Patterns of simultaneous contact allergies in patients with contact sensitization to oxidised linalool and oxidised limonene.

BACKGROUND: Contact allergy rates of linalool and limonene hydroperoxides (HPs) have increased. OBJECTIVES: To demonstrate the patterns of simultaneous positive patch test (PT) reactions and prevalences of multiple contact allergies (MCAs) in patients with contact allergy to linalool and/or limonene HPs. METHODS: A retrospective analysis of consecutive dermatitis patients in 2015-2020 was performed. RESULTS: Of all 4192 patients, 1851 had at least one positive PT reaction. Of these, 410 (22.2%) had MCAs, significantly related to a higher age (p-value = 0.003). Patients with an exclusively positive reaction to linalool HPs but not limonene HPs were shown to have MCAs (p-value <0.001, odds ratio (95% confidence interval) = 4.15 (3.01-5.73)). Patients with simultaneous contact allergies to both linalool and limonene HPs had contact allergies to many other screening and fragrance allergens. CONCLUSIONS: Simultaneous positive PT reactions to allergens in baseline series and fragrances are common in patients with the HPs contact allergy, especially linalool HPs. The pattern of simultaneous PT reactions principally suggested the co-sensitization of the cosmetic allergens.

SHP2: its association and roles in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease. Src homology 2 domain containing protein tyrosine phosphatase (SHP2) is a member of the protein tyrosine phosphatases (PTPs) family. To date, relationship between SHP2 and SLE pathogenesis is not elucidated. METHOD: We measured plasma levels of SHP2 in 328 SLE patients, 78 RA patients, 80 SS patients and 79 healthy controls by ELISA, and discussed association of SHP2 in SLE patients, potential of plasma SHP2 as a SLE biomarker. Moreover, histological and serological changes were evaluated by flow cytometry, HE/Masson examination, immunofluorescence test in pristane-induced lupus mice after SHP2 inhibitor injection to reveal role of SHP2 in lupus development. RESULTS: Results indicated that SHP2 plasma levels were upregulated in SLE patients and correlated with some clinical, laboratory characteristics such as proteinuria, pyuria, and may be a potential biomarker for SLE. After SHP2 inhibitor treatment, hepatosplenomegaly and histological severity of the kidney in lupus mice were improved. SHP2 inhibitor reversed DCs, Th1, and Th17 cells differentiation and downregulated inflammatory cytokines (IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α) and autoantibodies (ANA, anti-dsDNA) production in pristane-lupus mice. CONCLUSION: In summary, SHP2 correlated with SLE pathogenesis and promoted the development of lupus.

Pristane cadmium chloride nanoemulsion accelerates the onset of systemic lupus erythematosus in a C57BL/6 mouse model.

OBJECTIVE: To accelerate the onset of systemic lupus erythematosus in C57BL/6 mice by injecting cadmium chloride nanoemulsion and shorten the traditional modeling time. METHODS: Pristane cadmium chloride nanoemulsion was prepared, and 66 C57BL/6 mice were randomly divided into four groups. The pristane group was intraperitoneally injected with 0.6 mL of pristane blank nanoemulsion, the model group was injected with 0.6 mL of pristane cadmium chloride nanoemulsion, the Cadmium chloride control group was injected with 0.6 mL of cadmium chloride nanoemulsion, and the control group was injected with the same amount of 0.9% sodium chloride solution. Urine protein content, anti-dsDNA antibody content, Th1 cell/Th2 cell ratio, and kidney staining were detected in each group. RESULTS: The model group began to develop disease in the 4th week, the anti-dsDNA antibody level reached 566.71 ± 1.44 ng/L, and the proteinuria reached 245.38 ± 30.54 ng/mL. The model group showed an onset at least 5 weeks earlier than that in the pristane group. There was no significant difference in anti-dsDNA antibody content between Cadmium chloride control group and blank group. At the 12th week, the Th1/Th2 cell ratio in the model group significantly decreased, and the pathological changes in the kidneys were consistent with the typical manifestations of lupus in mouse models. CONCLUSION: These results suggest that cadmium chloride promotes earlier onset of pristane-induced systemic lupus erythematosus in a C57BL/6 mouse model.

Effect of Pulicaria mauritanica on Glucose Metabolism and Glycogen Content in Streptozotocin-Induced Diabetic Rats.

AIMS: The study aimed to assess the antihyperglycemic activity of Pulicaria mauritanica. BACKGROUND: Pulicaria mauritanica is a medicinal and aromatic plant used for the treatment of many diseases such as inflammation, diabetes, and intestinal disorders. OBJECTIVE: The main goals of this present paper were to confirm the antihyperglycemic capacity of aqueous extract from Pulicaria mauritanica in normoglycemic and diabetic rats over a period of time (7 days of treatment). METHODS: The effect of the aqueous extract of Pulicaria mauritanica from aerial parts (AEPM) on glucose and lipid metabolism was tested using an acute test (single dose during 6 hours) and subchronic assay (repeated oral administration for seven days) at a dose of 60 mg/kg and the serum glucose levels were measured in normoglycemic and streptozotocin(STZ)-induced diabetic rats. In addition, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus was evaluated. The antioxidant activity, phytochemical screening, and quantification of some secondary metabolites of this extract were also performed. RESULTS: AEPM at a dose of 60 mg/kg reduced the plasma glucose concentrations significantly in STZ-induced diabetic rats after a single oral administration (p<0.05). This lowering effect became more significant during the repeated oral administration in hyperglycemic rats (p<0.0001). Also, the findings showed that this plant exhibited a significant increase in liver and skeletal soleus muscle glycogen content in diabetic rats. AEPM revealed a remarkable antioxidant activity in addition to the presence of polyphenol compounds such as flavonoids, tannins, saponins, sterols, glucides, terpenoids, quinones, anthraquinones, and mucilage. CONCLUSION: The study shows that AEPM exhibits antihyperglycemic activity in diabetic rats, and it increases liver and muscle glycogen content.

Limonene and linalool hydroperoxides review: Pros and cons for routine patch testing.

Limonene and linalool are among the most common fragrance terpenes used in everyday products. They are pre-haptens, forming hydroperoxides (Lim-OOHs, Lin-OOHs) upon oxidation and inducing frequent positive patch test reactions in patients with dermatitis, and yet they are not routinely tested in Europe. This review evaluates current patch testing with Lim-OOHs and Lin-OOHs by asking whether hydroperoxide patch testing is warranted, examining the difficulties or challenges related to reading and interpreting hydroperoxide patch test results with currently available material, and assessing their relevance. Studies are increasingly pointing to high percentages of positive reactions in patients consecutively patch tested with these oxidized products. An association between a positive clinical history and a strong patch test reaction has been described, but problems with doubtful/irritant reactions have also been reported. Considering the high frequency of relevant positive reactions, the incorporation of Lim-OOHs 0.3% and Lin-OOHs 1% in the baseline series may be justified. Since exposure, sensitization, and elicitation limits of Lim-OOHs and Lin-OOHs in the products still need to be better determined, an assessment of previous exposure, possible sensitizations, and reactions may help to improve the clinical assessment.

What is the added value of patch testing with 30 fragrance allergens in addition to the European Baseline series?

BACKGROUND: Patch testing with the fragrance allergy markers in the European baseline series (EBS) does not identify all patients with fragrance allergy. Hydroperoxides of linalool and limonene have been shown to be useful allergens in detecting fragrance sensitization. OBJECTIVES: To evaluate the added value of testing with 30 fragrance allergens in addition to the EBS. METHODS: All patients with suspected fragrance allergy who underwent patch testing at the Amsterdam University Medical Centers between November 2019 and January 2021 to the EBS and fragrance series were included. RESULTS: Of 323 patients tested, 162 (50.2%) were found to be fragrance sensitized. The most sensitizing single allergens were the hydroperoxides of linalool (1.0 and 0.5% pet.) and limonene (0.3 and 0.2% pet.). Testing with the hydroperoxides of linalool and limonene identified 62 fragrance-sensitized patients (38.3%) who could not be detected by the common fragrance markers. Of all fragrance-sensitized patients, 21 (13.0%) would have been missed when not testing with the fragrance series. CONCLUSIONS: Patch testing with the fragrance series in addition to the EBS is valuable. To reduce the risk of false-negative reactions, it is advisable to test the hydroperoxides of linalool and limonene.

Contact allergy to oxidized linalool and oxidized limonene: Patch testing in consecutive patients with dermatitis.

BACKGROUND: Contact allergy to oxidized (ox.) linalool and ox. limonene has been reported to have a high prevalence, raising the question of inclusion into the baseline series. However, several important issues should be clarified and further investigated before inclusion can be warranted. OBJECTIVES: To report the trends of ox. terpenes allergy in patients with dermatitis, features of the patch test reactions, and clinical characteristics of the patients. METHODS: A retrospective analysis of 5773 patients was performed. All patients were patch tested with baseline series, individual ingredients of fragrance mix I and II, ox. linalool, and ox. limonene from 2013 to 2020. RESULTS: The prevalence rates of contact allergy to ox. linalool and ox. limonene were 7.0% and 5.1%, respectively. Significantly increasing trends of contact allergy were observed. More than 95% of contact allergy cases were identified on Day 3/4. Patients with contact allergy to ox. linalool and ox. limonene were significantly younger than those with contact allergy to other fragrances and were predominantly female. Strong reactions were associated with older age and multiple fragrance allergies. CONCLUSIONS: Contact allergy to ox. linalool and ox. limonene is becoming increasingly important, and findings show intriguing features. More studies concerning the clinical relevance before recommending these substances for screening are required.

A novel approach to Cestrum intermedium (mata-boi): anatomical and physical-chemical characterization, in vitro biological activities, and metabolites of a Brazilian native species

Abstract The Brazilian native species Cestrum intermedium, known as mata-boi, induces hepatotoxicity and death when ingested by cattle. While most studies on this species focus on toxicological features, our study is the first to describe the anatomy and in vitro biological activities of Cestrum intermedium. We investigated adult leaves and stems by histochemistry, described their anatomy, performed physical-chemical analysis, determined in vitro antioxidant and antimicrobial activities, and identified secondary metabolites. A few noteworthy anatomical features were the anomocytic stomata on the abaxial surface and the absence of trichomes, in addition to the circular shaped petiole with two projections on the adaxial surface. Histochemical analysis showed chemical markers such as alkaloids, usually reported as toxic, and terpenoids. Potassium nitrate (ATR-FTIR) and lupeol palmitate (NMR) were detected on the crude stem extract. Thermogravimetric and physical-chemical analysis provided fingerprint parameters for the species. Minimal Inhibitory Concentration (MIC) assay revealed that Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans were weakly inhibited by extract samples. Chloroform and ethyl acetate fractions presented high phenolic content, which resulted in in vitro antioxidant activity. These novel features expand the knowledge about this species, considering that previous studies mainly focused on its toxicity. Our study also provided characteristics that may help in avoiding misidentification between Cestrum members, especially when taxonomic keys cannot be employed, as in the absence of flowers and fruits.

Evaluation of copaiba oil as enhancer of ibuprofen skin permeation

Abstract The administration of medications on the skin through transcutaneous routes is a practice that has been used by mankind for millennia. Some studies have been reporting the use of terpenes and natural oils rich in terpenes as an enhancer of cutaneous penetration. Copaiba oil, due to its rich content of terpenes, presents itself as a great choice of penetration enhancer for drugs administered on the skin. In this study, we developed two cream formulations containing 5% of ibuprofen (IBU) and copaiba oil: IBCO5 and IBCO10 with 5% and 10% of copaiba oil respectively. Ex vivo cutaneous penetration/permeation studies of IBU were performed using pig ear skin as biological membrane in the Franz-type diffusion cells. The steady-state flux of IBU samples, IBCO5 (35.72 ± 6.35) and IBCO10 (29.78 ± 2.41) were significantly higher when compared with control without copaiba oil (10.32 ±1.52) and with a commercial product (14.44 ± 2.39). In the penetration analysis, the amount of IBU found in the samples IBCO5 and IBCO10 was markedly higher in the dermis than epidermis. Our results showed that copaiba oil possesses attracting properties in promoting skin penetration and permeation of IBU when added into cream formulations.

Interferon Lambda Regulates Cellular and Humoral Immunity in Pristane-Induced Lupus.

A pivotal role of type I interferons in systemic lupus erythematosus (SLE) is widely accepted. Type III interferons (IFN-λ) however, the most recently discovered cytokines grouped within the interferon family, have not been extensively studied in lupus disease models yet. Growing evidence suggests a role for IFN-λ in regulating both innate and adaptive immune responses, and increased serum concentrations have been described in multiple autoimmune diseases including SLE. Using the pristane-induced lupus model, we found that mice with defective IFN-λ receptors (Ifnlr1-/-) showed increased survival rates, decreased lipogranuloma formation and reduced anti-dsDNA autoantibody titers in the early phase of autoimmunity development compared to pristane-treated wild-type mice. Moreover, Ifnlr1-/- mice treated with pristane had reduced numbers of inflammatory mononuclear phagocytes and cNK cells in their kidneys, resembling untreated control mice. Systemically, circulating B cells and monocytes (CD115+Ly6C+) were reduced in pristane-treated Ifnlr1-/- mice. The present study supports a significant role for type III interferons in the pathogenesis of pristane-induced murine autoimmunity as well as in systemic and renal inflammation. Although the absence of type III interferon receptors does not completely prevent the development of autoantibodies, type III interferon signaling accelerates the development of autoimmunity and promotes a pro-inflammatory environment in autoimmune-prone hosts.

Effects of Some Insecticides (Deltamethrin and Malathion) and Lemongrass Oil on Fruit Fly (Drosophila melanogaster).

<b>Background and Objective:</b> The continuous use of pesticides in the ecosystem is of great concern, as some of them are highly stable and impact non-target organisms. The effect was tested of different concentrations of insecticides such as (Deltamethrin and Malathion) and natural products, Including, lemongrass oil on Fruit Fly (<i>Drosophila melanogaster</i>), to calculate the concentration at which the highest mortality occurred and death half the number of individuals after 96 hrs, as well as calculating the half-lethal time for individuals. <b>Materials and Methods:</b> This study, which evaluated the toxicity of five different concentrations (0.75, 1.00, 1.25, 1.50 and 1.75 mg L¹) of Malathion, (0.05, 0.10, 0.21, 0.53 and 1.48 mg L¹) of Deltamethrin and lemongrass oil (0.25, 0.50, 0.75, 1.00 and 1.50 mg L¹) on the insect of <i>Drosophila melanogaster</i> after 96 hrs of treatment. <b>Results:</b> From the results of this study, the concentration (LC₅₀= 2.938 mg L¹) of Malathion leads to kills half of the individuals, compared to Deltamethrin a higher concentration (LC₅₀= 4.8673 mg L¹) that leads to killing half of the individuals. While lemongrass oil the concentration (LC₅₀= 9.7478 mg L¹) leads to kills half of individuals. Also, when used Deltamethrin it takes (LT₅₀= 660.277) hours to kill half of the individuals compared to Malathion, which takes approximately (LT₅₀ = 321.862) hours to death half of the individuals. But lemongrass oil (LT₅₀= 819.745) hours to kill half of the individuals. <b>Conclusion:</b> In conclusion, the lemon plant and its components have excellent potential for being used in the control of <i>Drosophila melanogaster</i>, which had an effective role in biological control.

Total Glucosides of Paeony Ameliorate Pristane-Induced Lupus Nephritis by Inducing PD-1 ligands+ Macrophages via Activating IL-4/STAT6/PD-L2 Signaling.

Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4/80+CD11b+CD206+ M2-like macrophages with no any significant effect on F4/80+CD11b+CD86+ M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4/80+Arg1+ subset while decreasing the percentage of F4/80+iNOS+ subset. Importantly, TGP treatment increased the percentage of both F4/80+CD11b+PD-L1+ and F4/80+CD11b+PD-L2+ subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages in vitro while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS/IFN-γ in vitro, indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages in vivo. Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4/80+CD11b+CD206+ and F4/80+CD11b+PD-L2+ macrophages through IL-4/STAT6/PD-L2 signaling pathway.

Revisiting the Antiviral Efficacy of Terpenoids: Plausible Adjunct Therapeutics for Novel SARS-CoV-2?

Presently the world is witnessing the most devastating pandemic in the history of mankind caused by Severe Acute Respiratory Syndrome or SARS-CoV-2. This dreaded pandemic is responsible for escalated mortality rates across the globe and this is the worst catastrophe in the history of mankind. Since its outbreak, substantial scientific explorations focusing on the formulation of novel therapeutical and/or adjunct intervention against the disease are continuously in the pipeline. However, till date, no effective therapy has been approved and hence the present alarming situation urges the necessity of exploring novel, safe and efficient interventional strategies. Functionally, terpenoids are a class of secondary plant metabolites having multi facet chemical structures and are categorically documented to be the largest reservoir of bioactive constituents, predominant in nature. Intriguingly, very little is scientifically explored or reviewed in regards to the anti-CoV-2 attributes of terpenoids. The present article thus aims to revisit the antiviral efficacy of terpenoids by reviewing the current scientific literature and thereby provide an opinion on the plausibility of exploring them as potential therapeutical intervention to deal with ongoing CoV-2 pandemic.

A Novel Autoantibody Induced by Bacterial Biofilm Conserved Components Aggravates Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiple autoantibody production and often affects the kidneys, known as lupus nephritis. However, the mechanism underlying lupus nephritis development is unclear. Biofilms that protect bacteria from stress are ubiquitous in almost every environment. Here, we identified that a conserved peptide (HU1) derived from DNABII proteins, one of major bacterial biofilm components, was specifically recognized by sera from about 47% patients with SLE. Moreover, the serum anti-HU1 levels showed a significant positive correlation with lupus nephritis occurrence. Presence of antibodies against HU1 in pristane-induced mice aggravated lupus nephritis, although these antibodies also attenuated bacterial biofilm formation. We further identified that antibodies against HU1 cross-recognized protein disulfide isomerase (P4HB) located on the renal cell surface and inhibited the activities of this enzyme. Our findings reveal a novel mechanism underlying the development of lupus nephritis triggered by bacterial biofilms.

Abnormal thymic B cell activation and impaired T cell differentiation in pristane-induced lupus mice.

Changes in the thymus and potential mechanisms underlying the pathogenesis in pristane-induced lupus (PIL) mice are poorly understood. This study aimed to systematically and specifically examine changes in the thymus and the potential mechanisms responsible for immunological abnormalities in PIL mice. The results showed that PIL mice exhibit serious thymic hyperplasia, an elevated thymus index, a damaged histopathological structure and increased thymocyte apoptosis. We found that thymic T cell differentiation was impaired as the CD4+ CD8+ double-positive (DP) thymocyte frequency significantly decreased, becoming almost absent at 28 weeks after induction, while CD4 CD8- double-negative (DN) thymocytes and CD4+ CD8- single-positive (CD4+ SP) and CD4 CD8+ single-positive (CD8+ SP) cells were increased. This phenomenon might be explained by an inhibition of the DN-to-DP-cell transition and stimulation of DP cell conversion into CD4+ /CD8+ SP thymocytes. Moreover, we discovered a dramatic and abnormal increase in thymic B cells, that was associated with CD19, Irf8, Ebf1, Pax5, Irf4, Blk, CXCL13, CXCR5, CD79a, CD79b, Lyn, Syk, Btk, and BLNK gene accumulation, which exhibited positive interactions. We further verified that the mRNA expression of these genes was significantly upregulated and consistent with the RNA-seq results. These results suggest a role of these genes in the increase of B cells in the thymus of PIL mice. In summary, our results showed the changes in the thymus in PIL and elucidated the immunologic abnormalities of increased B cells, potentially providing insight into the associated molecular mechanisms and facilitating further research.

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1-/- mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1-/- mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1-/- mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

Dietary oleuropein and its acyl derivative ameliorate inflammatory response in peritoneal macrophages from pristane-induced SLE mice via canonical and noncanonical NLRP3 inflammasomes pathway.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease without an effective and safe treatment. Besides, macrophages are the major components of the innate immune system and play a critical role in the inflammation process in SLE. Secoiridoids from olive tree are phenolic compounds which have shown important pharmacological effects. Particularly, oleuropein (OL) has shown antioxidant, anti-inflammatory and immunomodulatory properties suggesting a potential application in a large number of inflammatory and reactive oxygen species (ROS)-mediated diseases. In addition, different studies have shown the importance of acyl derivatives of natural phenols due to their better hydrophilic/lipophilic balance.

Patch testing with purified and oxidized citronellol.

BACKGROUND: Citronellol is a commonly used fragrance terpene included in fragrance mix II. As with many other fragrance terpenes, citronellol is susceptible to autoxidation. Citronellol hydroperoxides are formed in large amounts and are the only oxidation products identified as sensitizers in oxidized citronellol. AIM: To compare frequencies of contact allergy to purified and oxidized citronellol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series, oxidized linalool, and oxidized limonene. METHODS: A total of 658 dermatitis patients were patch tested with purified and oxidized citronellol at 2.0%, 4.0%, 6.0%, and 1.0%, 2.0%, 4.0%, 6.0% petrolatum, respectively. The irritant properties of purified and oxidized citronellol were studied before patch testing. RESULTS: Few irritant reactions were observed in the pretest. Purified citronellol detected positive reactions in 0.15%-0.31% of patients, while oxidized citronellol detected positive reactions in 0.61%-4.5%. Among patients reacting to oxidized citronellol, 34%-50% showed concomitant reactions to fragrance markers of the baseline series and 75%-91% to oxidized linalool or oxidized limonene. CONCLUSION: Oxidized citronellol detects more cases of contact allergy than purified citronellol, and these cases are not all detected using fragrance mix II. Patch testing with oxidized citronellol will add to the tools in the diagnosis of fragrance allergy.

A benzimidazole inhibitor attenuates sterile inflammation induced in a model of systemic autoinflammation in female mice.

Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans.

Garcinol pacifies acrylamide induced cognitive impairments, neuroinflammation and neuronal apoptosis by modulating GSK signaling and activation of pCREB by regulating cathepsin B in the brain of zebrafish larvae.

The presence of acrylamide (ACR) in food results in evident cognitive decline, accumulation of misfolded proteins, neurotoxicity, neuroinflammation, and neuronal apoptosis leading to progressive neurodegeneration. Here, we used 4 dpf zebrafish larvae exposed to ACR (1mM/3days) as our model, and neuronal proteins were analyzed. Next, we tested the effect of garcinol (GAR), a natural histone-acetylation inhibitor, whose neuroprotection mechanism of action remains to be fully elucidated. Our result revealed that ACR exposure significantly impaired cognitive behavior, downregulated oxidative repair machinery, and enhanced microglia-induced neuronal apoptosis. Moreover, ACR mediated cathepsin-B (CAT-B) translocation acted as the intracellular secretase for the processing of amyloid precursor protein (APP) and served as an additional risk factor for tau hyper-phosphorylation. Here, GAR suppresses ACR mediated CATB translocation as similar with standard inhibitor CA-074. And, this pharmacological repression helped in inhibiting amyloidogenic APP processing and downstream tau hyper-phosphorylation. GAR neuroprotection was accompanied by CREB, ATF1, and BDNF activation promoting neuronal survival. At the same time, GAR subdued cdk5 and GSK3ß, the link between APP processing and tau hyper-phosphorylation. Taken together, our findings indicate that GAR rescued from ACR mediated behavioral defects, oxidative injury, neuroinflammation, undesirable APP processing, tau hyper-phosphorylation which in turn found to be CATB dependent.