PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway.

AIMS: PGE2 is one of the most abundant prostanoids in mammalian tissues, but its effect on neuronal receptors has not been well investigated. This study examines the effect of PGE2 on GABAA receptor currents in rat cerebellar granule neurons. METHODS: GABAA currents were recorded using a patch-clamp technique. Cell surface and total protein of GABAA ß1/2/3 subunits was carried out by Western blot analysis. RESULTS: Upon incubation of neurons with PGE2 (1 µM) for 60 minutes, GABAA currents were significantly potentiated. This PGE2-driven effect could be blocked by PKC or CaMKII inhibitors as well as EP1 receptor antagonist, and mimicked by PMA or EP1 receptor agonist. Furthermore, Western blot data showed that PGE2 did not increase the total expression level of GABAA receptors, but significantly increased surface levels of GABAA ß1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE2-induced increases in cell surface expression of GABAA receptors. CONCLUSION: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE2-induced increase in GABAA currents. This suggests that upregulation of postsynaptic GABAA receptors by PGE2 may have profound effects on cerebellar functioning under physiological and pathological conditions.

Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway.

Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K⁺ channels; however, the molecular mechanisms behind the effects of REV and the relevant α-subunit are not well defined. With the use of patch-clamp technique, cultured cerebellar granule cells, and HEK-293 cells transfected with the K(v)2.1 and K(v)2.2 α-subunits, we investigated the effect of REV on K(v)2.1 and K(v)2.2 α-subunits. Our data demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible, and mildly concentration-dependent manner and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting the cAMP/PKA pathway did not abolish the inhibition of K(v)2.2 current by REV. In contrast, activation of PKC with phorbol 12-myristate 13-acetate mimicked the inhibitory effect of REV on K(v)2.2 by modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC-α inhibitor completely eliminated the REV-induced inhibition of K(v)2.2. Moreover, the effect of REV on K(v)2.2 was reduced by preincubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC-α and PKC-ß were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited K(v)2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30.

Effect of Iron-Erythrocyte Metabolism-Related Indexes on Posttraumatic Growth in Patients on Maintenance Hemodialysis (MHD).

Purpose: To investigate the effect of iron-erythrocyte metabolism-related indexes on posttraumatic growth in MHD patients and their caregivers. Patients and Methods: A total of 170 pairs of MHD patients and their caregivers in Shanghai Changhai Hospital were enrolled in this research, which used sociodemographic characteristics, the Posttraumatic Growth Inventory (PTGI), the Perceived Social Support Scale (PSSS), and the Medical Coping Modes Questionnaire (MCMQ). The test data of 141 patients were retrieved from the hospital database. Results: Single-factor analysis showed that the PTGI score of patients with a mean corpuscular erythrocyte volume ≥ 100 fL was 85.4 ± 19.8 and those with a mean corpuscular erythrocyte volume lower than 100 fL were 70.6 ± 24.7; the PTGI scores of patients with reticulocytes >1.5% were 68.8 ± 25.8, and those with reticulocytes <1.5% were 78.4 ± 21.1; the PTGI scores of the caregivers whose serum iron was >10.6 µmol /L were 78.2 ± 21.6, and those with serum iron <10.6 µmol /L were 67.9 ± 22.8. The difference in MCMQ scores between the caregivers with transferrin saturation>50% and with transferrin saturation<20% was 18.9 ± 8.4. For the correlation test of serum iron, reticulocyte and PTGI scores for patients, the Pearson correlation coefficients were 0.239 and -0.193, respectively, and the correlation test between erythrocyte distribution width SD and the score of caregivers MCMQ scale, the Pearson correlation coefficient was 0.225; p for all was< 0.05, with significant differences. There was no significant difference in the scores of different scales for total iron binding capacity (TIBC) at different levels. Conclusion: The indexes related to iron erythrocyte metabolism in MHD patients are correlated with ruminant meditation of patients and their caregivers and promotion of posttraumatic growth. Good nutritional status, adequate hematopoietic material, and normal erythrocyte count and function are also important for them.

In Situ Electrospun Zein/Thyme Essential Oil-Based Membranes as an Effective Antibacterial Wound Dressing.

Wound dressings are an important element in promoting the healing of wounds. Electrospun fibrous materials have a highly porous structure and controllable antibacterial activity and are therefore popular as potential wound dressings. However, electrospun fibrous wound dressings are usually conveniently packaged for immediate use but cannot accommodate irregularly shaped wounds, and their misuse runs the risk of causing a secondary injury to the wound. To overcome these issues, in situ electrospun zein/thyme essential oil (TEO) nanofibrous membranes are proposed as a potential type of wound dressing and applied for wound management through an in situ electrospinning process, which uses a portable electrospinning device. The as-spun zein/TEO membranes show high gas permeability up to 154 ± 20.9 m2/s and superhydrophilicity with a 0° contact angle. With the addition of TEO, good antibacterial effects are also imparted onto the membrane to prevent infection. Moreover, the in situ electrospinning can directly deposit the zein/TEO membranes onto the site of the wound to accommodate the shape of the wound with increased convenience and perceived comfort. Experiments carried out on mice suggest that the in situ electrospun zein/TEO membrane greatly promotes the wound healing process within 11 days. The study results, therefore, suggest that wound dressings in the form of in situ electrospun zein/TEO membranes can be used to facilitate wound healing.

Performance of polyvinyl pyrrolidone-isatis root antibacterial wound dressings produced in situ by handheld electrospinner.

Antibacterial dressings are an increasingly important tool for the prevention and management of wound infections, particularly in light of concerns surrounding conventional drug-resistant antibiotics. Handheld electrospinning devices provide opportunities for the rapid application of antibacterial dressing materials to wounds, but spinning formulations need to be compatible with live biological surfaces. We report the development of a new antibacterial formulation compatible with handheld electrospinning, and its manufacture directly on a wound site. Nanofibrous dressing mats were produced from polyvinyl pyrrolidone (PVP) containing isatis root (Indigowoad root or Ban-Lan-Gen), a traditional Chinese medicine, commonly used for the treatment of infectious disease. The resulting wound dressing mats of PVP/isatis root exhibited well-defined fibrous structures and excellent surface wetting, and permeability characteristics. The presence of isatis root conferred antibacterial activity against gram negative and gram positive strains. Moreover, in a Kunming mouse skin injury model, direct electrospinning of PVP/isatis root formulations on to wound sites produced near complete wound closure after 11 days and epidermal repair in histological studies.

Inactivation of FoxM1 transcription factor contributes to curcumin-induced inhibition of survival, angiogenesis, and chemosensitivity in acute myeloid leukemia cells.

UNLABELLED: Aberrant expression of forkhead box protein M1 (FoxM1) contributes to carcinogenesis in human cancers, including acute myeloid leukemia (AML), suggesting that the discovery of specific agents targeting FoxM1 would be extremely valuable for the treatment of AML. Curcumin, a naturally occurring phenolic compound, is suggested to possess anti-leukemic activity; however, the underlying mechanism has not been well elucidated. In this study, we found that curcumin inhibited cell survival accompanied by induction of G2/M cell cycle arrest and apoptosis in HL60, Kasumi, NB4, and KG1 cells. This was associated with concomitant attenuation of FoxM1 and its downstream genes, such as cyclin B1, cyclin-dependent kinase (CDK) 2, S-phase kinase-associated protein 2, Cdc25B, survivin, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF), as well as the reduction of the angiogenic effect of AML cells. We also found that specific downregulation of FoxM1 by siRNA prior to curcumin treatment resulted in enhanced cell survival inhibition and induction of apoptosis. Accordingly, FoxM1 siRNA increased the susceptibility of AML cells to doxorubicin-induced apoptosis. More importantly, curcumin suppressed FoxM1 expression, selectively inhibited cell survival as well as the combination of curcumin and doxorubicin exhibited a more inhibitory effect in primary CD34(+) AML cells, while showing limited lethality in normal CD34(+) hematopoietic progenitors. These results identify a novel role for FoxM1 in mediating the biological effects of curcumin in human AML cells. Our data provide the first evidence that curcumin together with chemotherapy or FoxM1 targeting agents may be effective strategies for the treatment of AML. KEY MESSAGE: Curcumin inhibited AML cell survival and angiogenesis and induced chemosensitivity. Aberrant expression of FoxM1 induces AML cell survival and chemoresistance. Inactivation of FoxM1 contributes to curcumin-induced anti-leukemic effects. Curcumin together with FoxM1 targeting agents may be effective for AML therapy.