oxidative inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Osteoarthritis (OA) is a chronic degenerative disease, its main characteristic involves articular cartilage destruction and inflammation response, absent of effective medical treatment. Our current research aimed to explore anti-inflammatory effect of kirenol, a diterpenoid natural product compound, in the development of OA and its potential molecular mechanism through in vitro and in vivo study. Methods In vitro, chondrocytes were pretreated with kirenol for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α, IL-6, aggrecan, collagen-II, MMP13and ADAMTS5 were evaluated by the Griess reaction and ELISAs. The mRNA (aggrecan and collagen-II) and protein expression (COX-2, iNOS, P65, IκB, PI3K, AKT) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and P65. The in vivo effect of kirenol was evaluated in mice OA models induced by destabilization of the medial meniscus (DMM). Results We found that kirenol inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, ADAMTS-5. Besides, kirenol remarkably decreased IL-1β-induced degradation of aggrecan and collagen-II. Furthermore, kirenol significantly inhibited IL-1β-induced phosphorylation of PI3K/Akt and NF-κB signaling. In vivo, the cartilage in kirenol-treated mice exhibited less cartilage degradation and lower OARSI scores. Conclusions Taken together, the results of this study provide potent evidence that kirenol could be utilized as a potentially therapeutic agent in prevention and treatment of OA.

Genus Siegesbeckia has been utilized as herbal medicine for treating arthritis, stroke, rash and other diseases for hundreds of years in East Asia. Modern pharmacological researches demonstrated the species of genus Siegesbeckia contains numerous naturally occurring active compounds. Till now, 250 compounds have been separated from Siegesbeckia species, namely 128 diterpenoids, 71 sesquiterpenoids, 14 flavonoids and 37 other compounds. A number of studies showed Siegesbeckia extracts or constituents possessed various therapeutic activities, including anti-inflammation, analgesia, anti-cancer and so on. Some of them have a bright prospect in naturally occurring drug discovery. The information provided by this review is expected to be beneficial for further phytochemical and pharmacological studies of the genus Siegesbeckia. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a chronic degenerative disease, its main characteristic involves articular cartilage destruction and inflammation response, absent of effective medical treatment. Our current research aimed to explore anti-inflammatory effect of kirenol, a diterpenoid natural product compound, in the development of OA and its potential molecular mechanism through in vitro and in vivo study. Methods: In vitro, chondrocytes were pretreated with kirenol for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α, IL-6, aggrecan, collagen-II, MMP13and ADAMTS5 were evaluated by the Griess reaction and ELISAs. The mRNA (aggrecan and collagen-II) and protein expression (COX-2, iNOS, P65, IκB, PI3K, AKT) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and P65. The in vivo effect of kirenol was evaluated in mice OA models induced by destabilization of the medial meniscus (DMM). Results: We found that kirenol inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, ADAMTS-5. Besides, kirenol remarkably decreased IL-1β-induced degradation of aggrecan and collagen-II. Furthermore, kirenol significantly inhibited IL-1β-induced phosphorylation of PI3K/Akt and NF-κB signaling. In vivo, the cartilage in kirenol-treated mice exhibited less cartilage degradation and lower OARSI scores. Conclusions: Taken together, the results of this study provide potent evidence that kirenol could be utilized as a potentially therapeutic agent in prevention and treatment of OA. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is a type-1 inflammatory ailment characterized by the recurrent nasal rubbings, sneezing, and other unpleasant symptoms. AR is an imperative airway inflammatory ailment that affects nearly 20%–30% of the global population. Kirenol is a bioactive diterpenoid with numerous beneficial properties. Objectives: In this study, we aimed to assess the therapeutic role of kirenol against the ovalbumin (OVA)-induced AR in mice via suppression of oxidative and inflammatory responses. Materials and Methods: AR was induced in BALB/c mice via administration of OVA. Subsequently, the animals were administered with 20 and 30 mg/kg of kirenol. Dexamethasone was utilized as the standard drug. The frequencies of nasal rubbings and sneezing of the mice were recorded. The status of histamine, OVA-specific immunoglobulin E (IgE), prostaglandin-D2 (PGD2), and leukotriene C4 (LTC4) was examined by using commercial assay kits. The levels of eosinophil cationic protein (ECP), interleukin (IL)-4, IL-5, IL-6, IL-33, and tumor necrosis factor (TNF)-α were investigated through the marker-specific assay kits. The mononuclear cells were isolated from the spleen of the animals of untreated AR group and cultured in an RPMI-1640 medium. The mRNA expression of a thioredoxin-interacting protein (TXNIP) in the spleen cells was studied by real-time polymerase chain reaction technique. The status of oxidative stress and inflammatory cytokines was examined by using assay kits. Results: Kirenol (20 and 30 mg/kg)-administered AR mice exhibited reduced frequency of nasal rubbing and sneezing. Kirenol effectively reduced the status of OVA-specific IgE and histamine in AR mice. The status of PGD2, LTC4, IL-4, IL-5, IL-6, IL-33, TNF-α, ECP status, and eosinophil count was diminished by the kirenol. The level of malondialdehyde and reactive oxygen species was reduced and the activity of superoxide dismutase markedly was improved by the kirenol. The kirenol-supplemented spleen-derived mononuclear cells showed downregulation of mRNA expression of TXNIP. Conclusion: These results demonstrate the curative role of kirenol against the OVA-mediated AR in mice, which can be a promising agent to treat AR in humans in future. [ABSTRACT FROM AUTHOR]

Conventional anti-tumour chemotherapy is facing the challenges of poor specificity, high toxicity and drug resistance. Tumour microenvironment (TME) plays a critical role in tumour development and drug resistance. To address this problem, we constructed a novel anti-tumour nanoparticle platform RBC@BPQDs-DOX/KIR, black phosphorus nanoparticle quantum dots (BPQDs) with one of the chemotherapeutics (doxorubicin, DOX) and an anti-inflammatory traditional Chinese medicine active component (Kirenol, KIR). Red blood cell membrane (RBCm) vesicles were used as the shell to envelop several nanocores. The combination of DOX and KIR may promote therapeutic efficacy, at which the anti-apoptotic effect of the tumour cells was inhibited (by downregulating Bcl-2 and upregulating Bax) and the tumour progression-related inflammatory factors, such as tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) were downregulated. Furthermore, TME was remodelled and the anti-tumour effect of DOX was magnified. RBCm imparts high biocompatibility and enhanced permeability and retention (EPR) effects to RBC@BPQDs-DOX/KIR, thus enhancing its tumour passively targetability. Overall, the RBCm-camouflaged drug delivery system RBC@BPQDs-DOX/KIR as a promising therapy for targeted chemotherapeutics and anti-inflammatory therapeutics may provide a specific and highly efficient anti-tumour treatment choice.

Liver diseases are a major health issue in both men and women and cause significant mortality worldwide. The hepatoprotective effects of kirenol were evaluated in acetaminophen (APAP)‐induced toxicity in HepG2 cells and ethanol (EtOH)‐ induced hepatotoxicity in rats. The cytotoxicity of kirenol (IC50, 25 µM/ml) and APAP (20 µg/ml) with sylimarin (IC50, 15 µg/ml) was observed in HepG2 cells by 3‐(4,5‐dimethylthiazol‐2‐yl)−2,5‐diphenyltetrazolium bromide assay. Furthermore, reactive oxygen species formation, mitochondrial membrane potential, and oxidative stress markers such as thiobarbituric acid‐reactive substance, suproxide dismutase, and catalase were assayed. Rats were administered a different dose (10, 20, and 30 mg/kg/day) for a period of 4 weeks before a single dose of EtOH (40% vol/vol) 3 g/kg/day. EtOH administered rats appeared to have lower body weight gain, severe hepatic and kidney damage as proved by elevated aspartate transaminase, alanine transaminase, alkaline phosphatase, uric acid, increased malondialdehyde (MDA), and inflammatory markers, and reduced glutathione (GSH) levels. Results showed that the kirenol treatment enhanced the GSH and reduced MDA in the liver and renal tissues and restored TNF‐α and IL‐6. Histoanalysis proved the protective effects of kirenol. In conclusion, it was proved that the kirenol demonstrated a hepato‐protective effect in APAP‐ and EtOH‐induced liver toxicity in HepG2 cells and rats, respectively. [ABSTRACT FROM AUTHOR]

The thyroid cancer, especially papillary thyroid cancers are very common among population with high intake of iodine or iodine uptake. Even though several treatment options are available, there is still complication and side effects are still persistent. The role of signaling molecules in cancer signaling is very vast and their significance in progression of disease was increasing which leads to mortality of the patient. The major key players are PI3K, AKT and MAP kinase, involves in cell survival, proliferation, and inhibition of apoptosis and are the promising candidate for cancer treatment target, several researchers focuses these molecule to treat various acute and chronic diseases like cancer. On the other side, various literatures propose that natural compounds derived from plant source are shown potent anticancer property against several cancers. In our study we are looking in to one such active principle obtained from plant source, a diterpenoid compound kirenol, and its role thyroid cancer. Here, we report that kirenol role on various cellular mechanisms like induction of apoptosis, enhancing ROS indirectly by inhibiting antioxidants, altering the signaling mechanism of cell survival and apoptosis. Our study proposes that kirenol involved in the cancer cell cytotoxicity by inducing apoptosis and inhibition of cancer cell survival. Thus, targeting this signaling molecule with kirenol definitely favors and may lead to a therapeutic modality for thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: Ischemia/reperfusion (I/R)-induced stroke is a long-lasting disability. Numerous reports have demonstrated that inflammation is the major cause of ischemic cerebral injury. Therefore, it is important to develop an effective anti-inflammatory agent for the attenuation of I/R-induced brain injury. Objective: In this study, we examined the therapeutic role of kirenol against I/R-induced neuronal damage by inhibiting inflammation in Sprague-Dawley (SD) rats. Materials and Methods: I/R was induced in SD rats and subsequently were administered with 10 and 20 mg/kg of kirenol. Then, we assessed the neurological score, brain water content, and infarct size. The level of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione, and acetylcholinesterase, as well as the levels of malondialdehyde, was measured by using standard methods. The level of tumor necrosis factor (TNF)-α interleukin (IL)-1 β, IL-4, IL-6, and IL-10; and vascular endothelial growth factor was measured using standard kits. The targeted messenger RNA expression (NLRP3, NLRP4, TLR-4, TNF-α, caspase-1, ASC, and IL-1β) was quantified by polymerase chain reaction technique. Histopathological analysis of the brain tissue was performed. Results: According to our results, kirenol decreased the neurological deficit score, ameliorated the motor function, suppressed oxidative stress, reduced inflammation, and mediated the inhibition of TLR4/NLRP3-mediated inflammatory pathway. Conclusion: In conclusion, these findings demonstrate the protective effects of kirenol against I/R-induced cerebral injury. The mechanism of action is associated with the inhibition of inflammation through halting the TLR4/NLRP3 signaling pathway. In summary, kirenol is a potentially new compound which can be used to improve therapeutic strategies for stroke treatments. [ABSTRACT FROM AUTHOR]

This present findings hypothesized the modulatory effects of kirenol on expression pattern of cell proliferative and inflammatory markers during DMBA induced HBP carcinogenesis. The machinery pathways for chemomodulatory effect of kirenol was investigated by analyzing the levels of antioxidants histological changes, lipid peroxidation and molecular expression pathway of PCNA, NF‐κB in the DMBA only painted HBPC. Oral cancer was developed in the HBP model by DMBA (0.5%) three times a week for 14th weeks. We analyzed body weight with deregulated molecular expressions pattern of PCNA and NF‐κB was noticed in the DMBA induced hamsters compared to control hamsters. Oral administration of kirenol 30 mg/kg bw, to DMBA induced hamster models reverted the activity of the biochemical markers in Group 4. Besides, tumor tissues of hamsters receive antioxidant capability from kirenol exclaimed significant modifications in DMBA induced causes: inhibits cell proliferation (inhibits PCNA expression) and suppresses inflammation (decreased NF‐κB expression) of markers. Taken together, the protective effect of that kirenol an augmenting inflammation of the started cells and exhibited antiproliferative, anti‐inflammatory, antilipid peroxidative and restores the xenobiotic enzymes levels (phase I and II) system and enhances antioxidant properties in oral carcinoma hamsters, in which turn, is reflected diminished tumor burden, volume, and multiplicity. [ABSTRACT FROM AUTHOR]

Kirenol, a potential natural diterpenoid molecule, is mainly found in Sigesbeckia species. Kirenol has received a lot of interest in recent years due to its wide range of pharmacological actions. In particular, it has a significant ability to interact with a wide range of molecular targets associated with inflammation. In this review, we summarise the efficacy and safety of kirenol in reducing inflammation, as well as its potential mechanisms of action and opportunities in future drug development. Based on the preclinical studies reported earlier, kirenol has a good therapeutic potential against inflammation involved in multiple sclerosis, inflammatory bowel disorders, diabetic wounds, arthritis, cardiovascular disease, bone damage, and joint disorders. We also address the physicochemical and drug-like features of kirenol, as well as the structurally modified kirenol-derived molecules. The inhibition of pro-inflammatory cytokines, reduction in the nuclear factor kappa-B (NF-κB), attenuation of antioxidant enzymes, stimulation of heme-oxygenase-1 (HO-1) expression, and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation are among the molecular mechanisms contributing to kirenol’s anti-inflammatory actions. Furthermore, this review also highlights the challenges and opportunities to improve the drug delivery of kirenol for treating inflammation. According to the findings of this review, kirenol is an active molecule against inflammation in numerous preclinical models, indicating a path to using it for new drug discovery and development in the treatment of a wide range of inflammations.

Kirenol is a diterpenoid extracted from the Chinese herbal medicine Siegesbeckiae. Siegesbeckiae has been used to treat Rheumatoid arthritis (RA) in China for several centuries. RA is characterized by the proliferation of synoviocytes in inflamed synovia, as well as by their expression of inflammatory cytokines. In the present study, we found that Kirenol inhibited the migration, invasion, and proinflammatory of IL-6 secretion of RA-associated synovial fibroblasts (FLS) at a concentration of 100–200 μg/ml in vitro. Proinflammatory cytokines production and synovium hyperplasia and cartilage erosion were also inhibited in a collagen-induced arthritis (CIA) mouse model upon Kirenol treatment. Together, our results thus confirm that Kirenol has potent therapeutic efficacy in RA owing to its ability to suppress negative FLS activities.

Conventional anti-tumour chemotherapy is facing the challenges of poor specificity, high toxicity and drug resistance. Tumour microenvironment (TME) plays a critical role in tumour development and drug resistance. To address this problem, we constructed a novel anti-tumour nanoparticle platform RBC@BPQDs-DOX/KIR, black phosphorus nanoparticle quantum dots (BPQDs) with one of the chemotherapeutics (doxorubicin, DOX) and an anti-inflammatory traditional Chinese medicine active component (Kirenol, KIR). Red blood cell membrane (RBCm) vesicles were used as the shell to envelop several nanocores. The combination of DOX and KIR may promote therapeutic efficacy, at which the anti-apoptotic effect of the tumour cells was inhibited (by downregulating Bcl-2 and upregulating Bax) and the tumour progression-related inflammatory factors, such as tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) were downregulated. Furthermore, TME was remodelled and the anti-tumour effect of DOX was magnified. RBCm imparts high biocompatibility and enhanced permeability and retention (EPR) effects to RBC@BPQDs-DOX/KIR, thus enhancing its tumour passively targetability. Overall, the RBCm-camouflaged drug delivery system RBC@BPQDs-DOX/KIR as a promising therapy for targeted chemotherapeutics and anti-inflammatory therapeutics may provide a specific and highly efficient anti-tumour treatment choice. [ABSTRACT FROM AUTHOR]

Siegesbeckia orientalis has been reported to exhibit anti-allergic, anti-infertility, anti-inflammatory, anti-rheumatic, and immunosuppressive activities. However, there are very few studies describing its stimulatory effects on exercise capacity. This study elucidated whether S. orientalis extract (SOE) standardized to kirenol content can enhance exercise endurance by increasing mitochondrial biogenesis. SOE significantly improved the running distance and time in mice fed normal diet (ND) and high-fat diet (HFD). SOE also enhanced mitochondrial biogenesis by stimulating the mitochondrial regulatory genes including peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM) in the skeletal muscles of ND and HFD mice. Furthermore, SOE upregulated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/PGC-1α/peroxisome proliferator-activated receptor delta (PPARδ) signaling pathway in the skeletal muscles of ND and HFD mice. Kirenol markedly increased adenosine triphosphate production and mitochondrial activity by stimulating the expression of markers of mitochondrial biogenesis and upregulating the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway in L6 myotubes. These results show that SOE has the potential to be used to develop an exercise supplement capable of stimulating mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway. [ABSTRACT FROM AUTHOR]

Kirenol is a diterpenoid extracted from the Chinese herbal medicine Siegesbeckiae. Siegesbeckiae has been used to treat Rheumatoid arthritis (RA) in China for several centuries. RA is characterized by the proliferation of synoviocytes in inflamed synovia, as well as by their expression of inflammatory cytokines. In the present study, we found that Kirenol inhibited the migration, invasion, and proinflammatory of IL-6 secretion of RA-associated synovial fibroblasts (FLS) at a concentration of 100–200 μg/ml in vitro. Proinflammatory cytokines production and synovium hyperplasia and cartilage erosion were also inhibited in a collagen-induced arthritis (CIA) mouse model upon Kirenol treatment. Together, our results thus confirm that Kirenol has potent therapeutic efficacy in RA owing to its ability to suppress negative FLS activities. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A semisynthesis of epoxy-pimarane diterpenoids was accomplished. • Their absolute configurations of 4 was confirmed by X-ray crystallographic data. • All these compounds were assessed their potential as FXa inhibitor agents. Abstract Kirenol is one of the biologically active diterpenoids from Siegesbeckia pubescens. In terms of the high content and typical structure, many ent -diterpenoids separated from S. pubescens were presumed to be biologically related to kirenol. Among them, epoxy-pimarane diterpenoids are belonging to a special family of naturally occurring compounds that attracted our attentions on their putative biosynthesis pathway and biological activities. Here, we designed and synthesized two known 14,16-epoxy-pimarane diterpenoids (2 and 3) and five 8,15-epoxy-pimarane diterpenoids (4 – 8) from kirenol. Their absolute structures were determined by 1D and 2D NMR data and the absolute configurations of 4 were confirmed by X-ray crystallographic data. Their inhibition effects on factor Xa (FXa) were evaluated to assess the potentiality of epoxy-pimarane diterpenoids as FXa inhibitor agents. [ABSTRACT FROM AUTHOR]

Siegesbeckia glabrescens (Compositae), an annual herb indigenous to Korean mountainous regions and has been eaten as a food in Korea. This study investigated ABTS, DPPH and nitric oxide (NO) radical-scavenging activities, and melanin production and TYR inhibitory effects-guided fractionation to identify therapeutic phytochemicals from S. glabrescens that can attenuate oxidation and melanogenesis in murine melanoma B16F10 cells. Nine compounds with inhibitory effects on melanin production, and TYR activity, and ABTS, DPPH, and NO radical scavenging activity were isolated from the 100% ethanol fraction from S. glabrescens. Among the nine compounds, kirenol (K), methyl ent-16α, 17-dihydroxy-kauran-19-oate (MDK) had strong inhibitory effects on melanin production and TYR activity with antioxidant effects. Western blot analysis revealed that K and MDK suppressed tyrosinase-related protein (TYRP)-1, TYRP-2 and microphthalmia-associated transcription factor (MITF) expression. Moreover, these two compounds inhibited intracellular reactive oxygen species (ROS) level in tert-butyl hydroperoxide (t-BHP)-treated B16F10 cells. Our results suggest that S. glabrescens containing active compounds such as K and MDK, which has antioxidant and antimelanogenesis effects, is the potent therapeutic and functional material for the prevention of oxidation-induced hyperpigmentation.

Arthritis is a group of diseases characterized by joint pain, swelling, stiffness, and limited movement. Osteoarthritis, rheumatoid arthritis, and gouty arthritis are the most common types of arthritis. Arthritis severely affects the quality of life of patients and imposes a heavy financial and medical burden on their families and society at large. As a widely used traditional Chinese medicine, Herba siegesbeckiae has many pharmacological effects such as anti-inflammatory and analgesic, anti-ischemic injury, cardiovascular protection, and hypoglycemic. In addition, it has significant therapeutic effects on arthritis. The rich chemical compositions of H. siegesbeckiae primarily include diterpenoids, sesquiterpenoids, and flavonoids. As one of the main active components of H. siegesbeckiae, kirenol and quercetin play a vital role in reducing arthritis symptoms. In the present study, the research progress in arthritis treatment with the active components of H. siegesbeckiae is reviewed. [Display omitted] • The active components of Herba siegesbeckiae treat arthritis with multiple targets. • There are similarities and differences in the mechanism of action of active components of Herba siegesbeckiae on arthritis. • The active components of Herba siegesbeckiae can play a better role through nanotechnology. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is an acute and life-threatening inflammatory disease of the lung parenchyma that is associated with high mortality worldwide. No therapeutic strategies have been developed for the mitigation of the proinflammatory response that characterizes ALI. Kirenol has anti-inflammatory, antiarthritic, and immunoregulatory effects. In the present study, we investigated the protective effects of kirenol against lipopolysaccharides (LPS)-induced ALI in mice. Kirenol reduced the LPS-induced histopathology changes involving edema and thickening of the interstitial or alveolar walls, infiltration of leukocytes, formation of hyaline membrane. Pretreatment with kirenol reduced leukocytes infiltration in bronchoalveolar lavage fluid (BALF), the alveolar-capillary barrier disruption and lipid peroxidation in lung tissues induced by LPS. Kirenol significantly inhibited the secretion of cytokines, IL-1β, IL6, and TNFα, into the BALF of the mice with LPS-induced ALI through NFκB activation. Moreover, kirenol attenuated the downregulation of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and catalase that was induced by LPS. HO-1 expression and the phosphorylation of Nrf2 and AMPK2 were also induced by kirenol. The results indicate that kirenol can be developed as a treatment strategy for ALI, and its effects are induced through the inhibition of the NF-κB proinflammatory pathway and promotion of AMPK2/Nrf2-mediated HO-1 and antioxidant enzymes (AOE) activation.

Kirenol is a bioactive substance isolated from Herba Siegesbeckiae. Although the anti‐inflammatory activity of kirenol has been well documented, its role in autophagy remains unknown. The present study aimed to investigate the protective role of kirenol on inflammation challenged by lipopolysaccharide (LPS) in acute lung injury (ALI) cell and mouse models and unravel the underlying mechanisms, with a particular focus on autophagy. For this purpose, an ALI cell and mouse models were established, and the effects of kirenol on the expression of molecules related to inflammation and autophagy were examined. The present results revealed that kirenol could significantly inhibit inflammatory cytokines secretion in cells and in the mice injured by LPS; this effect may be attributed to enhanced autophagy as evidenced by the up-regulation of LC3‐II and the down-regulation of p62 both in vitro and in vivo. Phosphorylated AMPK and ULK1 increased, while phosphorylated mTOR decreased in the kirenol-treated ALI cell model. Moreover, inhibition of autophagy using AMPK inhibitor or 3-MA or chloroquine (CQ) reversed the anti-inflammatory and autophagy-enhancement effects of kirenol exposure in vitro , indicating that kirenol could enhance autophagy by activating the AMPK-mTOR-ULK1 pathway. The results of RNA sequencing suggested that kirenol was strongly related to the biological functions of acute inflammatory response and the AMPK signaling pathway. Further in vivo ALI mouse model studies demonstrated the protective role of kirenol against lung inflammation, such as improved histopathology, decreased lung edema, and leukocyte infiltration were abolished by 3-MA. These findings implicate that kirenol can inhibit LPS-induced inflammation via the AMPK-mTOR-ULK1 autophagy pathway. [ABSTRACT FROM AUTHOR]

Kirenol has been reported to possess anti-oxidant, anti-inflammatory, anti-allergic, anti-adipogenic, and anti-arthritic activities; however, its effect on osteoblast differentiation has not yet been reported. The aim of the present study was to evaluate the effect of kirenol on osteoblast differentiation through activation of the bone morphogenetic protein (BMP) and Wnt/β-catenin signaling pathways in MC3T3-E1 cells. Kirenol markedly promoted alkaline phosphatase (ALP) activity and mineralization. Kirenol not only increased the expression of osteoblast differentiation markers, such as ALP, type I collagen (ColA1), and osteopontin (OPN), but also increased the expression of osteoprotegerin/receptor activator of nuclear factor kappa B ligand (OPG/RANKL) ratio. The effects of kirenol on osteoblast differentiation were accompanied by stimulating the expression of the BMP and Wnt/β-catenin signaling pathways, including BMP2, runt-related transcription factor 2 (Runx2), osterix (Osx), low density lipoprotein receptor related protein 5 (LRP5), disheveled 2 (DVL2), β-catenin, cyclin D1 (CCND1), and phosphorylated glycogen synthase kinase 3β (GSK3β). In addition, kirenol up-regulated the expression of β-catenin, CCND1, ALP, and ColA1 which were down-regulated by siRNA knockdown of β-catenin. Overall, these results demonstrate that kirenol is capable of promoting osteoblast differentiation in MC3T3-E1 cells through activation of the BMP and Wnt/β-catenin signaling pathways, suggesting that it is a potential candidate target for treating or preventing osteoporosis. [ABSTRACT FROM AUTHOR]

High hydrostatic pressure (HHP) extraction method was optimized to maximize the extraction yield of kirenol from Siegesbeckia orientalis. Operating parameters such as extraction pressure (100-600 MPa), pressure holding time (3-20 min), feed-to-solvent ratio (1:10-1:90 (w/v)), and solvent (ethanol) concentration (0-100%) were investigated individually by mono-factor experiments. Then, the optimal extraction conditions were determined using response surface methodology. Box-Behnken design was applied to evaluate the effects of three independent variables (extraction pressure, solvent concentration, and feed-to-solvent ratio) on the extraction yield of kirenol from S. orientalis. Extraction pressure, solvent concentration, and feed-to-solvent ratio affected the extraction yields significantly, whereas the pressure holding time had no significant effect. The optimal processing conditions, which gave a maximum extraction yield of 85.9% kirenol from the raw material, were as follows: extracting pressure 320 MPa, pressure holding time 5min, ethanol concentration 18%, and feed-to-solvent ratio 1:76 (w/v). [ABSTRACT FROM AUTHOR]

Highlights: [•] Kirenol inhibits the adipogenic transcription factors and lipogenic enzymes. [•] Kirenol stimulates the Wnt/β-catenin signaling pathway components. [•] Kirenol inhibits adipogenesis through activation of the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] Developed a LC-ESI–MS/MS method firstly for the determination of Kirenol in biological samples. [•] Firstly determinate ent-16β,17-dihydroxy-kauran-19-oic acid in rat plasma. [•] Firstly compare the pharmacokinetic behaviors after oral administration of Herba Siegesbeckiae extract with the single substances. [•] Higher specificity and good sensitivity with LLOQ of 50.0ng/mL for Kirenol and 25.0ng/mL for ent-16β,17-dihydroxy-kauran-19-oic acid. [•] Short analysis time of 4.0min. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis is characterized by the imbalance of T cells, which leads to increased pro-inflammatory and reduced anti-inflammatory cytokines. Modulating the balance among T cells is crucial for the treatment of RA. Kirenol is a major diterpenoid components of Herba Siegesbeckiae, which has been applied for arthritic therapy for centuries. Since prior research showed Kirenol exhibited anti-inflammatory effect in rats, in this study we have evaluated the effect and mechanism of bioactive Kirenol in a rat model of collagen-induced arthritis (CIA) on modulation of T cells. After immunization with bovine type II collagen (CII), Wistar rats were orally administered saline (CIA group), 2mg/kg Kirenol or 2mg/kg prednisolone daily for 30 days. The severity of arthritis was clinically and histologically assessed. The numbers of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and IFNγ+CD4+ and IL4+CD4+ T cells were determined by flow cytometry, the mRNA expression level of Foxp3 was quantified by RT-PCR, cytokine levels were measured by ELISA and CII-induced cell proliferation was quantified in vitro. Kirenol significantly delayed the occurrence and reduced the disease severity of CIA. Histological analysis confirmed Kirenol suppressed joint inflammation and inhibited cartilage and bone destruction, compared to the CIA group. Kirenol also upregulated the mRNA expression of Foxp3, increased the numbers of CD4+CD25+Foxp3+ and IL4+CD4+ T cells, and reduced the number of IFNγ+CD4+ T cells. Kirenol reduced the levels of TNF-α, IL-17A and IL-6 in synovial fluid and TNF-α, IL-17A and IFN-γ in serum, and increased the serum levels of IL-4, IL-10 and TGF-β1. In addition, Kirenol inhibited the ability of CII to induce splenocyte, PBMC and lymph node cell proliferation in vitro, compared to cells from CIA rats. In conclusion, these results suggest that Kirenol may be a potential immunosuppressant for the treatment for rheumatoid arthritis. [Copyright &y& Elsevier]

Background: Despite the excellent anti-inflammatory and anti-rheumatic efficacy associated with kirenol generation, the content of kirenol in Siegesbeckea orientalis is quite low. Objective: This study was designed to establish a reliable kirenol production protocol by transformed root cultures of S. orientalis and to investigate the antimicrobial activities of kirenol, hairy root, and S. orientalis. Materials and Methods: Transformed root cultures of S. orientalis were established by the transformation of Agrobacterium rhizogenes A4. Transgenic status of the roots was confirmed by polymerase chain reaction (PCR) using rolB specific primers. The biomass and kirenol accumulation of hairy root clones were assessed using four different culture media: MS, MS/2, B5, and white. The antimicrobial activities of kirenol, hairy root, and S. orientalis were evaluated by the disc diffusion method. Results: The optimum media for kirenol synthesis was MS. The content of kirenol in transformed hairy roots made up about 80% of that observed in natural leaves of S. orientalis (1.6 mg/g dry weight). All tested samples displayed antimicrobial activity against Gram-positive pathogens including Staphylococcus epidermidis, Staphylococcus aureus, and Acinetobacter baumannii, with MIC ranging from 78 to 625 μg/mL. Discussion and Conclusion: The high level of kirenol contents was obtained from hairy roots of S. orientalis. Kirenol was effective against gram-positive bacteria. Interestingly, the extract from hairy roots showed a diverse antimicrobial effect from that of kirenol and S. orientalis. [ABSTRACT FROM AUTHOR]

Abstract: Molecular imprinted polymers (MIPs) were prepared by thermal polymerization using a non-covalent molecularly imprinting strategy with kirenol as the template, acrylamide (AM) as the functional monomer and ethylene glycol dimethacrylamide (EGDMA) as the cross-linker in the porogen of tetrahydrofuran (THF). The synthesized MIPs were characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR). Its molecular recognition property was investigated by UV spectrogram. High-pressure liquid chromatography (HPLC) was used for analysis of target analytes. The polymers were evaluated further by batch rebinding experiments, and from the derived isotherms their binding capacity and binding strength were determined. Then the selectivity of the MIPs was checked toward the selected structurally related compounds and the recognition coefficients for kirenol, darutigenol, and ent-2-oxo-15, 16, 19-trihydroxypimar-8(14)-ene (TD) were 2.47, 3.43 and 3.40, respectively. The properties of MIPs for SPE were also evaluated. The results obtained demonstrate that the good imprinting effect and the excellent selectivity of MIPs were obtained. The optimized molecular imprinted SPE procedure was applied to extract kirenol directly from the extracts of the aerial part of Siegesbeckia pubescens herb. A selective extraction of kirenol from traditional Chinese medicine (TCM) was achieved with extraction yield of 80.9%. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Siegesbeckia orientalis has been traditionally used as a topical anti-inflammatory and analgesic agent. Aims of the study: Current study was designed to explore the topical anti-inflammatory and analgesic effects of a constituent isolated from Siegesbeckia orientalis (Compositae), in order to validate its folk use. Materials and methods: Kirenol was isolated from ethanolic extract of Siegesbeckia orientalis. Several topical formulations containing kirenol were investigated for anti-inflammatory and analgesic activities in rat. The effects were studied using carrageenan-induced rat acute inflammation model, complete Freund''s adjuvant (CFA)-induced chronic inflammation and formalin test in rats. Piroxicam gel and methyl salicylate ointment were studied as positive control for anti-inflammatory and analgesic activity, respectively. Results: The anti-inflammatory effect of kirenol 0.4–0.5% (w/w) was similar to the effect of piroxicam gel 4h after carrageenan injection. The analgesic activity of topical preparation with more than 0.4% (w/w) was observed in the late phase. These effects may be due, at least in part, to the pro-inflammatory cytokine production of IL-1β and TNF-α. The administration of kirenol cream at the dose of 0.3, 0.4 and 0.5% (w/w) significantly inhibited the development of joint swelling induced by CFA, which was auxiliary supported by histopathological studies. Conclusion: Kirenol has demonstrated its significant potential to be further investigated for its discovery as a new lead compound for management of topical pain and inflammation, although further pharmacological research is necessary to fully understand its mechanism of action. It also supports the potential beneficial effect of topically administered Siegesbeckia orientalis in inflammatory diseases. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Kirenol is a diterpenoid compound purified from the Chinese Herba Siegesbeckiae. Siegesbeckiae has been employed for the treatment of arthritis for centuries, its safety and efficacy are documented through a long history of human use. Aim of the study: To investigate the effects on collagen-induced arthritis (CIA) and anti-inflammatory mechanism of Kirenol. Materials and methods: Kirenol was administrated intragastrically in rats after the onset of CIA. Pathological changes were evaluated by paw swelling and histopathology. Concentration of IL-1β in synovial fluid and adrenal corticotropin (ACTH) in plasma were determined by Elisa. Western blot was performed to detect the expression of Annexin-1 and glucocorticoid receptor alpha (GRα) in synovium. NF-κB DNA binding activity was assessed by electrophoretic mobility shift assays (EMSA). Results: Kirenol (1, 2, and 4mg/kg) and Prednisolone depressed paw swelling and reduced IL-1β of synovial fluid in the CIA rats (p <0.05 or p <0.01). Kirenol and Prednisolone upregulated nuclear Annexin-1 and inhibited NF-κB activity in synovium of CIA. The inhibitory effect of Kirenol and Prednisolone on NF-κB activity was enhanced by anti-Annexin-1 Ab. Prednisolone, but not Kirenol, downregulated plasma ACTH and GRα expression significantly (p <0.01). Conclusion: Kirenol and Prednisolone can upregulate nuclear Annexin-1 which interacts with NF-κB to inhibit NF-κB activity, reduce cytokines expression and thereby attenuate inflammation of CIA joints. Kirenol does not lead to ACTH or GR downregulation, which is in contrast to classic glucocorticoid Prednisolone. Kirenol shares with GCs similar anti-inflammatory mechanism but bypass the considerable limitation of GCs treatment. [Copyright &y& Elsevier]

Kirenol, a potential natural diterpenoid molecule, is mainly found in Sigesbeckia species. Kirenol has received a lot of interest in recent years due to its wide range of pharmacological actions. In particular, it has a significant ability to interact with a wide range of molecular targets associated with inflammation. In this review, we summarise the efficacy and safety of kirenol in reducing inflammation, as well as its potential mechanisms of action and opportunities in future drug development. Based on the preclinical studies reported earlier, kirenol has a good therapeutic potential against inflammation involved in multiple sclerosis, inflammatory bowel disorders, diabetic wounds, arthritis, cardiovascular disease, bone damage, and joint disorders. We also address the physicochemical and drug-like features of kirenol, as well as the structurally modified kirenol-derived molecules. The inhibition of pro-inflammatory cytokines, reduction in the nuclear factor kappa-B (NF-κB), attenuation of antioxidant enzymes, stimulation of heme-oxygenase-1 (HO-1) expression, and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation are among the molecular mechanisms contributing to kirenol's anti-inflammatory actions. Furthermore, this review also highlights the challenges and opportunities to improve the drug delivery of kirenol for treating inflammation. According to the findings of this review, kirenol is an active molecule against inflammation in numerous preclinical models, indicating a path to using it for new drug discovery and development in the treatment of a wide range of inflammations. [ABSTRACT FROM AUTHOR]

Kirenol (Kr) is an ent -pimarane type diterpenoid that has been reported from Siegesbeckia orientalis , S. pubescens , and S. glabrescens (family Asteraceae). These plants have been used traditionally for treating various ailments such as hypertension, neurasthenia, rheumatoid arthritis, asthma, snakebites, allergic disorders, paralysis, soreness, cutaneous disorders, rubella, menstrual disorders, numbness of limbs, dizziness, headache, and malaria. Importantly, in recent years, Kr has received great attention due to its diversified pharmacological activities. The current work aims to give an overview on the reported pharmacological activities of Kr. Furthermore, the findings regarding its methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, identification, semisynthetic analogues, and toxicity are highlighted to provide a reference and perspective for its further investigation. Electronic databases including ScienceDirect, Web of Knowledge, SCOPUS, Wiley Online Library, Taylor & Francis, PubMed, Springer, JACS, and Google Scholar were searched up to the beginning of 2021 to identify the reported studies. A total of 93 articles have been reviewed. The reported data suggested that Kr possessed various bioactivities including cytotoxic, apoptotic, anticancer, anti-inflammatory, cardio-protective, anti-photo-aging, anti-adipogenic, antimicrobial, muscle function improvement, fracture and wound healing, and anti-arthritic. In addition, studies revealed that the antioxidative and anti-inflammatory activities of Kr may mediate many of its therapeutic potentials as confirmed by several in-vitro and in-vivo studies. This review provides an updated summary of the recent studies on Kr, including methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, and identification, as well as semisynthetic analogues, pharmacological activities, and toxicity. Thus, this work can provide useful considerations for planning and design future research on Kr. [Display omitted] [ABSTRACT FROM AUTHOR]

Siegesbeckia glabrescens (Compositae), an annual herb indigenous to Korean mountainous regions and has been eaten as a food in Korea. This study investigated ABTS, DPPH and nitric oxide (NO) radical-scavenging activities, and melanin production and TYR inhibitory effects-guided fractionation to identify therapeutic phytochemicals from S. glabrescens that can attenuate oxidation and melanogenesis in murine melanoma B16F10 cells. Nine compounds with inhibitory effects on melanin production, and TYR activity, and ABTS, DPPH, and NO radical scavenging activity were isolated from the 100% ethanol fraction from S. glabrescens. Among the nine compounds, kirenol (K), methyl ent-16α, 17-dihydroxy-kauran-19-oate (MDK) had strong inhibitory effects on melanin production and TYR activity with antioxidant effects. Western blot analysis revealed that K and MDK suppressed tyrosinase-related protein (TYRP)-1, TYRP-2 and microphthalmia-associated transcription factor (MITF) expression. Moreover, these two compounds inhibited intracellular reactive oxygen species (ROS) level in tert-butyl hydroperoxide (t-BHP)-treated B16F10 cells. Our results suggest that S. glabrescens containing active compounds such as K and MDK, which has antioxidant and antimelanogenesis effects, is the potent therapeutic and functional material for the prevention of oxidation-induced hyperpigmentation. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is an acute and life-threatening inflammatory disease of the lung parenchyma that is associated with high mortality worldwide. No therapeutic strategies have been developed for the mitigation of the proinflammatory response that characterizes ALI. Kirenol has anti-inflammatory, antiarthritic, and immunoregulatory effects. In the present study, we investigated the protective effects of kirenol against lipopolysaccharides (LPS)-induced ALI in mice. Kirenol reduced the LPS-induced histopathology changes involving edema and thickening of the interstitial or alveolar walls, infiltration of leukocytes, formation of hyaline membrane. Pretreatment with kirenol reduced leukocytes infiltration in bronchoalveolar lavage fluid (BALF), the alveolar-capillary barrier disruption and lipid peroxidation in lung tissues induced by LPS. Kirenol significantly inhibited the secretion of cytokines, IL-1β, IL6, and TNFα, into the BALF of the mice with LPS-induced ALI through NFκB activation. Moreover, kirenol attenuated the downregulation of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and catalase that was induced by LPS. HO-1 expression and the phosphorylation of Nrf2 and AMPK2 were also induced by kirenol. The results indicate that kirenol can be developed as a treatment strategy for ALI, and its effects are induced through the inhibition of the NF-κB proinflammatory pathway and promotion of AMPK2/Nrf2-mediated HO-1 and antioxidant enzymes (AOE) activation. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear.Purpose: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo.Methods: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model.Results: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression.Conclusions: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis. [ABSTRACT FROM AUTHOR]

Damaged lesion remedial is a devastating impediment of diabetes that escorts to noteworthy disease state, predominantly bottom end diseases. Herbal outputs have exposed to be effectual in managing skin abrasions. Kirenol is recognized to encourage angiogenesis, fibroblast propagation, and exposure of cytokines and development factors concerned in wound remedial. The current study is executed to appraise the wound curing action of kirenol in streptozotocin-persusded diabetic rats by macroscopic parameters, histopathological, enzymatic, and biomolecular methods. Proportion of injure disclosure and reduction was augmented in the kirenol managed group. Histopathological examination exposed declined inflammatory cell applicability and amplified production of fibroblasts, new blood vessels, and displacement of collagen subsequent to kirenol treatment. RT-PCR study displayed diminished concentration of NF-κB, COX-2, iNOS, MMP-2 and MMP-9 levels in reply to kirenol. In accordance with all above findings our present study indicates that kirenol upholds wound medicinal prospective in hyperglycemic circumstances and might be constructive as a dealing and management for unceasing lesions in diabetic patients. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Relevance: Herba Siegesbeckiae, mainly includes Sigesbeckia orientalis L, Sigesbeckiae pubescens Makino and Sigesbeckiae glabrescens Makino. Herba Siegesbeckiae, also known as 'Xi-Xian Cao' (Chinese: ), has been regarded as an important traditional Chinese medicine since Tang dynasty. The dried aerial parts of Herba Siegesbeckiae are also being used as a herbal medicine in many countries such as Japan, Korea and Vietnam. In China, Herba Siegesbeckiae has been used for the treatment of rheumatic arthralgia with aching and weakness of loins and knees, as well as numbness of limbs., Aim of This Review: The aim of this review was to provide critical analysis on the scientific evidence to support the traditional uses of Herba Siegesbeckiae. The information available on its in botanical characteristics, traditional uses, chemical constituents, pharmacological activities, clinical studies, toxicity and quality control was summarized to understand the current research and provided the leas for future study., Materials and Methods: The search terms "Herba Siegesbeckiae", "Sigesbeckia orientalis", "Sigesbeckia pubscens" and "Sigesbeckia glabrescens" were used to obtain the information from electronic databases such as Web of Science, China National Knowledge Infrastructure, PubMed, Google Scholar and SciFinder Scholar and other web search instruments (Springer, Yahoo search). The information provided in this review was based on peer-reviewed papers in English and Chinese. Besides, information was also collected from ancient documents., Result: The studies showed that Herba Siegesbeckiae contains sesquiterpenoids, diterpenoids, flavonoids and organic acids, etc. Due to these constituents, it displayed numerous pharmacological activities, such as anti-inflammatory, antitumor, antiallergic, antioxidant, antithrombotic and antibacterial activities. In addition, it showed effects in protecting myocardial and cerebral ischemia injury., Conclusions: According to its traditional uses, chemical constituents, pharmacological activities and clinic studies, Herba Siegesbeckiae is regarded as a promising medical plant with various chemical compounds and numerous pharmacological activities. However, fewer experimental studies were focused on toxicity and quantitative study of 3 species. It suggested that further in-depth study of toxicity and quality control were critical for future evaluation of drug efficacy and safety., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.

Background: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear., Purpose: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo., Methods: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model., Results: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca 2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression., Conclusions: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objective: To investigate whether kirenol, the major pharmacologically active compound of the Chinese medicinal herb Herba Siegesbeckiae , can protect mice from dextran sulfate sodium (DSS)-induced ulcerative colitis (UC)., Methods: C57BL/6 mice with or without kirenol pretreatment were treated with DSS in drinking water for 7 days to induce UC. The symptoms of UC including weight loss, diarrhea and bloody stool were observed daily and graded using the disease activity index (DAI). Colon injury of the mice was assessed by measuring the length of the colon and HE staining of the colon tissue. The levels of inflammatory cytokines produced by the mesenteric lymph nodes (MLNs) lymphocytes were measured using enzyme-linked immunosorbent assay; the apoptosis of the lymphocytes and CD4 + T cells was analyzed using flow cytometry., Results: The mice receiving pretreatment with kirenol showed obviously ameliorated symptoms of UC and milder pathological changes in the colon as compared with the control mice. Kirenol treatment significantly down-regulated the secretion of IFN-γ, IL-17A, IL-6 and TNF-α by the MLNs lymphocytes and increased the apoptosis of lymphocytes, especially CD4 + T cells in the DSS-treated mice., Conclusions: Kirenol can protect against T cell-mediated colon injury in DSS-treated mice possibly by suppressing the secretion of inflammatory mediators and inducing apoptosis of the inflammatory lymphocytes.

Anti-photoaging effects of standardized Siegesbeckia glabrescens extract (SGE) and its major active compound kirenol were investigated using Hs68 human dermal fibroblasts and hairless mice, respectively. UVB-irradiated hairless mice that received oral SGE (600 mg/kg/day) showed reduced wrinkle formation and skinfold thickness compared with the UVB-irradiated control. Furthermore, SGE treatment increased the mRNA levels of collagen synthesis genes (COL1A1, COL3A1, COL4A1, and COL7A1) and activated antioxidant enzyme (catalase), while suppressing matrix metalloproteinase (MMP-2, -3, -9, and -13) expression. In Hs68 fibroblasts, kirenol also significantly suppressed MMP expression while increasing the expression of COL1A1, COL3A1, and COL7A1. Collectively, our data demonstrate that both SGE and kirenol attenuated UVB-induced photoaging in hairless mice and fibroblasts through inhibition of the mitogen-activated protein kinases and nuclear factor kappa B pathways, suggesting that SGE has potential to serve as a natural anti-photoaging nutraceutical.