Interleukin-4 suppresses the expression of macrophage NADPH oxidase heavy chain subunit (gp91-phox)

AbstractThe production of superoxide anion by NADPH oxidase is a principal nonspecific bactericidal activity of macrophages and neutrophils in host defense. However, exuberant production of superoxide anion also damages host tissues. Cloning and DNA sequencing of the 91 kDa subunit (gp91-phox) open reading frame indicated a high degree of sequence conservation, greater than 90% in nucleotide and amino acid sequences, between the porcine and human cDNAs. We show in pigs that interleukin-4 (IL-4), a T lymphocyte cytokine which plays a major role in mediating antibody responses to pathogens, suppresses superoxide anion production in macrophages by specifically reducing the level of mRNA encoding gp91-phox. Messenger RNA levels are suppressed approx. 70% within 4 h and persist for 24 h without any change in the rate of mRNA turnover. Nuclear run-on analysis showed that IL-4 did not alter the rate of gp91-phox gene transcription under conditions in which IL-1β transcription was inhibited. These results indicate that IL-4 suppresses the inflammatory response of macrophages by mechanisms that include post-transcriptional regulation of the 91 kDa catalytic subunit of NADPH oxidase, and transcriptional regulation of inflammatory cytokine expression

Inhibition of miR-665 alleviates neuropathic pain by targeting SOCS1

Purpose: To investigate the effect of miR-665 in neuropathic pain and the possible molecular mechanism involved.Methods: A neuropathic pain model was established using chronic constriction injury (CCI) methods in Sprague Dawley (SD) rats. Mechanical and thermal hyperalgesia were measured using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), respectively. The inflammation response was determined by assessing the production of inflammation factors. The target relationship of miR-665 and suppressor of cytokine signaling 1 (SOCS1) was verified by luciferase assay.Results: In the CCI rat model, PWT and PWL decreased following treatment with miR-665 (p < 0.01). MiR-665 was elevated in the spinal cord and microglia of CCI rats at different time points (p < 0.01). Down-regulation of miR-665 increased PWT and PWL and inhibited the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in CCI rats (p < 0.01). Luciferase assay results indicate that SOCS1 was the target of miR-665 (p < 0.01). SOCS1 decreased in CCI rats (p < 0.01) after treatment with miR-665. MiR-665 negatively regulated the expression of SOCS1 (p < 0.01). Down-regulation of SOCS1 reversed the alleviating effect of decreased miR-665 on pain sensitivity and inflammationresponse (p < 0.01).Conclusion: Down-regulation of miR-665 alleviates neuropathic pain by targeting SOCS1, and hence making miR-665 a promising therapeutic target for neuropathic pain. Keywords: MiR-665, SOCS1, Neuropathic pain, CCI, Spinal cor

Fractal Evolution Characteristics on the Three-Dimensional Fractures in Coal Induced by CO2 Phase Transition Fracturing

To analyze the transformed effect of three-dimensional (3D) fracture in coal by CO2 phase transition fracturing (CO2 -PTF), the CO2 -PTF experiment under a fracturing pressure of 185 MPa was carried out. Computed Tomography (CT) scanning and fractal theory were used to analyze the 3D fracture structure parameters. The fractal evolution characteristics of the 3D fractures in coal induced by CO2 -PTF were analyzed. The results indicate that the CO2 phase transition fracturing coal has the fracture generation effect and fracture expansion-transformation effect, causing the maximum fracture length, fracture number, fracture volume and fracture surface area to be increased by 71.25%, 161.94%, 3970.88% and 1330.03%. The fractal dimension (DN) for fracture number increases from 2.3523 to 2.3668, and the fractal dimension (DV) for fracture volume increases from 2.8440 to 2.9040. The early dynamic high-pressure gas jet stage of CO2 -PTF coal influences the fracture generation effect and promotes the generation of 3D fractures with a length greater than 140 µm. The subsequent quasi-static high-pressure gas stage influences the fracture expansion-transformation effect, which promotes the expansion transformation of 3D fractures with a length of less than 140 µm. The 140 µm is the critical value for the fracture expansion-transformation effect and fracture generation effect. Five indicators are proposed to evaluate the 3D fracture evolution in coal caused by CO2 -PTF, which can provide theoretical and methodological references for the study of fracture evolution characteristics of other unconventional natural gas reservoirs and their reservoir stimulation

Regulated proteolysis of the alternative sigma factor SigX in Streptococcus mutans: implication in the escape from competence

BACKGROUND: SigX (σ(X)), the alternative sigma factor of Streptococcus mutans, is the key regulator for transcriptional activation of late competence genes essential for taking up exogenous DNA. Recent studies reveal that adaptor protein MecA and the protease ClpC act as negative regulators of competence by a mechanism that involves MecA-mediated proteolysis of SigX by the ClpC in S. mutans. However, the molecular detail how MecA and ClpC negatively regulate competence in this species remains to be determined. Here, we provide evidence that adaptor protein MecA targets SigX for degradation by the protease complex ClpC/ClpP when S. mutans is grown in a complex medium. RESULTS: By analyzing the cellular levels of SigX, we demonstrate that the synthesis of SigX is transiently induced by competence-stimulating peptide (CSP), but the SigX is rapidly degraded during the escape from competence. A deletion of MecA, ClpC or ClpP results in the cellular accumulation of SigX and a prolonged competence state, while an overexpression of MecA enhances proteolysis of SigX and accelerates the escape from competence. In vitro protein-protein interaction assays confirm that MecA interacts with SigX via its N-terminal domain (NTD(1–82)) and with ClpC via its C-terminal domain (CTD(123–240)). Such an interaction mediates the formation of a ternary SigX-MecA-ClpC complex, triggering the ATP-dependent degradation of SigX in the presence of ClpP. A deletion of the N-terminal or C-terminal domain of MecA abolishes its binding to SigX or ClpC. We have also found that MecA-regulated proteolysis of SigX appears to be ineffective when S. mutans is grown in a chemically defined medium (CDM), suggesting the possibility that an unknown mechanism may be involved in negative regulation of MecA-mediated proteolysis of SigX under this condition. CONCLUSION: Adaptor protein MecA in S. mutans plays a crucial role in recognizing and targeting SigX for degradation by the protease ClpC/ClpP. Thus, MecA actually acts as an anti-sigma factor to regulate the stability of SigX during competence development

Leczenie oksytocyną zapobiega stłuszczeniu szpiku kostnego obserwowanemu u królików z cukrzycą wywołaną alloksanem — badanie przy użyciu protonowej spektroskopii rezonansu magnetycznego

Introduction: Oxytocin might be used therapeutically as an ally to rescue osteopathy resulting from diabetes. However, the in vivo effects of oxytocin on marrow adipogenesis in diabetes remain unknown. In this longitudinal study, we aimed to investigate the protective ef­fects of oxytocin on diabetes-induced marrow adiposity in rabbits using proton MR spectroscopy. Material and methods: Forty-five female New Zealand rabbits were randomly divided into controls, diabetes, and diabetes treated with oxytocin (ip, 0.78 mg/kg) for six months. Marrow fat fraction (FF) was determined by proton MR spectroscopy at baseline, and at three and six months. Bone mineral density was measured by dual-energy X-ray absorptiometry. Serum biomarkers, glycolipid metabolism, and histological analysis of marrow adipocytes were determined. Results: Oxytocin treatment had positive metabolic effects in diabetic rabbits, which was based on the changes in glucose metabolism, insulin sensitivity, and lipid profiles. The diabetic rabbits demonstrated dramatic marrow adiposity in a time-dependent manner; at three and six months the FF percentage changes from baseline were 10.1% and 25.8%, respectively (all P < 0.001). Moreover, oxytocin treatment significantly reversed FF values and quantitative parameters of marrow adipocyte in diabetic rabbits to levels of naive control rabbits. Oxytocin improved bone formation marker in diabetic rabbits compared to the saline group. Also, treatment of diabetic rabbits with oxytocin significantly mitigated bone deterioration when compared with the saline-treated diabetic group (all P < 0.05). Conclusions: Oxytocin appears to alleviate harmful effects of hyperglycaemia on marrow adiposity. Proton MR spectroscopy may be a valuable tool, providing complementary information on efficacy assessments.Wstęp: Oksytocyna może być stosowana terapeutycznie w osteopatii wynikającej z cukrzycy, jednakże jej wpływ in vivo na stłuszczenie szpiku kostnego w przebiegu cukrzycy pozostaje niezbadany. Niniejsze badanie przekrojowe ma na celu zbadać ochronne działanie oksy­tocyny na wywołane cukrzycą stłuszczenie szpiku kostnego u królików przy użyciu protonowej spektroskopii rezonansu magnetycznego. Materiał i metody: Czterdzieści pięć samic królików nowozelandzkich podzielono losowo na grupę kontrolną, grupę z cukrzycą oraz grupę z cukrzycą leczoną oksytocyną (0.78 mg/kg, i.p.) przez sześć miesięcy. Frakcja tłuszczu (ang. fat fraction; FF) szpiku kostnego została określona za pomocą protonowej spektroskopii rezonansu magnetycznego na początku badania oraz po trzech i sześciu miesiącach. Gęstość mineralną kości zmierzono za pomocą absorpcjometrii promieniowania rentgenowskiego o podwójnej energii. Określono również biomarkery surowicy krwi, metabolizm glikolipidów oraz sporządzono analizę histologiczną adipocytów szpiku kostnego. Wyniki: Leczenie oksytocyną przyniosło pozytywne efekty metaboliczne u królików z cukrzycą, co stwierdzono na podstawie zmian w me­tabolizmie glukozy, wrażliwości na insulinę oraz profili lipidowych. Zauważono drastyczny wzrost stłuszczenia szpiku kostnego u królików z cukrzycą w sposób zależny od czasu; po trzech i sześciu miesiącach, procentowe zmiany frakcji tłuszczu w stosunku do wartości wyjściowej wynosiły odpowiednio 10,1% i 25,8% (wszystkie P &lt; 0.001). Co więcej, leczenie oksytocyną znacząco odwracało wartości frakcji tłuszczu oraz ilościowe parametry adipocytów szpiku kostnego u królików z cukrzycą do poziomu królików z grupy kontrolnej. Oksytocyna poprawiała marker tworzenia kości u królików z cukrzycą w porównaniu do grupy, której podawano sól fizjologiczną. Ponadto, leczenie oksytocyną królików z cukrzycą znacząco łagodziło niszczenie kości w porównaniu do grupy z cukrzycą, której podawano sól fizjologiczną (wszystkie P &lt; 0.05). Wnioski: Oksytocyna wydaje się zmniejszać szkodliwy wpływ hiperglikemii na stłuszczenie szpiku kostnego. Protonowa spektroskopia rezonansu magnetycznego może być cennym narzędziem, dostarczającym uzupełniających informacji na temat oceny skuteczności leczenia

Effects of taurine on male reproduction in rats of different ages

<p>Abstract</p> <p>Background</p> <p>It has been demonstrated that taurine is one of the most abundant free amino acids in the male reproductive system, and can be biosynthesized by male reproductive organs. But the effect of taurine on male reproduction is poorly understood.</p> <p>Methods</p> <p>Taurine and β-alanine (taurine transport inhibitor) were offered in water to male rats of different ages. The effects of taurine on reproductive hormones, testis marker enzymes, antioxidative ability and sperm quality were investigated.</p> <p>Results</p> <p>The levels of T and LH were obviously increased by taurine supplementation in rats of different ages, and the level of E was also significantly elevated in baby rats. The levels of SOD, ACP, SDH and NOS were obviously increased by taurine administration in adult rats, but the levels of AKP, AST, ALT and NO were significantly decreased. The levels of SOD, ACP, LDH, SDH, NOS, NO and GSH were significantly elevated by taurine administration in aged rats, but the levels of AST and ALT were significantly decreased. The motility of spermatozoa was obviously increased by taurine supplement in adult rats. The numbers and motility of spermatozoa, the rate of live spermatozoa were significantly increased by taurine supplement in aged rats.</p> <p>Conclusions</p> <p>The present study demonstrated that a taurine supplement could stimulate the secretion of LH and T, increase the levels of testicular marker enzymes, elevate testicular antioxidation and improve sperm quality. The results imply that taurine plays important roles in male reproduction especially in aged animals.</p

Mg-ZIF nanozymes disrupt the level of ROS for osteosarcoma killing via POD activity

Osteosarcoma (OS) is notorious for its high malignancy, and conventional chemotherapy drugs, while killing tumor cells, often inflict significant harm on the patient’s body. The tumor microenvironment of OS is characterized by high levels of hydrogen peroxide (H2O2). Leveraging this feature, we have developed Mg-ZIF nanoparticles, which incorporate magnesium (Mg) to confer robust peroxidase (POD)-like enzymatic activity. These Mg-ZIF nanozymes can generate highly lethal superoxide anions within tumor cells in a responsive manner, thereby achieving effective tumor destruction. Both in vitro and in situ OS models have corroborated the anti-tumor efficacy of Mg-ZIF nanozymes, while also validating their biosafety. The design of Mg-ZIF nanozymes opens a new avenue for the treatment of OS, offering a promising therapeutic strategy

Bead-on-string structure formed by electrohydrodynamic printing

A Bead-on-String (B-S) structure which consists of droplet and filament is generated based on electrohydrodynamic printing system. The formation process of the B-S structure is demonstrated and discussed. Subsequently, the influence of the substrate moving speed on the B-S structure is investigated. The size of the droplet in the B-S structure decreases with the substrate moving speed. When the substrate moving speed is higher than the jetting speed, satellite droplet will appear and its number increases with the substrate moving speed. The effect of the solution concentration on the deposited patterns is also studied. A continuous line is printed with 3 wt% PEO solution. The B-S structure is generated when the concentration of the PEO solution is within 5-15 wt%. Moreover, the size of the droplet decreases with the increasing of the solution concentration. At the concentration of 18 wt%, nanofiber is produced and a pattern similar to the B-S structure is deposited on the substrate