Costunolide ameliorates angiotensin II-induced atrial inflammation and fibrosis by regulating mitochondrial function and oxidative stress in mice: A possible therapeutic approach for atrial fibrillation.

Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment.

Nerolidol attenuates dehydroepiandrosterone-induced polycystic ovary syndrome in rats by regulating oxidative stress and decreasing apoptosis.

AIMS: Although nerolidol (NRL) is a naturally occurring sesquiterpene alcohol with many pharmacological activities, its role in dehydroepiandrosterone DHEA-induced polycystic ovary syndrome PCOS is unknown. This study aims to explore the potential beneficial effects and underlying molecular mechanisms of nerolidol treatment on polycystic ovary syndrome. MAIN METHODS: Pre-pubertal female Sprague-Dawley rats were randomly assigned into four groups (n = 8/group); group I: control; group II: PCOS; group III: P + NRL; group IV: NRL. Biochemical parameters related to oxidative stress, inflammation, apoptosis, and hormones were estimated in the blood and ovarian tissues. Histopathological, ultrastructural, and immunohistochemical analyses were performed. Bax, P53, Cas-3, and Bcl-2 gene expression levels were detected with RT-PCR. The membrane array analysis detected chemokine, cytokine, and growth factor protein profiles. KEY FINDINGS: In light of the available data, it can deduce that nerolidol has a significant ameliorating effect on lipid peroxidation, oxidative stress, inflammation, histopathological damage, and apoptosis accompanying PCOS in female rats. SIGNIFICANCE: PCOS is not only a reproductive pathology but also a systemic condition and its etiopathogenesis is still not fully understood. Since changes in PCOS have important long-term effects on health, this study evaluated the efficacy of nerolidol, a phytotherapeutic for the control of biochemical, apoptotic, histopathological, and metabolic changes.

Occupational Contact Dermatitis Caused by Artichokes.

Introduction: Few cases of skin diseases caused by exposure to artichokes have been published. Artichokes contain sesquiterpene lactones, which are known to be sensitizing. Irritant contact dermatitis (ICD) has also been diagnosed. To our knowledge, no protein contact dermatitis (PCD) has yet been reported to be induced by artichoke. Objectives: The aim of this study was to identify the different types of contact dermatitis that may be due to occupational exposure to artichokes and the professions concerned. Materials and Methods: We conducted a descriptive study, retrieving data from the French national database of occupational diseases for the period of 2001 to 2018. Results: Fifty-six cases were retrieved, and 10 cases were included in this study after data analysis and reading the clinical reports: 7 allergic contact dermatitis (ACD), 2 PCD, and 1 ICD caused by artichokes. Patients were farmers (4), agri-food workers (3), market gardener (1), cashier (1), and store employee (1). Conclusions: This is the first series of occupational contact dermatitis that can be induced by artichokes. Exposure to artichokes can lead to ICD, ACD, PCD, and perhaps contact urticaria. The sesquiterpene lactone mix patch test is not always sufficient to confirm an ACD by artichokes. Irritant contact dermatitis can be associated with ACD from artichokes or evolve on its own.

Allergic contact dermatitis to Compositae: An Australian case series.

BACKGROUND: Allergic contact dermatitis (ACD) to Compositae is caused by sensitisation to sesquiterpene lactones (SQLs) and subsequent exposure can occur from direct handling or from airborne transmission. Plants from the Compositae family are ubiquitous globally and their plant extracts are also used in various products. OBJECTIVES: Investigation of contact allergy (CA) and allergic contact dermatitis (ACD) to Compositae at a single dermatology centre. METHODS: A retrospective case review was performed on patients undergoing patch testing to Compositae between January 2011 and December 2020 in Melbourne, Australia. RESULTS: Of 3679 patients, 44 (1.2%) patch tested positive to Compositae and 19 (43.2%) reactions were deemed relevant. Thirteen cases (68.4%) were from direct contact with Compositae plants, mostly in gardeners. Six cases (31.6%) were from personal products and all these patients were female. Involvement of the face was significant (p = 0.007). Simultaneous allergic reactions included SQL mix in eight (42.1%), fragrance mix in seven (36.8%), potassium dichromate in three (15.8%) and colophonium in two (10.5%) cases. CONCLUSION: Contact with Compositae from gardening contributed most cases of ACD; however, personal products accounted almost one-third of cases. Treatment options remain limited and avoidance is the most important aspect of management.

Contribution of spathulenol to the anti-nociceptive effects of Psidium guineense.

Objectives: Araçá-verdadeiro is the popular name of Psidium guineense (Myrtaceae), whose fruits and leaves are used in Brazilian folk medicine for treatment of inflammation and pain. The focus of the present research was an investigation of the anti-nociceptive, and anti-inflammatory effects of the essential oil from P. guineense (EOPG) leaves, and of spathulenol. The anxiolytic and antidepressive effects associated with chronic pain were also investigated in models of acute or persistent nociception or/and inflammatory pain.Methods and Results: Oral treatment with EOPG (10-100 mg/kg) or spathulenol (10 mg/kg) significantly inhibited formalin-induced nociceptive responses, both sensitivity to cold and edema. Oral treatment with EOPG (10 mg/kg) and spathulenol (10 mg/kg) did not reduce locomotor activity (open field test). Local administration of spathulenol (1000 µg/paw) significantly prevented formalin-induced nociceptive sensitivity to cold and paw edema, and carrageenan-induced mechanical hyperalgesia, paw edema and sensitivity to cold. In the Freund's complete adjuvant (CFA) model, oral treatment with EOPG (10 mg/kg) or spathulenol (10 mg/kg) for 21 days significantly inhibited all analyzed parameters. The percentage maximal inhibition by spathulenol was 76.00% (mechanical hyperalgesia), 71.90% (cold response), 85.00% (edema), 77.16% (myeloperoxidase activity), 97.72% (time in the closed arms in the elevated plus maze), and 49.00% (immobility time in the tail suspension test), in the CFA model. Models employed male Swiss mice, except for the CFA test, which employed C57bL6 male mice (n=6 /group).Conclusion: This study demonstrates that EOPG is an anti-nociceptive and anti-hyperalgesic agent, in acute and continuous treatment, and an anxiolytic and antidepressive agent when tested with the chronic pain experimental state.

Concomitant positive patch test reactions in FreeStyle-allergic patients sensitized to isobornyl acrylate.

BACKGROUND: Concomitant positive patch test reactions in patients sensitized to isobornyl acrylate (IBOA) have rarely been documented. OBJECTIVES: To report concomitant sensitizations in patients with allergic contact dermatitis (ACD) from the glucose sensor FreeStyle Libre and sensitized to IBOA. METHODS: In 2019, 26 patients with suspected ACD from FreeStyle Libre were patch tested to a baseline series and to a (meth) acrylate series containing IBOA and 2-phenoxyethyl acrylate (PEA) 0.1% pet. Diabetes devices and patch test preparations were analyzed with gas chromatography - mass spectrometry (GC-MS) for the presence of IBOA and PEA. RESULTS: Of the 26 patients, 18 (69%) were sensitized to IBOA, and eight (44%) and 11 (61%) of these were co-sensitized to sesquiterpene lactones and fragrances, respectively. Ten patients (56%) were co-sensitized to PEA, which, contrary to IBOA, could not be detected in any device. The PEA test material was shown to be contaminated with IBOA. CONCLUSIONS: Contact allergy to IBOA appears to be declining and IBOA-sensitized patients are most often co-sensitized to sesquiterpene lactones and fragrances. Vigilance is required when patch testing (acrylate) materials obtained from industry, as these might be contaminated and, hence, alter the results and their interpretation.

Impact of sesquiterpene lactones on the skin and skin-related cells? A systematic review of in vitro and in vivo evidence.

Although anti-inflammatory properties are attributed to sesquiterpene lactones (SL), cutaneous hypersensitivity reactions are proposed as limitations for SL-based therapies. Thus, the impact of SL on the skin and skin-related cells was systematically reviewed. Studies indexed in electronic databases were screened from the PRISMA strategy. The risk of bias in all studies was verified from the SYRCLE's tool. Thirty original studies were recovered and analyzed. Mice and guinea pig, keratinocytes and fibroblasts were predominantly investigated from in vivo and in vitro studies, respectively. In vivo studies indicated that most SL induced contact dermatitis associated with edema, erythema, and inflammatory infiltrate. Conversely, in vitro evidence was consistent with a dose-dependent anti-inflammatory effect of SL in response to reduced cytokines, 5-LOX, and COX-2 levels or activity in keratinocytes, fibroblasts, macrophages and dendritic cells; which are events potentially triggered by downregulation of gene expression and/or inhibition of the NF-κB signaling pathway. In vivo studies presented uncertain to high-risk of bias mainly associated with underreporting of randomization and experimental blinding. The current evidence supports potent cutaneous immunomodulatory properties of SL. Although in vitro and in vivo studies indicate opposite anti- or proinflammatory effects, this contradiction exhibits a dose-dependent component. In addition, the anti-inflammatory pathways activated by SL are better understood from in vitro evidence. However, additional studies are required to elucidating specific anti-inflammatory and proinflammatory mechanisms triggered by SL in vivo. Thus, controlling the sources of bias described in this review can contribute to improving the quality of the evidence in further investigations.

Expanding Patch Testing Beyond the Baseline Series: Usefulness of Customized Antimicrobials, Vehicles, and Cosmetics Series.

BACKGROUND: Testing cosmetics and their ingredients is essential to avoid missing relevant allergens and to monitor fluctuating incidence of hypersensitivity. OBJECTIVE: The aim of this study was to review the usefulness of patch testing with a customized antimicrobials, vehicles, and cosmetics (AVC) series over 15 years at a single Canadian site. METHODS: Between January 1, 2005, and December 31, 2019, patients suspected of having cosmetics allergy were patch tested with a 40-allergen AVC series in addition to the North American Contact Dermatitis Group standard screening series. We reviewed the patch test results of 2868 patients. RESULTS: We consecutively patch tested with the baseline series 6103 patients, of which 2868 (47%) were also tested with the AVC series. Of 53 different allergens that were tested at some point, 26 remained in the series throughout the 15-year span. The most common positive allergens were thimerosal (4.52%), polyvidone-iodine (2.25%), propolis (2.06%), sodium metabisulfite (1.94%), dodecyl gallate (1.53%), carmine (1.10%), lauryl glucoside (1.01%), sandalwood oil (0.7%), and tert-butylhydroquinone (0.7%). CONCLUSIONS: Although the expansion of the North American Contact Dermatitis Group standard screening series has decreased the yield from the AVC series from 21.1% to 13.9%, it still remains a useful adjunct for patients suspected of having cosmetics or disinfectants allergy.

Sesquiterpenes and their derivatives-natural anticancer compounds: An update.

Sesquiterpenes belong to the largest group of plant secondary metabolites, which consist of three isoprene building units. These compounds are widely distributed in various angiosperms, a few gymnosperms and bryophytes. Sesquiterpenes and their allied derivatives are bio-synthesized in various plant parts including leaves, fruits and roots. These plant-based metabolites are predominantly identified in the Asteraceae family, wherein up to 5000 complexes have been documented to date. Sesquiterpenes and their derivatives are characteristically associated with plant defence mechanisms owing to their antifungal, antibacterial and antiviral activities. Over the last two decades, these compounds have been reportedly demonstrated health promoting perspectives against a wide range of metabolic syndromes i.e. hyperglycemia, hyperlipidemia, cardiovascular complications, neural disorders, diabetes, and cancer. The high potential of sesquiterpenes and their derivatives against various cancers like breast, colon, bladder, pancreatic, prostate, cervical, brain, liver, blood, ovarium, bone, endometrial, oral, lung, eye, stomach and kidney are the object of this review. Predominantly, it recapitulates the literature elucidating sesquiterpenes and their derivatives while highlighting the mechanistic approaches associated with their potent anticancer activities such as modulating nuclear factor kappa (NF-kB) activity, inhibitory action against lipid peroxidation and retarding the production of reactive oxygen & nitrogen species (ROS&RNS).

Compositae sensitization in Danish children and adolescents.

BACKGROUND: Compositae plant sensitization in children is relatively frequent. From 1995-2006, we found a prevalence of 1.8% sesquiterpene lactone (SL) mix/parthenolide patch test positives among consecutive eczema patients <18 years. OBJECTIVES: To report the results of patch test screening for Compositae sensitization in patients <18 years in the last 13 years. METHODS: Children and adolescents <18 years, diagnosed with Compositae sensitization between 2007 and 2019, were included. RESULTS: Among 388 children tested, 12 (3%) were Compositae-sensitized, and 11 (2.8%) had positive reactions to SL mix. Compositae mix 5% pet. elicited positive reactions in six of seven patients tested, and dandelion extract 2.5% pet. in six of 10 patients tested. The mean age of the five girls and seven boys was 9.4 years and 11.7 years, respectively. Eleven children had a personal and one a family history of atopy, and 11 children had hand eczema. Only two were mono-sensitized to Compositae. CONCLUSIONS: SL mix is a suitable screening agent among children and adolescents in our area, well supplemented with Compositae mix 5% and dandelion extract. The study emphasizes the importance of Compositae screening in children with a personal and/or family history of atopy, hand eczema or widespread airborne dermatitis, summer exacerbation, and plant exposure.

Oral provocation of patients allergic to sesquiterpene lactones with German chamomile tea to demonstrate possible systemic allergic dermatitis.

BACKGROUND: Most patients with contact allergy to Asteraceae plants are patch test positive to sesquiterpene lactone mix (SLM). There are several reports among these patients of a flare-up of hand eczema after ingestion of food and beverages originating from Asteraceae plants. AIM: To investigate whether German chamomile tea can elicit systemic allergic dermatitis. PATIENTS AND METHODS: Individuals with or without contact allergy to SLM were patch tested with an extract of German chamomile tea. Six weeks later, they were provoked with capsules containing either freeze-dried German chamomile tea or placebo capsules containing lactose, in a double-blind, randomized study. A numerical rating scale (NRS) was used to ascertain the volunteers' opinion of their hand eczema status. The study individuals were examined to detect a possible flare-up of healed patch test reactions to chamomile. RESULTS: None of the subjects had a flare-up of healed patch test reactions. According to the NRS, SLM-positive individuals experienced a significant worsening of hand eczema, independently of whether they received chamomile or lactose capsules. CONCLUSION: No evidence suggestive of systemic allergic dermatitis was found.

Chronic Actinic Dermatitis Revisited.

BACKGROUND: Chronic actinic dermatitis (CAD) is a persistent eczematous photodermatitis classically described in older, white men with contact allergy to plants. However, evidence from recent studies suggests that some demographics of CAD patients may be changing. OBJECTIVE: The aims of the study were to determine the frequency of CAD in patients presenting with photosensitive eruptions and to identify the allergens and photoallergens most closely associated with this condition. METHODS: We identified all patients with a diagnosis of CAD from 246 consecutive records of patients undergoing photopatch testing from July 1994 to June 2018 and summarized the demographics and test results in comparison with non-CAD patients. CONCLUSIONS: Nineteen (7.7%) of the 246 patients evaluated had CAD with a male-to-female ratio of 1:1.7 among CAD patients. Compared with non-CAD patients, photocontact allergy and/or contact allergy to sesquiterpene lactone mix and contact allergy to fragrances were significantly more common in CAD. Contact allergy to p-phenylenediamine was also common. The results of this study suggest that CAD presents in a broader demographic range, including both men and women of both light and dark skin types. Phototesting and photopatch testing should be considered when patients present with clinical findings consistent with CAD.

Differential blockade by huperzine A and donepezil of sympathetic nicotinic acetylcholine receptor-mediated nitrergic neurogenic dilations in porcine basilar arteries.

Nicotinic acetylcholine receptor activation on the perivascular sympathetic nerves via axo-axonal interaction mechanism causes norepinephrine release, which triggers the neurogenic nitrergic relaxation in basilar arteries to meet the need of a brain. Donepezil and huperzine A, which are the cholinesterase inhibitors used for Alzheimer's disease therapy, exert controversial effects on nicotinic acetylcholine receptors. Therefore, we investigated how donepezil and huperzine A via the axo-axonal interaction regulate the neurogenic vasodilation of isolated porcine basilar arteries and define their action on different subtypes of the nicotinic acetylcholine receptor by using blood vessel myography, calcium imaging, and electrophysiological techniques. Both nicotine (100 µM) and transmural nerve stimulation (TNS, 8 Hz) induce NO-mediated dilation in the arteries. Nicotine-induced vasodilations were concentration-dependently inhibited by huperzine A and donepezil, with the former being 30 fold less potent than the latter. Both cholinesterase inhibitors weakly and equally decreased TNS-elicited nitrergic vasodilations. Neither huperzine A nor donepezil affected isoproterenol (a ß adrenoceptor-agonist)- or sodium nitroprusside (a NO donor)-induced vasodilation. Further, huperzine A was less potent than donepezil in inhibiting nicotine-elicited calcium influxes in rodent superior cervical ganglionic neurons and inward currents in α7- and α3ß2-nicotinic acetylcholine receptor-expressing Xenopus oocytes. In conclusion, huperzine A may exert less harmful effect over donepezil on maintaining brainstem circulation and on the nicotinic acetylcholine receptor-associated cognition deficits during treatment for Alzheimer's disease.

Elemene injection combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: To evaluate the short-term efficacy, long-term efficacy, and adverse events (AEs) of elemene plus transcatheter arterial chemoembolization (TACE) in comparison with TACE alone for the treatment of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Full-text Database, Wanfang Data, CBM, and VIP were searched by 2 reviewers using the same search strategy for clinical studies on elemene plus TACE in the treatment of HCC. These articles were screened according to pre-established inclusion and exclusion criteria, and the qualities of the included studies were assessed using the Newcastle-Ottawa scale. The primary outcomes were the objective response rate (ORR), the 1-year survival rate and AEs. Review Manager 5.3 and Stata 15.0 were used for the meta-analysis. RESULTS: A total of 10 studies involving 543 patients (TACE + elemene = 277, TACE alone = 266) were included. The results showed that the ORR was significantly improved in the combined treatment group compared to the TACE alone group (odds ratio [OR] = 2.72, 95% confidence interval [CI]: 1.84-4.00, P < .05). TACE + elemene significantly increased the 1-year survival rate (OR = 2.79, 95% CI: 1.58-4.95, P < .05). We also found no significant difference in gastrointestinal reactions (OR = 0.97, 95% CI: 0.57-1.64, P = .90), fever (OR = 0.80, 95% CI: 0.37-1.71, P = .56), or bone marrow suppression (OR = 0.73, 95% CI: 0.44-1.22, P = .23) between the 2 groups. CONCLUSION: Based on current findings, TACE + elemene injection may improve the ORR and the 1-year survival rate for HCC patients compared to TACE alone. Arterial perfusion may be superior to intravenous guttae.

Screening for Compositae contact sensitization with sesquiterpene lactones and Compositae mix 2.5% pet.

BACKGROUND: Compositae contact sensitization may be difficult to diagnose, because of a lack of reliable screening allergens. OBJECTIVES: To assess the suitability of Compositae mix II 2.5% pet. (CM2.5) as a screening mix in the baseline series combined with sesquiterpene lactone (SL) mix and parthenolide (PTH). METHODS: CM2.5 was added to the baseline series, which included SL mix and PTH 0.1% pet., in January 2015, and PTH was included in TRUE Test Panel 3 in October 2015. All Compositae-sensitive patients diagnosed or tested in the next 4 years were assessed. RESULTS: Altogether, 57 patients (2.7%) presented with Compositae allergy. On primary testing in 53 newly diagnosed patients, SL mix elicited positive reactions most frequently (53% positive), followed by CM2.5 (47% positive), and PTH (45% positive). CM2.5 and PTH pet. elicited a few irritant reactions. Three patients had late reactions. Altogether, 16 patients (28%) were not detected by any of the three screening agents. CONCLUSIONS: SL mix is an indispensable, although insufficient, screening mixture in Denmark. It may be relatively safely supplemented with CM2.5 and PTH in the TRUE Test system for screening, but, when Compositae sensitization is suspected, further extracts should be tested on the basis of the history.

Allergic contact dermatitis in atopic individuals: Results of a 30-year retrospective study.

BACKGROUND: The association between atopic dermatitis (AD) and contact allergy, remains unclear, with studies to date showing conflicting results. OBJECTIVES: To investigate the prevalence of contact allergy in AD individuals compared to those without AD. METHODS: Results of 46 250 patients patch tested in a single centre over a span of 30 years were reviewed, comparing those with AD with those without AD. Collected data were analysed with corrections for multiple confounding variables, including date of patch testing to account for changes in allergens tested over the period. RESULTS: Nine allergens showed a statistically significant difference between the two groups. Contact allergy to nickel, cobalt and primin was less likely to arise in those with AD, whilst substances found in topical dermatological products were more likely to be associated with AD. CONCLUSIONS: This is the largest single centre study of contact sensitization in atopy reported to date. The previously reported association between contact allergy to sesquiterpene lactone and AD is reinforced. The decreased incidence of metal allergy suggests distinct immunological effector mechanisms in sensitization to these allergens. In keeping with previous publications, exposure to topical treatments for AD can result in sensitisation and contact allergy and clinicians should consider patch testing in AD individuals who report worsening of their skin despite continued treatment with topical medicaments.