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BACKGROUND@#Radiation enteritis (RE) is a common complication of abdominal or pelvic radiotherapy, which when severe, could be life-threatening. Currently, there are no effective treatments. Studies have shown that mesenchymal stem cells (MSCs)-derived exosomes (MSC-exos) exhibit promising therapeutic effects in inflammatory diseases. However, the specific role of MSC-exos in RE and the regulatory mechanisms remain elusive. @*METHODS@#In vivo assay was carried out by injecting MSC-exos into the total abdominal irradiation (TAI)-induced RE mouse model. For in vitro assay, Lgr5-positive intestinal epithelial stem cells (Lgr5+ IESC) were extracted from mice, followed by irradiation along with MSC-exos treatment. HE staining was performed to measure histopathological changes. mRNA expression of inflammatory factors TNF-a and IL-6 and stem cell markers LGR5, and OCT4 were quantified by RT-qPCR. EdU and TUNEL staining was performed to estimate cell proliferation and apoptosis. MiR-195 expression in TAI mice and radiation-induced Lgr5+ IESC was tested. @*RESULTS@#We found that the injection of MSC-exos inhibited inflammatory reaction, increased stem cell marker expression, and maintained intestinal epithelial integrity in TAI mice. Furthermore, MSC-exos treatment increased the proliferation and simultaneously suppressed apoptosis in radiation-stimulated Lgr5+ IESC. MiR-195 expression increased by radiation exposure was decreased by MSC-exos therapy. MiR-195 overexpression facilitated the progress of RE by counteracting the effect of MSC-exos. Mechanistically, the Akt and Wnt/b-catenin pathways inhibited by MSC-exos were activated by miR-195 upregulation. @*CONCLUSION@#MSC-Exos are effective in treating RE and are essential for the proliferation and differentiation of Lgr5+ IESCs. Moreover, MSC-exos mediates its function by regulating miR-195 Akt b-catenin pathways.
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Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.
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BACKGROUND:Previous research have confirmed that CD34 is closely related to oncogenesis, progress, recurrence, metastasis and drug-resistance of various cancers, but its role in nasopharyngeal carcinoma remains unclear. OBJECTIVE:Tosortcels positive and negative for CD34 in nasopharyngealcarcinoma cel lines and to detect cel proliferation and migration. METHODS:Expressionsof CD34 in nasopharyngeal carcinoma cel lines 5-8F, 6-10B, CNE1 and CNE2 were detected by flow cytometry. And CD34+and CD34-cels were sorted based on cel surfacemarkers for purity identification. Afterwards, proliferation and migrationof CD34+and CD34-celswere detected by MTT assay, colony-formation assay and scratch assay. RESULTS AND CONCLUSION:Al four nasopharyngeal carcinoma cel lines expressed CD34 in 0.1%-0.2%, and the level of CD34 was closely related to the cel growth density. The purity of CD34+cel was more than 98% in the sorted CD34+celpopulations, but no CD34+cels were found inthe sorted CD34-celpopulations.At 1, 3, 5 and 7 daystheproliferation rate of CD34+cel, populationswas significantly higher than that of CD34-cels (P< 0.05). Consistently, thecolony-formation efficiencyof CD34+cel was significantlyhigher than that ofCD34-cels (P< 0.05). Moreover, CD34+cels migrated significantly faster than CD34-cels by scratch assay (P< 0.05). In conclusion, CD34+cels culturedin vitro display higher proliferation and migration capacities, indicating that CD34+celshavethe potential of nasopharyngeal carcinoma stem cels.
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Objective To evaluate the protective effect of propofol on liver in severely scalded rabbits.Methods Twenty healthy male New Zealand rabbits, aged 3-4 months, weighing 2.3-2.5 kg, were randomly divided into either scald group (group S, n =10) or propofol group (group P, n =10).Thirty percent of the total body surface was shaved chemically with 10％ sodium sulphate and then exposed to 98 ℃ water for 20 s to produce third degree thermal injury at the back and buttocks of anesthetized rats.In group P, propofol was injected at a dose of 1.5 mg/kg at 1 h after scald, followed by an infusion of 4 mg· kg-1 · h 1 for4 h.The equal volume of normal saline was given in groupS.Before scald (T1), at 1 h after scald (T2) , and at 6, 12 and 24 h after administration of propofol or normal saline (T3-5) , blood samples were taken from the internal jugular vein for determination of serum alanine aminotransferase (ALT) activity (by lactate dehydrogenase method), aspartate aminotransferase (AST) activity (by MDH), and tumor necrosis factor-alpha (TNF-α) concentrations (by enzyme linked immunosorbent assay).The rabbits were sacrificed at T5, and their livers were removed and cut into sections which were stained with haematoxylin and eosin and examined under microscope.Results The serum ALT and AST activities and TNF-α concentrations were significantly higher at T2-5 than at T1.Compared with the values at T2, the serum ALT and AST activities and TNF-α concentrations in group S and serum TNF-α concentrations in group P were significantly increased at T3-5, and no significant change was found in the serum ALT and AST activities at T3-5 in group P.Compared with group S, the serum ALT and AST activities and TNF-α concentrations were significantly decreased at T3 5, and the pathological changes were mitigated in group P.Conclusion Propofol provides protective effect on liver in severely scalded rabbits.
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Objective To explore the role of pulmonary function analysis in drug efficacy evaluation of radiation-induced lung injury.Methods Totally 30 C57BL/6 mice were randomly divided into 3 groups:control group, radiation group and dexamethasone group.Mice in radiation group and dexamethasone group were irradiated with 20 Gy X-ray on the whole chest.Then mice in dexamethasone group was intraperitoneally injected with dexamethasone at the dose of 4.5 mg/( kg· d) for 2 weeks and then the dose was halved up to 1 month after radiation while control group and radiation group were intraperitoneally injected with 0.9%saline.One month after irradiation, pulmonary function of all the mice was tested with EMKA system.Then mice were sacrificed and pathological changes of pulmonary tissue were observed by HE staining. Furthermore, the area of alveolar cavity was measured with the Image-pro plus software.Results One month after irradiation, the pulmonary function parameters of mice in radiation and dexamethasone groups, such as mid-expiratory flow, minute volume,tidal volume,peak inspiratory flow,and peak expiratory flow,decreased obviously compared with the control group, but those parameters of the dexamethasone group decreased much less significantly than in the radiation group.The pathological changes of pulmonary tissues showed that the area of alveolar cavity of radiation group and dexamethasone group was smaller than that of the control group, but the extent of the loss of alveolar cavity area of the dexamethasone group was less than in the radiation group.Neutrophils infiltration could be found in the radiation group and dexamethasone group, but was less serious in the dexamethasone group.The result of pulmonary function analysis was coincident with pathological changes of the lung.Conclusion Dexamethasone can alleviate radiation induced pulmonary injury.Pulmonary function analysis combined with pathological observation of pulmonary tissues can effectively evaluate the efficacy of drugs in radiation induced lung injury.
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The studies on the chemical compositions and pharmacological actions of Chaenomeles speciosa Nakai were systemized and compared with those of the other plants of Chaenomeles in this paper. The pharmacological effects of the fruit of Chaenomeles inclu-ding anti-tumor, anti-oxidation, anti-inflammation and analgesia, antibacterial, hypoglycemic and hypolipidemic action and so on were reviewed to provide scientific basis for the further studies and utilization of Chaenomeles.
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This paper demonstrates the successful application of a novel approach to the computer aided design (CAD) of removable partial denture (RPD) framework. Firstly, we get the data of the partially edentulous cast, a mandibular Kennedy Class II, through a 3D-optical grating measuring system after corresponding pretreatment. Then, the reverse engineering software and 3D CAD software was used to design basis, big conjunction, clasp, small conjunction of the RPD framework. Finally 3D surface model of the RPD framework was created in preparation for direct manufacture using rapid prototyping (RP) methods and foundry. The result indicated that the RPD framework was fabricated successfully and the resulting frameworks provided a satisfactory fit.
Subject(s)
Humans , Computer-Aided Design , Dental Alloys , Dental Casting Technique , Dental Prosthesis Design , Methods , Denture Design , Methods , Denture, Partial, RemovableABSTRACT
Objective To investigate the effects of adenovirus containing human beta-nerve growth factor (Ad-hNGFβ) gene on substance P (SP) and calcitonin gene-related peptide (CGRP) content of the spinal cord in a rat model of neuropathic pain by chronic constrictive injury (CCI). Methods Forty-eight male SD rats weighing 200-250 g were randomly divided into 3 groups (n=16 each) : group Ⅰ sham operation; group Ⅱ CCI and group Ⅲ CCI + Ad-hNGFβ gene IT. The animals were anesthetized with intraperitoneal choral hydrate 300-350 mg/kg. The right sciatic nerve was exposed and 4 ligatures were placed on the sciatic nerve at 1-2 nun intervals as described by Bennet and Xie[5]. In sham operation group, right sciatic nerve was exposed but not ligated. In group Ⅰ and Ⅱ artificial cerebrnspinal fluid was injected IT instead of Ad-hNGFβ gene. The behavior score and the paw-withdrawal latency (PWL) to radiant heat and mechanical stimulus were measured one day before operation and every 4 days within the 28 days after gene transfection. Four animals were killed at 4, 7, 14 and 28 day after IT gene transfection in each group and lumbar segment (L4-6 ) of the spinal cord was removed for determination of SP and CGRP content by immunohistochemistry. Results The behavior scores were significantly higher and PWL to radiant heat and mechanical stimulus were significantly lower in group Ⅱ and Ⅲ than in group Ⅰ. There was no significant difference in the behavior score and PWL to mechanical stimulus between group Ⅱ and Ⅲ while the PWL to radiant heat was significantly higher in group Ⅲ than in group Ⅱ. After operation SP and CGRP content were significantly higher in group Ⅱ and group Ⅲ than in group Ⅰ , and significangly lower in group Ⅲ than in group Ⅱ 7-28 days after operation. Conclusion The recomhinant Ad-hNGFβ gene transfection can attenuate heat hyperalgesia by reducing SP and CGRP content of the spinal cord in a rat model of neuropathic pain induced by CCI.
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Objective To observe the effects of over-expression of matrix metalloproteinase-12 (MMP-12) on the transformation of pulmonary fibroblasts in radiation damaged rats. Methods Thirty-two male Wistar rats (weighed 250-280g) were randomly assigned into control group and 1, 2 and 4 weeks after irradiation groups (8 each). The whole lungs of rats in irradiation groups were irradiated by 60 Co ?-ray at a dose of 20Gy, and the lung specimens were harvested 1, 2 and 4 weeks after radiation. The change of MMP-12 activity was detected by gelatin zymography, the degradation and collapse of elastic fibers were observed by tissue specific staining, the "cross talking" phenomenon between alveolar type Ⅱ cells and mesenchymal cells was observed by transmission electron microscopy, the content of TGF-?1 was determined by ELISA, and the expression of ?-smooth muscle actin (?-SMA) was examined by immunohistochemistry. Results MMP-12 activity began increasing 1 week after irradiation, and seemed to decrease 4 weeks after irradiation. Elastin, a part of the basement membrane of alveolar wall, began to degrade and collapse 1 week after radiation, and became worse 4 weeks after irradiation. The expressions of both TGF-?1 and ?-SMA were elevated gradually within 4 weeks after radiation. The "cross talking" phenomenon was found by electron microscopy between alveolar type Ⅱ cells and mesenchymal cells. Conclusions Increased activity of pulmonary MMP-12 has been found after radiation, which may promote the transformation of pulmonary fibroblasts by degrading elastin and ultimately initiate the pulmonary fibrosis.