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Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumors and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain (ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro andin vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicines, particularly those who are resistant to or relapsing from IDH1mi.
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Humans , Oxidative Phosphorylation , Berberine , Electron Transport , Mitochondria , Leukemia, Myeloid, Acute , Isocitrate DehydrogenaseABSTRACT
Objective@#To observe the effects of fecal microbiota transplantation (FMT) on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats and to investigate the possible mechanism in order to provide new thoughts for the treatment of acute lung injury.@*Methods@#Forty-five adult healthy male SPF level SD rats were randomly divided into three groups of normal saline (NS), LPS and FMT with 15 in each group. ALI was induced by intraperitoneal injection of rats with 5 mg/kg of LPS. The FMT group was given 10 ml/kg of fecal microbiota solution intervention (twice a day for two consecutive days) after ALI induction. Five rats in each group were randomly selected and sacrificed at 24 h, 48 h and 72 h after intervention. Pathological changes in lung tissues were examined with hematoxylin and eosin (HE) staining and pathological scores were assessed. Right lung samples were weighed to measure wet/dry (W/D) ratios. Abdominal aorta blood samples were collected for PaO2 analysis. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) in bronchoalveolar lavage fluid (BALF) were detected by enzyme linked immunosorbent assay (ELISA). Expression of transforming growth factor-β (TGF-β) and intracellular signal transduction protein Smads (Smad3 and Smad7) at mRNA level was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Expression of ERK1/2 and p-ERK1/2 at protein level was detected by Western blot (WB). Rat fecal samples were collected to extract DNA and the PCR products of V3 and V4 regions were sequenced by Illumina MiSeq. Bioinformatics analysis on microbiota was conducted with Illumina MiSeq based on operational taxonomic unit (OTU) clustering.@*Results@#Compared with the NS group, the LPS group showed significantly widened alveolar septa, massive inflammatory cell infiltration and some alveolar collapse in lung tissues. Compared with the LPS group, the FMT group showed significantly alleviated inflammatory cell infiltration, reduced swelling in pulmonary interstitial tissues, and less damage to pulmonary structure. Compared with the NS group, the W/D lung ratio, PaO2 concentration and TNF-α, IL-1 and IL-6 levels in BALF in the LPS group significantly increased at 24 h after intervention and then gradually decreased, but still higher than those in the NS group (P<0.05). The W/D lung ratio, PaO2 concentration and TNF-α, IL-1 and IL-6 levels in BALF of the FMT group were significantly lower than those of the LPS group (P<0.05). Compared with the NS group, the expression of TGF-β1 and Smad3 at mRNA level in lung tissues increased at all time points in the LPS group, while the expression of Smad7 at mRNA level decreased (P<0.05). The expression of TGF-β1 and Smad3 at mRNA level in the FMT group were significantly lower than that in the LPS group (P<0.05), while the expression of Smad7 at mRNA level was higher (P<0.05). Compared with the NS group, p-ERK expression significantly increased in the LPS group with the highest expression at 24 h and gradually decreased at 48 h and 72 h (P<0.05). The expression of p-ERK in the FMT group was significantly lower than that in the LPS group (P<0.05). Results of the intestinal microbiota sequencing revealed 1 362 OTU in the NS group, 1 443 OTU in the LPS group and 1 510 OTU in the FMT group. There were 336 OTU shared by them accounting for 26.4%. The constitution of intestinal microbiota in the LPS group was significantly different with that of normal rats and characterized by high diversity with increased Firmicutes/Bacteroidetes ratio and decreased gene abundance of intestinal microbiota. After the intervention of fecal bacteria transplantation, the constitution of intestinal microbiota in the FMT group was similar to that of the NS group, showing decreased Firmicutes/Bacteroidetes ratio and increased gene abundance of the bacterial community (P<0.05).@*Conclusions@#FMT might inhibit immune inflammation, reduce the production and secretion of inflammatory markers in the body, alleviate alveolar epithelial damage and abnormal repair through regulating intestinal microbiota and TGF-β1/Smads/ERK pathway to improve the LPS-induced endotoxic ALI in rats.
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Objective To evaluate the method, clinical efficacy and safety of one phase treat-ment of renal calculi associated with pyonephrosis by percutaneous nephrolithotripsy(PCNL) by pneu-matic combined with ultrasonic lithotriptor. Methods Sixty-six cases of renal calculi accompanied with pyonephrosis were treated with PCNL. The renal calyx was punctured under ultrasound gui-dance, then the tract was dilated from F8 to F16 by peel-away vascular access sheathes. After the in-sertion of the flexible sheath, metallic dilator was inserted and the flexible sheath was pulled out. The tract was dilated by metallic sheath to F21 and the operation sheath and nephroseope were placed into working tract. EMS III LithoClast Master was used. Ultrasonic powered lithotriptor probe with suc-tion was used to clear the liquor puris and calculus fragments with low-pressure or no-pressure. The combined pneumatic and ultrasonic powered lithotriptor was used to break and clear the calculi. Re-salts Of the 66 cases, there was no bacteremia or pyaemia intraoperatively and postoperatively. And there was no other severe complication occurred intraoperatively. One phase PCNL was successfully completed in 60 cases. Other 4 cases had residual calculi less than 1.5 em in diameter and received ESWL to break the calculi, 2 cases had bigger residual calculi and accepted second PCNL 1 week after the first intervention. In the follow-up period, the 3 month post-operative serum Cr was 56-203 μmol/L with an average decrease of 40 μmol/L, GFR was 5.0-56.2 ml/min with an average increase of 23.6 ml/min compared with the pre-operative data. At 6 months postoperative serum Cr was 56-158 μmol/L with average decrease of 31 μmol/L, GFR was 5.0-79.2 ml/min with an average in-crease of 30.2 ml/min. Conclusion Application of PCNL in the treatment of patients with renal cal-culi accompanied with pyonephrosis is safe, cost-effective and clinically efficient by pneumatic com-bined with ultrasonic lithotriptor.
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Objective To study the effect of dexamethasone on pulmonary fibrosis model induced by bleomycin in rats and the expression of STAT1 and PDGF in lung tissue,and to discuss the possible mechanism.Methods Forty-five Wistar rats were randomly divided into three groups(15 in each group).They were dexamethasone group(DXM group),bleomycin group(BLM group) and control group(NS group):① The DEX group were intratracheally instilled with belomycin(BLM)(5mg/kg,in 1ml 0.9% NaCl solution),and then were treated with dexamethasone 3mg/kg via celiac injection daily;② BLM group were intratracheally instilled with BLM(5mg/kg),and then were treated with saline 3mg/kg via celiac injection daily;③ NS group were intratracheally instilled with saline(5mg/kg),and then were treated with saline 3mg/kg via celiac injection daily.Five rats in each group were sacrificed at 7,14,and 28 days after intratrachel instillation.Histological changes of the lungs were evaluated by HE stain.The bronchoalveolar lavage fluid(BALF) of right lung was gotten and the cells counting as well as differentiation were figured out.The expression of STAT1 and PDGF protein was assessed by immunohistochemistry.Results(1) The total number of inflammatory cells in BALF in BLM group was the highest at day 7 and diminished at day 14 and 28,which was significant different compared with that of the NS group(P
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Diagnostics probation teaching has important value in the medical teaching for foreign students. The practice experiences of diagnostics probation teaching for foreign students in the last 3 years are reviewed from the management of teaching,practice of teaching,supervision of teaching and examine of teaching in order to improve the effect of diagnostics probation teaching for foreign students.