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BACKGROUND AND OBJECTIVES: The TWIK-related potassium (TREK) channel subfamily, including TREK1 and TREK2, is a novel cold receptor. Ostruthin, a TREK1 and TREK2 agonist, is a component found in the plant Paramignya trimera and is traditionally used as an anticancer medicine in Vietnam, with its stems and roots treating various ailments. The female hormone progesterone (P4) influences body temperature in women; however, the effect of P4 on thermoregulation via TREK has not been examined. This study aims to investigate the effects of P4 on thermoregulatory responses in ostruthin-administered ovariectomized rats, which are animal models of human menopause. METHODS: Wistar rats were ovariectomized and implanted with silastic tubes with or without P4 (P4(+) and P4(-) groups). The TREK agonist or vehicle was injected intraperitoneally. Body temperature, locomotor activity, tail skin temperature, and thermoregulatory behavior (assessed by tail-hiding behavior) were continuously measured. Plasma concentrations of catecholamines, triiodothyronine, and thyroxine were also measured. RESULTS: In both the P4(+) and P4(-) groups, the change in body temperature was greater among the rats administered the TREK agonist compared to the vehicle. No significant differences were observed between the groups in locomotor activity, tail skin temperature, or tail-hiding behavior. The dopamine concentration in the P4(+) group was lower than that in the P4(-) group. CONCLUSIONS: Ostruthin, the TREK agonist, increases body temperature in ovariectomized rats; however, P4 may not affect these responses in ovariectomized rats.

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ETHNOPHARMACOLOGICAL RELEVANCE: Dried roots of Peucedanum decursivum, a traditional Chinese medicine (TCM), has historically respiratory diseases such as cough, thick phlegm, headache, fever, and gynecological diseases, rheumatoid arthritis, and nasopharyngeal carcinoma. AIM OF THE STUDY: Made an endeavor to evaluate the research trajectory of P. decursivum, comprehensively discern its developmental status, and offer a guideline for future investigations. MATERIALS AND METHODS: A meticulous search of literatures and books from 1955 to 2024 via databases like PubMed, Web of Science and CNKI was conducted, including topics and keywords of " P. decursivum" "Angelica decursivum" and "Zihua Qianhu". RESULTS: P. decursivum and its prescriptions have traditionally been used for treating phlegm-heat cough, wind-heat cough, gastrointestinal diseases, pain relief and so on. It contains 234 identified compounds, encompassing coumarins, terpenes, volatile oils, phenolic acids, fatty acids and derivatives. It exhibits diverse pharmacological activities, including anti-asthmatic, anti-inflammatory, antioxidant effects, anti-hypertensive, anti-diabetic, anti-Alzheimer, and anti-cancer properties, primarily attributed to coumarins. Microscopic identification, HPLC fingerprinting, and bioinformatics identification are the primary methods currently used for the quality control. CONCLUSION: P. decursivum demonstrates anti-asthmatic, anti-inflammatory, and antioxidant effects, aligning with its traditional use. However, experimental validation of its efficacy against phlegm and viruses is needed. Additionally, analgesic effects mentioned in historical texts lack modern pharmacological studies. Numerous isolated compounds exhibit highly valuable medicinal properties. Future research can delve into exploring these substances further. Rigorous of heavy metal contamination, particularly Cd and Pb, is necessary. Simultaneously, investigating its pharmacokinetics and toxicity in humans is crucial for the safety.

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We have previously shown that a single dose of a TREK-1 channel activator, ostruthin, exhibited antidepressant and anxiolytic effects in acute behavioral test models in mice. To assess the potential clinical application, it is essential to evaluate the effects of long-term administration of ostruthin in a chronically stressed mouse model, which is considered to be similar to the clinical condition of major depression in humans. Here, we tested the effects of a single and a 7-day administration of ostruthin on mice that were subjected to chronic unpredictable mild stress (CUMS). A single administration of ostruthin showed antidepressive effects in the tail suspension and forced swim tests of CUMS-treated mice. Unexpectedly, the 7-day administration exhibited only insignificant antidepressive and anxiolytic effects. The 7-day regimen did not affect food intake or body-weight gain, suggesting the absence of apparent cytotoxicity. The mice receiving the 7-day administration had significantly lower blood concentrations of ostruthin compared to those receiving a single dose, suggesting an upregulation of drug-metabolizing activities. These findings suggest that there is a need for stable TREK-1 channel activators that are not affected by drug metabolism.

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Antibiotic resistance is a growing problem and may become the next major global health crisis if no timely actions are taken. Mycobacterial infections are widespread and, due to antibiotic resistance, also hard to treat and a major cause of mortality. Natural compounds have the potential to increase antibiotic effectiveness due to their resistance modulatory and antimicrobial effects. In this study, Peucedanum ostruthium extracts, fractions, and isolated compounds were investigated regarding their antimicrobial and resistance-modulatory effects as well as efflux pump inhibition in Mycobacterium smegmatis. P. ostruthium extracts were found to have anti-mycobacterial potential and resistance modulating effects on ethidium bromide activity. The major antibacterial effect was attributed to ostruthin, and we found that the more lipophilic the substrate, the greater the antimicrobial effect. Imperatorin caused potent modulatory effects by interfering with the action of the major LfrA efflux pump in M. smegmatis. The plant P. ostruthuim has a complex effect on M. smegmatis, including antibacterial, efflux pump inhibition, resistance modulation, and membrane permeabilization, and its major constituents, ostruthin and imperatorin, have a distinct role in these effects. This makes P. ostruthium and its coumarins promising therapeutics to consider in the fight against drug-resistant mycobacteria.

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In tumor necrosis factor (TNF) signaling, IκB kinase (IKK) complex-mediated activation of NF-κB is a well-known protective mechanism against cell death via transcriptional induction of pro-survival genes occurring as a late checkpoint. However, recent belief holds that IKK functions as an early cell death checkpoint to suppress the death-inducing signaling complex by regulating receptor interacting protein kinase1 (RIPK1) phosphorylation. In this study, we propose that two major gernaylated 7-hydroxy coumarins, 6-geranyl-7-hydroxycoumarin (ostruthin) and 8-geranyl-7-hydroxycoumarin (8-geranylumbelliferone, 8-GU) isolated from Paramignya timera, facilitate RIPK1-dependent dual modes of apoptosis and necroptosis by targeting IKKß upon TNF receptor1 (TNFR1) ligation. Analysis of events upstream of NF-κB revealed that 8-GU and ostruthin drastically inhibited TNF-induced IKK phosphorylation, while having no effect on TAK1 phosphorylation and TNFR1 complex-I formation. Interestingly, 8-GU did not affect the cell death induced by Fas ligand or TNF-related apoptosis-inducing ligand or that induced by DNA-damaging agents, indicating that 8-GU sensitizes TNF-induced cell death exclusively. Moreover, 8-GU accelerated TNF-driven necroptosis by up-regulating necrosome formation in FADD deficient cancer cells harboring RIPK3. Thus, the present study provides new insights into the molecular mechanism underlying geranylated 7-hydroxy coumarin-mediated control of the RIPK1-dependent early cell death checkpoint and suggests that 8-GU is a potential anti-cancer therapeutic via an alternative apoptosis-independent strategy to overcome TNF resistance.

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ETHNOPHARMACOLOGICAL RELEVANCE: Notopterygium incisum Ting ex H.T. Chang, known in Chinese as 'Qianghuo' is a traditional Chinese medicinal herb with the rhizome and roots associated with meridians of the kidney and urinary bladder. It is pungent, bitter and warm in nature. It has been used over the years to disperse cold, prevent painful obstructions from wind, damp and warm pain. It has also been used with other herbs to treat wind-cold exterior syndrome and wind-cold-damp bi-syndromes and has been known to grow well in regions of high altitude such as Gansu, Tibet etc. THE AIM OF THE REVIEW: This systematic review focuses on the ethnopharmacological uses of this herb, including recent advances on the phytochemical and pharmacological study of N. incisum. Recent analytical methods developed for the quantitative and qualitative determination of constituents in this herb have also been reviewed. Additionally, future trends and prospects in the study of this herb have been proposed. MATERIALS AND METHOD: Various literature and electronic databases such as Pubmed, Science Direct, Springer, Wiley etc were searched and data obtained. Other online academic libraries such as Google Scholar and ethnopharmacological literature were searched systematically for more information on the herb. RESULTS: This review focuses on the ethnopharmacological uses of N. incisum and also the various chemical constituents present in the herb and their various therapeutic effects such as analgesic, anti-inflammatory, anti-cancer and antioxidants effects. Analytical methods developed for the quantitative and qualitative determination of various compounds in this herb were further reviewed. CONCLUSION: In this paper, we have reviewed various researches conducted on N. incisum especially in areas of its ethnopharmacological use, phytochemicals, pharmacology and developed analytical methods. This herb has been used over the years in treating headache, rheumatoid arthritis, cold, diaphoretic etc, prompting many types of research into identifying which compounds are responsible for these activities and their mechanism of action. More research is needed in the area of pharmacokinetics and toxicology to give further information on the clinical use and control the quality of the herb.

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CONTEXT: Paramignya trimera (Oliv.) Burkill (Rutaceae) has been used to treat liver diseases and cancer. However, the anti-inflammatory effects of this medicinal plant and its components have not been elucidated. OBJECTIVE: This study investigated chemical constituents of the P. trimera stems and evaluated anti-inflammatory effects of isolated compounds. MATERIALS AND METHODS: Cytotoxicity of isolated compounds (5-40 µM) toward BV2 cells was tested using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) for 24 h. Inhibitory effects of isolated compounds (5-40 µM) on nitrite and PGE2 concentrations were determined using Griess reaction and PGE2 ELISA kit, respectively (pretreated with the compounds for 3 h and then stimulated for 18 h with LPS). Inhibitory effects of compounds (5-40 µM) on iNOS and COX-2 protein expression were evaluated by Western blot analysis (pretreated with the compounds for 3 h and then stimulated for 24 h with LPS). RESULTS: Seven coumarins were isolated and identified as: ostruthin (1), ninhvanin (2), 8-geranyl-7-hydroxycoumarin (3), 6-(6',7'-dihydroxy-3',7'-dimethylocta-2'-enyl)-7-hydroxycoumarin (4), 6-(7-hydroperoxy-3,7-dimethylocta-2,5-dienyl)-7-hydroxycoumarin (5), 6-(2-hydroxyethyl)-2,2-dimethyl-2H-1-benzopyran (6), and luvangetin (7). Compounds 1-4 and 7 inhibited NO and PGE2 production in LPS-stimulated BV2 cells, with IC50 values ranging from 9.8 to 46.8 and from 9.4 to 52.8 µM, respectively. Ostruthin (1) and ninhvanin (2) were shown to suppress LPS-induced iNOS and COX-2 protein expression. DISCUSSION AND CONCLUSION: The present study provides a scientific rationale for the use of P. trimera in the prevention and treatment of neuroinflammatory diseases. Ostruthin and ninhvanin might have potential therapeutic effects and should be considered for further development as new anti-neuroinflammatory agents.

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