Antipruritic effects of geraniol on acute and chronic itch via modulating spinal GABA/GRPR signaling.

BACKGROUND AND PURPOSE: Itch (pruritus) is a common unpleasant feeling, often accompanied by the urge of scratching the skin. It is the main symptom of many systemic and skin diseases, which can seriously affect the patient's quality of life. Geraniol (GE; trans-3,7-dimethyl-2,6-octadien-1-ol) is a natural monoterpene with diverse effects, including anti-inflammatory, antioxidant, neuroprotective, anti-nociceptive, and anticancer properties. The study aims to examine the effects of GE on acute and chronic itch, and explore the underlying mechanisms. METHODS: Acute itch was investigated by using Chloroquine and compound 48/80 induced model, followed by manifestation of diphenylcyclopropenone (DCP)-induced allergic contact dermatitis and the acetone-ether-water (AEW)-induced dry skin model in mice. The scratching behavior, skin thickness, c-Fos expression, and GRPR protein expression in the spinal cord were subsequently monitored and evaluated by behavioral tests as well as pharmacological and pharmacogenetic technologies. RESULTS: Dose-dependent intraperitoneal injection of GE alleviated the acute itch, induced by chloroquine and compound 48/80, as well as increased the spinal c-Fos expression. Intrathecal administration of GE suppressed the GABAA receptor inhibitor bicuculline-induced itch, GRP-induced itch, and the GABAergic neuron inhibition-induced itch. Furthermore, the subeffective dose of bicuculline blocked the anti-pruritic effect of GE on the chloroquine and compound 48/80 induced acute itch. GE also attenuated DCP and AEW-induced chronic itch, as well as the increase of spinal GRPR expression in DCP mice. CONCLUSION AND IMPLICATIONS: GE alleviates both acute and chronic itch via modulating the spinal GABA/GRPR signaling in mice. Findings of this study reveal that GE may provide promising therapeutic options for itch management. Also, considering the pivotal role of essential oils in aromatherapy, GE has great application potential in aromatherapy for treating skin diseases, and especially the skin with severe pruritus.

Cytokines and Chemokines Modulation of Itch.

Itch (pruritus) is a common cutaneous symptom widely associated with many skin complaints, and chronic itch can be a severe clinical problem. The onset and perpetuation of itch are linked to cytokines, such as interleukin (IL)-31, IL-4, IL-13, IL-33, thymic stromal lymphopoietin, and tumor necrosis factor-alpha, and chemokines, such as chemokine (C-C motif) ligand 2 and C-X-C motif chemokine ligand 10. This review highlights research that has attempted to determine the attributes of various cytokines and chemokines concerning the development and modulation of itch. Through such research, clinical approaches targeting cytokines and/or chemokines may arise, which may further the development of itch therapeutics.

Geraniol enhances inhibitory inputs to the paraventricular thalamic nucleus and induces sedation in mice.

BACKGROUND: Plant extracts with sedative effects have a long history of clinical use for treating insomnia and epilepsy. Geraniol (GE), a plant-derived acyclic monoterpene, reduces locomotion and prolongs barbiturate-induced anesthesia in rats. However, the mechanisms of GE in sedation remain elusive. PURPOSE: This study aimed to investigate the mechanisms of GE in sedation in mice. METHODS: GE was administered systemically by nebulization and intraperitoneal injection. Open field tests, acute seizure tests, and electroencephalogram (EEG) recordings were performed to examine the sedative effects of GE in mice. The time of loss of the righting reflex and return of the righting reflex were recorded in anesthesia experiments to examine the effect of GE on anesthesia. In vitro c-Fos staining and in vivo fiber photometry recordings were performed to detect the activity change of the paraventricular thalamic nucleus (PVT). Microinjection of GE into PVT and related behavioral tests were performed to confirm that PVT was a critical target for GE. Whole-cell recordings were performed to dissect the effects of GE on PVT neurons via GABAA receptors. Molecular docking was performed to examine the interaction between GE and GABAA receptor subunits. RESULTS: We found that GE reduced locomotion, relieved acute seizures, altered the EEG, and facilitated general anesthesia in mice. Next, we found that GE decreased c-Fos expression and suppressed the calcium activity in PVT. Microinjection of GE into PVT reduced locomotion and facilitated anesthesia. Furthermore, electrophysiology results showed that GE induced dramatic membrane hyperpolarization and suppressed the activity of PVT neurons, mainly by prolonging spontaneous inhibitory postsynaptic currents and inducing tonic inhibitory currents. Molecular docking results indicated that the ß3 subunit might be a potential target for GE. CONCLUSION: By combined using behavioral tests, immunohistochemistry, calcium recording, and electrophysiology, we systematically revealed that GE inhibits PVT and induces sedation in mice. Essential oils have long been considered part of traditional medicine, and they are playing a critical role in aromatherapy. Since GE has a comparatively ideal safety property and multiple delivery methods, GE has great application potential in aromatherapy. Our study also provides a potential candidate for further development of sedatives and anaesthetics.

Functional characterization of tyrosine decarboxylase genes that contribute to acteoside biosynthesis in Rehmannia glutinosa.

MAIN CONCLUSION: The RgTyDCs possess typical decarboxylase functional activity in vitro and in vivo and participate in acteoside biosynthesis in R. glutinosa, positively controlling its production via activated acteoside/tyrosine-derived pathways. Acteoside is an important ingredient in Rehmannia glutinosa and an active natural component that contributes to human health. Tyrosine decarboxylase (TyDC) is thought to play an important role in acteoside biosynthesis. Several plant TyDC family genes have been functionally characterized and shown to play roles in some bioactive metabolites' biosynthesis by mediating the decarboxylation of L-tyrosine and L-dihydroxyphenylalanine (L-DOPA); however, one TyDC (named RgTyDC1) in R. glutinosa has been identified to date, but the family genes that contribute to acteoside biosynthesis remain largely characterized. Here, by in silico and experimental analyses, we isolated and identified three RgTyDCs (RgTyDC2 to RgTyDC4) in this species; these genes' sequences showed 50.92-82.55% identity, included highly conserved domains with homologues in other plants, classified into two subsets, and encoded proteins that localized to the cytosol. Enzyme kinetic analyses of RgTyDC2 and RgTyDC4 indicated that they both efficiently catalysed L-tyrosine and L-dopa. The overexpression of RgTyDC2 and RgTyDC4 in R. glutinosa, which was associated with enhanced TyDC activity, significantly increased tyramine and dopamine contents, which was positively correlated with improved acteoside production; moreover, the overexpression of RgTyDCs led to upregulated expression of some other genes-related to acteoside biosynthesis. This result suggested that the overexpression of RgTyDCs can positively activate the molecular networks of acteoside pathways, enhancing the accumulation of tyramine and dopamine, and promoting end-product acteoside biosynthesis. Our findings provide an evidence that RgTyDCs play vital molecular roles in acteoside biosynthesis pathways, contributing to the increase in acteoside yield in R. glutinosa.

Effects of the coupling water and fertilizer on soil phosphorus components in alfalfa field in Eastern Inner Mongolia, China.

Soil phosphorus (P) could be categorized into organic and inorganic forms, with diffe-rent capabilities of nutrient supply. Exploring soil P components through liquid 31P-NMR would provide an important theoretical basis for soil P nutrition regulation. This study addressed the characteristic of P in alfalfa (Medicago sativa) soil via the pot experiment. There were two scenarios of treatments with conventional and dry water combined with different P fertilizer levels (P0-P4: 0, 0.025, 0.05, 0.1, and 0.2 g P2O5·kg-1soil). The characteristics of P components in alfalfa soil under water-fertilizer coupling conditions were measured by liquid 31P-NMR. Results showed that under different water and fertilizer treatments, soil inorganic P was mainly composed of inorganic orthophosphate, pyrophosphate and inorganic polyphosphate. Inorganic orthophosphate was the dominant component of inorganic P, which could be reduced by drought. High P application (P4) could increase the contents of soil inorganic polyphosphates and inorganic pyrophosphates. Among the organic P components, monoester orthophosphate was dominant, the conversion and utilization of which in alfalfa soil were affected by drought. Overall, the rational management of water and fertilizer could effectively regulate the conversion and utilization of P nutrients in alfalfa soil in Eastern Inner Mongolia.

Glial IL-33 signaling through an ST2-to-CXCL12 pathway in the spinal cord contributes to morphine-induced hyperalgesia and tolerance.

Morphine and other opiates are highly effective for treating moderate to severe pain. However, morphine-induced hyperalgesia and analgesic tolerance prevent durable efficacy in patients. Here, we investigated the underlying molecular mechanisms of this phenomenon. We found that repeated subcutaneous injections of morphine in mice increased the abundance of the cytokine interleukin-33 (IL-33) primarily in oligodendrocytes and astrocytes and that of its receptor ST2 mainly in astrocytes. Pharmacological inhibition or knockdown of IL-33 or ST2 in the spinal cord attenuated morphine-induced hyperalgesia and analgesic tolerance in mice, as did global knockout of either Il33 or St2, which also reduced morphine-enhanced astroglial activation and excitatory synaptic transmission. Furthermore, a pathway mediated by tumor necrosis factor receptor­associated factor 6 (TRAF6) and the kinase JNK in astrocytes was required for IL-33­mediated hyperalgesia and tolerance through promoting the production of the chemokine CXCL12 in the spinal cord. The findings suggest that targeting IL-33­ST2 signaling could enable opioids to produce sustained analgesic effects in chronic pain management.

Perioperative analgesia with parecoxib sodium improves postoperative pain and immune function in patients undergoing hepatectomy for hepatocellular carcinoma.

RATIONALE, AIMS, AND OBJECTIVES: Acute postoperative pain can result in immune dysfunction, which can be partly mitigated by efficient pain management. Opioids that have been widely applied to analgesia have been shown to suppress immune function, which has a negative impact on the treatment of patients with cancer. This study investigated the effects of perioperative fentanyl analgesia alone or in combination with parecoxib sodium on postoperative pain, immune function, and prognosis in patients undergoing hepatectomy of hepatocellular carcinoma (HCC). METHODS: A total of 80 patients scheduled for hepatectomy between October 2013 and August 2014 were included. Patients were randomly divided into two groups (n = 40) and allocated to receive parecoxibsodium 40 mg (group P) or placebo (group C) 30 minutes before induction of anaesthesia, followed by 40 mg every 12 hours for 48 hours after the operation. All patients had access to patient-controlled analgesia with intravenous fentanylpostoperatively. Venous blood samples were collected at the following time points: 30 minutes before induction of anaesthesia (T0), the end of the surgery (T1), 24 hours after surgery (T2), and 72 hours after surgery (T3). The percentages of CD3+, CD4+, CD8+, CD4+/CD8+ T cells, and CD3+CD16+CD56+ (NK) cells at these time points were quantified by flow cytometry (FCM).Visual analogue scale (VAS) scores, total fentanyl consumption, and adverse effects were recorded. The prognostic differences in overall survival (OS) and disease-free survival (DFS) between the two groups was also investigated. RESULTS: For both groups, the percentages of CD3+, CD4+ T cells, and the ratio of CD4+/CD8+ significantly decreased at T1 and T2 (P < .05). The percentages of CD3+ T cells were significantly lower in group C than that in group P at T2 (P < .05). In group C, the amount of CD3+ T cells was lower at T3 compared with T0 (P < .05). The percentages of NK cells significantly decreased at T1 in both groups (P < .05). The percentages of NK in group P were recovered nearly to baseline (T0) at T2, which was higher than that of group C (P < .05). In group C, the percentages of NK cells have not recovered nearly to baseline at T3 compared with T0 (P < .05). VAS scores at rest and on cough in group P were significantly lower than those in group C at 2, 6, 12, and 24 hours after operation (P < .05), and there were no significant differences in VAS scores between the two groups at 48 hours after surgery (P > .05). There were no significant differences regarding the incidence of adverse effects between the two groups (P > .05). Kaplan-Meier analysis indicated that the DFS time in group P was significantly longer than in group C (19.0 months, 95% confidence interval [CI], 9.8-28.2 vs 14.0 months, 95% CI, 8.1-19.9; P < .05). There was no significant difference in OS time (36.0 months, 95% CI, 13.4-58.9 vs 14.0 months, 95% CI, 10.6-25.4; P > .05) between two groups. CONCLUSIONS: The present study indicated that perioperative analgesia of parecoxib sodium combined with patient-controlled analgesic fentanyl resulted in better preserved immune function with enhancement of the analgesic efficacy to fentanyl alone of HCC patients undergoing hepatectomy and helped postpone postoperative tumour recurrence.

A rare case of type 1 leprosy reactions following tetanus infection in a borderline tuberculoid leprosy patient and a literature review.

BACKGROUND: Type 1 leprosy reaction, also known as "reversal reaction", is related to cellular immune responses to Mycobacterium leprae antigens. The risk factors that trigger type 1 leprosy reactions are poorly understood. Leprosy with concurrent tetanus is rare, and there are no publicly available reports of a leprosy patient infected with tetanus that induced type 1 leprosy reactions. CASE PRESENTATION: A 56-year-old Chinese Han female presented to our hospital with symptoms of erythematous plaques and pain over her left upper limb for 2 days and foreign object sensation in her throat for 3 days. The patient had a 6-year history of leprosy. Type 1 leprosy reactions were initially considered, followed by treatment with methylprednisolone. Two days later, the patient's symptoms were aggravated, with neck muscle tension and difficulty in opening her mouth, and the erythematous plaques had spread over most of her left upper limb. After further careful examinations, we confirmed the diagnosis of tetanus with concurrent type 1 leprosy reactions. The patient was given anti-tetanus treatment for 12 days and anti-leprosy reaction treatment for 4 months; the diseases were eventually controlled. CONCLUSIONS: This report suggests that tetanus infection may be a trigger for type 1 leprosy reactions.

Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma.

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is a factor implicating in vascular differentiation and angiogenesis. Several lines of evidence indicate that aberrant expression of AGGF1 is associated with tumor initiation and progression. The aim of this study was to investigate the expression and prognostic value of AGGF1 in hepatocellular carcinoma (HCC), as well as its relationship with clinicopathological factors and tumor angiogenesis. Immunohistochemistry was performed to evaluate the expression of AGGF1 in HCC and paracarcinomatous tissues collected from 70 patients. Vascular endothelial growth factor (VEGF) and CD34 expression levels were examined in the 70 HCC tissues. Prognostic significance of tumoral AGGF1 expression was determined. Notably, AGGF1 expression was significantly higher in HCC than in surrounding non-tumor tissues (65.7 vs. 25.7 %; P < 0.001). AGGF1 expression was significantly correlated with tumoral VEGF expression and CD34-positive microvessel density. Moreover, AGGF1 expression was significantly associated with tumor size, tumor capsule, vascular invasion, Edmondson grade, alpha-fetoprotein level, and TNM stage. Kaplan-Meier survival analysis showed that high AGGF1 was correlated with reduced overall survival (OS) rate (P = 0.001) and disease-free survival (DFS) rate (P < 0.001). Multivariate analysis identified AGGF1 as an independent poor prognostic factor of OS and DFS in HCC patients (P = 0.043 and P = 0.010, respectively). Taken together, increased AGGF1 expression is associated with tumor angiogenesis and serves as an independent unfavorable prognostic factor for OS and DFS in HCC. AGGF1 may represent a potential therapeutic target for HCC.

Development and characterization of microsatellite loci for the pseudometallophyte Commelina communis (Commelinaceae).

UNLABELLED: • PREMISE OF THE STUDY: Microsatellite primers were developed for the pseudometallophyte Commelina communis (Commelinaceae), an important pioneer plant for phytoremediation of copper-contaminated soil. Two wild populations collected from metalliferous and nonmetalliferous sites were used to assess the polymorphism at each locus. • METHODS AND RESULTS: Based on the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method, a total of 34 pairs of simple sequence repeat (SSR) markers were designed. When 40 specimens from two populations were screened, 12 microsatellite loci were found to be highly polymorphic. The number of alleles per locus ranged from one to 11 and the observed and expected heterozygosity per locus ranged from 0.000 to 1.000 and from 0.195 to 0.941, respectively. • CONCLUSIONS: These markers will be useful for examining genetic diversity, population structure, and gene flow in populations of C. communis under different edaphic conditions and guiding sustainable management plans for phytoremediation.

High-level expression of HOXB13 is closely associated with tumor angiogenesis and poor prognosis of hepatocellular carcinoma.

Homeobox B13 (HOXB13) is generally considered as a crucial regulator of terminal cellular differentiation. More recently, the absent or aberrant expression of HOXB13 has been increasingly implicated in cancer development and metastasis. However, the expression of HOXB13 in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis and prognosis still remain unclear. The aim of the study was to evaluate the expression of HOXB13 in patients with HCC and explore the relationship of HOXB13 expression with clinicopathologic factors, tumor angiogenesis and prognosis. Immunohistochemistry was performed to determine the expression of HOXB13 in HCC and corresponding paracarcinomatous tissues from 72 patients. Vascular endothelial growth factor (VEGF) and CD31 were only examined in tissues of HCC patients mentioned above. The results showed that HOXB13 expression was significantly (P <0.001) higher in HCC (69.4%) than that in surrounding non-tumor tissues (26.4%), positively correlated with tumor VEGF (P <0.001) and microvessel density (MVD) (P = 0.013). Besides, it was associated with tumor capsula (P <0.001), vascular invasion (P <0.001), Edmondson grade (P <0.001), AFP (P = 0.007) and TNM stage (P <0.001). Univariate analysis showed poorer overall survival (OS) rate and disease free survival (DFS) rate in patients expressing higher levels of HOXB13. HOXB13 was also found to be an independent poor prognostic factor of OS and DFS in multivariate analysis. Taken together, our results suggest that increased HOXB13 expression is associated with tumor angiogenesis and progression in HCC and may function as a promising biomarker for unfavorable prognosis of HCC.

Diagnostic and prognostic significance of peroxiredoxin 1 expression in human hepatocellular carcinoma.

Peroxiredoxin 1 (Prdx1) is a member of the peroxiredoxin family of antioxidant enzymes and implicated in cell differentiation, proliferation, and apoptosis. The aim of the present study was to determine the expression and diagnostic and prognostic significance of Prdx1 in human hepatocellular carcinoma (HCC). Prdx1 expression was examined in 76 HCC patients and 20 healthy volunteers. The relationships between Prdx1 expression and clinicopathological features were analyzed. Receiver operating characteristics analysis was used to calculate the diagnostic accuracy of serum Prdx1, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of Prdx1 on overall survival (OS) and disease-free survival (DFS) of HCC patients was investigated. Prdx1-positive rate was significantly (p < 0.05) higher in HCC (77.1 %) than in adjacent non-tumorous liver tissues (18.4 %). Prdx1 immunoreactivity was positively correlated with tumor vascular endothelial growth factor expression and microvessel density. Prdx1 expression was significantly associated with tumor size, microvascular invasion, Edmondson grade, tumor capsula status, serum AFP, and tumor-node-metastasis stage. The combination of serum Prdx1 and AFP had a markedly higher area under the curve than serum Prdx1 alone. Positive Prdx1 expression was associated with unfavorable OS (p = 0.004) and DFS (p = 0.001). Multivariate analysis revealed intra-tumoral Prdx1 staining as an independent poor prognostic marker for OS (p = 0.006) and DFS (p = 0.002). Taken together, our data suggest that increased Prdx1 expression is associated with tumor angiogenesis and progression in HCC and serves as a promising biomarker for detection and prognosis of this malignancy.

Characterization of the Haloarcula hispanica amyH gene promoter, an archaeal promoter that confers promoter activity in Escherichia coli.

Archaea form a third domain of life that is distinct from Bacteria and Eukarya. According to the current knowledge, the basal transcription machinery of Archaea (including the core promoter architecture, the RNA polymerase, and the basal transcription factors) closely resembles that of Eukarya in structure and function, while differing considerably from the bacterial paradigm. In the present study, the promoter region of the halophilic archaeon Haloarcula hispanica's amyH gene was isolated and characterized, and it was surprisingly revealed that the amyH gene promoter could confer promoter activity (i.e., drive transcription) in haloarchaea (Archaea) as well as in Escherichia coli (Bacteria), where the transcriptions driven are initiated at the same adenine base. Further investigation revealed that the core structure of the amyH gene promoter possesses a combination of the typical structural characteristics of archaeal promoter, which are eukaryotic-like, and those of bacterial promoter. Our results indicate that the core promoter structures of some archaeal genes may possess a combination of eukaryotic- and bacterial-like features, and moreover, suggest a possible evolutionary relationship between basal transcription signals and transcription mechanisms of Archaea and the other two domains of life.

Alkaloids from roots of Stemona sessilifolia and their antitussive activities.

Protostemonamide ( 1), a new protostemonine-type alkaloid, and 12 known compounds were isolated from the roots of Stemona sessilifolia. Their structures were elucidated by 1 D and 2 D NMR spectral and other spectroscopic studies. The main alkaloidal constituents, protostemonine ( 2), stemospironine ( 4), and maistemonine ( 7), showed significant antitussive activity in a citric acid-induced guinea pig cough model following peripheral administration; stemonamine ( 11) had antitussive activity following i. c. v. administration.

[Analysis of promoter sequence and its activity of homologues gene rad25 of eukaryotes from halophilic archaea].

The transcriptional product in Halobacterium halobium R1 similar to eukaryotic gene rad25 was analyzed by RT-PCR. Using bgaH as the reporter genes, the promoter function of eukaryotic rad25-like DNA fragment in halophilic archaea was investigated by promoter probe analysis. The important functional regions, which could influence the promoter activity of rad25-like gene, were identified by deletion analysis of the promoter sequence in Haloferax volcanii. It is found that the DNA fragment of promoter similar to eukaryotic gene rad25 contains the typical characteristic sequence of archaeal promoter. These results indicate that rad25-like gene in Halobacterium halobium R1 is active and may play a role on the NER pathway as the eukaryotic pattern.