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.

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.

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.

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.