OBJECTIVE To observe the effects of endogenous metabolite mesaconate combined with Sodium lactate Ringer’s injection （LR） on prolonging the golden treatment time window and its resuscitation efficacy in rats with hemorrhagic shock under high-altitude conditions. METHODS Rats were divided into the shock group， LR group， and 5， 20， 50 mg/kg mesaconate+LR groups， with 20 rats in each group， to investigate the effect of additional use of mesaconate on the golden treatment time window. After establishing a model of uncontrolled hemorrhagic shock under high-altitude conditions in all groups by housing in a hypobaric hypoxia chamber combined with splenic artery transection， rats in the shock group received no resuscitation， while rats in the LR group and mesaconate+LR groups underwent low-pressure resuscitation with LR or mesaconate combined with LR. Blood pressure control， fluid infusion volume， blood loss rate and survival status were observed in each group. Rats were further divided into the normal group， shock group and mesaconate （50 mg/kg）+LR group， with 10 or 20 rats in each group， to evaluate the resuscitation effects after extending the golden treatment time window by additionally using mesaconate. Except for the normal group， the other groups underwent the same procedure to establish an uncontrolled hemorrhagic shock model under high-altitude conditions. Rats in the shock group received no resuscitation. In the mesaconate+LR group， after 3 h of low-pressure resuscitation， bleeding control was performed by ligation of the spleen artery， and the infusion volume and blood loss rate were recorded； subsequently， the rats received LR resuscitation with twice the volume of blood loss. Then， blood gas indicators of the mesaconate+LR group were measured at different time points. Survival rates， indicators related to sublingual microcirculatory perfusion， liver and kidney blood flow， indicators related to the function of vital organs， and lung and brain water content were observed in all groups. RESULTS LR infusion alone could effectively maintain mean arterial pressure （MAP） within 50-60 mmHg for approximately 1 h. The administration of mesaconate combined with LR during hypotensive resuscitation could maintain MAP within 50-60 mmHg for over 3 h， with significantly reduced fluid infusion volume and blood loss rate in 50 mg/kg mesaconate+LR group， compared to the LR group （ P ＜0.05）. In the LR group， rats maintained low pressure for up to 1 hour with a survival rate of 52.94%， and no rats survived beyond 2 h. In the 5， 20 and 50 mg/kg mesaconate+LR groups， rats maintained low pressure for up to 1 h with a survival rate exceeding 80%； in the 20 and 50 mg/kg mesaconate+LR groups， rats maintained low pressure for up to 3 h with a survival rate exceeding 70%. After complete resuscitation with mesaconate combined with LR， the 72 h survival rate of rats was 43.75%， and significant improvements in blood gas parameters were observed compared to the end of the shock phase （ P ＜0.05）. Compared to the shock group， the mesaconate+LR group showed significant recovery in sublingual microcirculatory indicators， and liver/kidney blood flow after complete resuscitation （ P ＜0.05）， with significant reductions in heart， liver and kidney function-related indicators and lung water content （ P ＜0.05）. CONCLUSIONS Mesaconate combined with LR significantly extends the golden treatment time window for hemorrhagic shock in rats under high-altitude conditions， improves blood gas parameters， sublingual microcirculatory perfusion， and liver/kidney blood flow， mitigates vital organ impairment and pulmonary edema， and increases the survival rate of shocked rats.

Objective To investigate the protective effect of mitochondrial fission inhibitor 1(Mdivi-1),on organ function in rats with explosive blast injury combined with hemorrhagic shock.Methods A total of 192 SD rats(half male and half female,12 weeks old,weighing about 220 g)were randomly divided into 6 groups:Sham group(only surgical incision along the midline of the abdomen),model group(ESH group,thermal radiation and shock wave injury followed by femoral artery hemorrhage),lactated Ringer's solution resuscitation group(ESH+LR group,LR solution infusion in the femoral vein for resuscitation),and low-,middle-and high-dose Mdivi-1 groups(0.1,0.5 and 1.0 mg/kg Mdivi-1 intervention after infusion of LR solution).Fluorescent protein tracing was used to determine the leakage amount of fluorescent protein in the lung and kidney tissues to evaluate the vascular permeability.Evans blue dye staining was employed to observe the intestinal permeability and pulmonary vascular permeability.Laser Doppler flowmetry was applied to monitor the tissue blood perfusion in the liver,kidneys,and intestine.Serum levels of cardiac injury marker troponin I(TNI),liver function markers aspartate aminotransferase(AST)and alanine aminotransferase(ALT),and renal function markers serum creatinine(Scr)and blood urea nitrogen(BUN)were detected to evaluate the functions of corresponding organs.The water contents of the lungs and brain were calculated by measuring wet weight and dry weight of the lung and brain tissues.Blood pressure,heart rate,and respiratory rate were monitored.The survival time and 72-hour survival rate were recorded and calculated.Results Compared with the Sham group,the ESH group exhibited significantly increased vascular permeability in the lungs and kidneys as well as intestinal tissue(P<0.05),along with obviously elevated water contents in the lungs and brain(P<0.05),and decreased blood perfusion in the liver,kidneys,and intestine by 57.1%,39.2%,and 43.2%of the Sham group,respectively(P<0.05),elevated levels of TNI,AST,ALT,Scr and BUN(P<0.05),mean survival time of 3.8±1.1 h,and a 72-hour survival rate of 0(P<0.05).Although LR solution resuscitation reduced vascular permeability and alleviated organ injury in rats with explosive injury combined with hemorrhagic shock,there were no significant differences compared to the ESH group(P>0.05).Mdivi-1 treatment notably decreased vascular permeability in the lungs and kidneys and intestine,and water contents in the lungs and brain when compared with the LR group(P<0.05),with the dose of 0.5 mg/kg demonstrating the most significant effect.Additionally,Mdivi-1 treatment also significantly enhanced organ perfusion,improved organ functions,prolonged survival time,and increased survival rate.The 0.5 mg/kg treatment resulted in a 72-hour average survival time 55.64 h and a survival rate of 62.5%.Conclusion Mitochondrial fission inhibitor Mdivi-1 can reduce the permeabilities in the lungs,kidneys and intestine,improve tissue blood perfusion,protect the organ functions of the heart,liver and kidneys,and finally prolong survival time and increase survival rate in rats with concomitant explosive blast injury and hemorrhagic shock.

Objective To explore the protective effect of L-carnitine on myocardial systolic dysfunction in sepsis and its underlying mechanism.Methods A mouse sepsis model was established by cecal ligation and puncture(CLP).Ten-week-old male SPF-grade C57BL/6 mice(body weight 20～30 g)were randomly divided into 5 groups via random number table:Sham group,Sepsis group,L-carnitine group,L-carnitine+Etomoxir(Eto)group,and Eto group.Echocardiography assessed cardiac function,ELISA measured serum creatine kinase isoenzyme MB(CK-MB)levels,and 72-hour survival rates were recorded to evaluate L-carnitine's effects on cardiac function.Cardiomyocytes were isolated,and a cell microtensiometer was used to detect cardiomyocyte contractile function and calcium transients.Myocardial tissues were collected from each group,and ELISA was used to determine the contents of triglyceride(TG),free fatty acid(FFA),and adenosine triphosphate(ATP).An in vitro sepsis model was constructed by stimulating HL-1 cardiomyocytes with lipopolysaccharide(LPS)for 12 hours,which was divided into 5 groups:control(CTRL)group,LPS group,L-carnitine group,L-carnitine+Eto group,and Eto group.ELISA was used to detect the contents of TG,FFA,and ATP as well as the activity of carnitine palmitoyltransferase 1A(CPT1A)in cardiomyocytes.A cellular energy metabolism analysis system was employed to measure fatty acid oxidation capacity,and Western blot was used to detect the protein expression of CPT1A in cardiomyocytes.BODIPY-FL-C16(green fluorescently labeled palmitic acid)was utilized to detect the distribution of fatty acids in the cytoplasm and mitochondria via immunofluorescence technology,thereby observing the ability of cells to transport fatty acids into mitochondria.Results Compared with the Sham group,cardiac function was significantly impaired in the Sepsis group,as evidenced by decreased ejection fraction and mean arterial pressure(P<0.05),along with elevated levels of the cardiac injury marker CK-MB(P<0.05).Treatment with L-carnitine significantly improved myocardial function,restored blood pressure in septic mice,and increased their survival rate from 12.50%to 81.25%(P<0.05).Compared with the Sham group,the contractile function and calcium transients of acutely isolated single cardiomyocytes were significantly reduced in the Sepsis group(P<0.05),while L-carnitine treatment remarkably restored the contractile function and calcium release capacity of septic cardiomyocytes(P<0.05).Both in vivo and in vitro experiments showed that TG and FFA levels were significantly increased(P<0.05),and ATP levels was significantly decreased(P<0.05)in the Sepsis and LPS groups—effects significantly reversed by L-carnitine treatment.Compared with the CTRL group,the basal oxidation rate and maximum oxidation capacity of fatty acids in cardiomyocytes of the LPS group were significantly reduced(P<0.05),and L-carnitine treatment notably improved these indicators.Compared with the CTRL group,the expression and activity of CPT1A in cardiomyocytes of the LPS group were significantly decreased(P<0.05),while L-carnitine treatment significantly increased the expression and activity of CPT1A(P<0.05).In LPS group cardiomyocytes,green fluorescently labeled palmitic acid primarily formed numerous granular/clumpy aggregates in the cytoplasm with minimal mitochondrial colocalization.In the L-carnitine group,the green fluorescent granules in the cytoplasm of cardiomyocytes were smaller,and colocalization with mitochondria was increased.However,the L-carnitine+Eto group exhibited similar phenomena to the LPS group.In addition,both in vivo and in vitro experiments demonstrated that treatment with the CPT1A inhibitor Eto reversed the effect of L-carnitine.Compared with the L-carnitine group,the ATP content in the L-carnitine+Eto group was significantly decreased(P<0.05),while the FFA content was significantly increased(P<0.05).Conclusion L-carnitine facilitates fatty acid entry into mitochondria for β-oxidation via a CPT1A-dependent mechanism,thereby ameliorating fatty acid oxidation dysfunction in septic cardiomyocytes and improving myocardial contractile function.

BACKGROUND:Berberine has the potential to induce osteogenic differentiation of various mesenchymal stem cells under normal conditions and special conditions such as high glucose,infection and inflammation.It is a natural small molecule drug that can induce bone formation in seed cells instead of growth factors,and has great application prospect in bone tissue engineering. OBJECTIVE:To review and summarize the research progress in the osteogenic mechanism and efficacy of berberine,especially its osteogenic potential under high glucose,infection and inflammation conditions,and its biological safety,so as to provide theoretical basis for its development and application in bone tissue engineering. METHODS:PubMed,WanFang,and CNKI were searched for relevant literature using the keywords of"berberine,bone defects,bone repair,bone regeneration,osteoinductive,osteoporosis,osteoblast,osteoclast,bone tissue engineering,bone,high glucose,diabetes,inflam*,infect*"in English and Chinese,respectively.A total of 105 literatures were selected for review. RESULTS AND CONCLUSION:Berberine can be used to treat multiple diseases including bone diseases,and it has the ability to promote bone regeneration.This article systematically reviews the mechanism of berberine on bone regeneration and in vivo and in vitro studies.Studies have shown that it can play a role in bone repair by promoting osteogenesis,inhibiting osteoclast formation and activity,and preventing osteoporosis.It shows excellent osteogenic differentiation potential mainly via Wnt/β-catenin,PI3K/AKT,EGFR/MEK/p38MAPK,cAMP/PKA/CREB,ERK and other signaling pathways.Berberine can also relieve the inhibition of osteogenic differentiation caused by high glucose,infection and inflammation,which provides more possibilities for the treatment of bone defects in patients with diabetes or infection and inflammation in the bone defect site.Berberine also has the advantages of low toxicity,low price,easy access(currently it can be synthesized),which is a relatively ideal bone induction potential drug.In recent years,the application of berberine in the treatment of bone defect tends to be localized,mainly through the combination with bone tissue engineering technology to improve bioavailability,and has shown good bone repair effect and excellent biological safety in animal experiments.In addition,preclinical experiments have shown splendid bone regeneration potential in the conditions of diabetes,local infection and inflammation.In the future,more studies are needed to fully reveal the osteogenic mechanism and biological safety of berberine,and seek the most suitable controlled release loading system to make artificial bone replacement materials with good mechanical strength,efficacy and biological safety.

At present, countries around the world are paying greater attention to the protection of medicinal plants and traditional medicinal knowledge resources, and are looking for various ways to protect medicinal plants. Many countries have established their own databases to save the medicinal plant information resources. This paper focuses on the introduction of medicinal plant databases in six countries including Malaysia, Philippines, and Singapore, and compares their basic information. It is difficult to achieve integration and sharing among these databases. It brings certain difficulties to the use of researchers in related fields. It is suggested that the construction of a multinational common medicinal plant database should be included in the "Belt and Road Initiative" to systematically organize massive information, enhance exchanges between countries on traditional medicinal plants, and achieve medicinal plant information sharing, and the establishment of a shared database will reduce optimization and maintenance to a certain extent or renewal work, laying the foundation for the protection, development and sustainable use of traditional medicinal plant resources.

Objective:To determine the role of type Ⅱ alveolar epithelial stem cells (AEC Ⅱ) in radiation-induced pulmonary injury and investigate the potential mechanism by observing the dynamic changes in the expression levels of anti-prosurfactant protein C (proSP-C) proSP-C (AEC Ⅱ biomarker), homeobox only protein X (HOPX, type I alveolar epithelial cell biomarker) or vimentin (a mesenchymal marker) and transforming growth factor β 1(TGF-β 1), a profibrotic cytokine. Methods:Eight-week old C57BL/6j female mice were exposed to X-ray thoracic irradiation. Mouse lungs were collected at 8 different time points of 24 h, 1 week, 1 to 6 months after irradiation. The histopathological changes of the lungs at different time points were observed with H& E staining to determine the time of formation of pulmonary fibrosis. In addition, the co-expression of proSP-C with HOPX or vimentin in AEC Ⅱ was confirmed by immunofluorescence staining to track AEC Ⅱ phenotypes at different injury phases following thoracic irradiation. The expression levels of those proteins and TGF-β 1 were quantitatively detected by Western blot. Results:After thoracic exposure to a single dose of 20 Gy X-ray for 3 months, the fibrotic lesions in the lungs could be noted. The co-expression of proSP-C with vimentin or HOPX could be observed in AEC Ⅱ. Western blot demonstrated that the expression levels of TGF-β 1 and those proteins were also changed along with the lung injury. Conclusion:AEC Ⅱ can be differentiated into mesenchymal-like cells after X-ray irradiation due to the up-regulated expression of TGF-β 1, which is a potential cause of radiation-induced pulmonary fibrosis.

OBJECTIVE： To analyze effectiveness and economy of domestic vancomycin hydrochloride for injection （trade name： Laikexin） vs. imported vancomycin hydrochloride for injection （trade name： Vancocin） in treatment of intracranial infection induced by MRSA， and to provide decision-making reference for the selection of clinical drugs. METHODS： Clinical data of patients with suspected MRSA intracranial infections receiving Laikexin or Vancocin were collected by retrospective study method from neurosurgery department of our hospital during Jan. 2016 to Jun. 2017， including 115 cases of Laikexin and 42 cases of Vancocin. Using response rate （including clinical cure and clinical improvement） as indexes， cost-effectiveness analysis was performed for Laikexin and Vancocin in the treatment of intracranial infection induced by MRSA by using decision tree model. Sensitivity analysis was conducted for 10％ decrease of cost and response rate. RESULTS： Response rate and excepted cost of Laikexin were 85.21％ and 13 125.96 yuan， cost-effectiveness ratio （CER） was 15 404.25. Response rate and excepted cost of Vancocin were 78.57％ and 15 619.17 yuan， CER was 19 879.31. There was no statistical significance in response rate between Laikexin and Vancocin （P＜0.05）. There was no difference between sensitivity analysis and cost-effectiveness analysis. CONCLUSIONS： The efficacy of Laikexin and Vancocin in the treatment of MRSA intracranial infection is similar， but the CER of Laikexin is lower than that of Wenkexin.

Background and purpose:Chemotherapy is an alternative treatment option, which could still get a therapeutic effect, when the EGFR-TKI treatment of non-small cell lung cancer failed. Studies have shown that RR, TYMS, ERCC1 and TUBB3 have respectively relationship with chemosensitivity of gemcitabine, pemetrexed, platinum-based drugs and microtubule-based chemotherapy drugs.The expression levels of these molecular markers can predict the sensitivity of these chemotherapy drugs. The patients with RRMI, TS, ERCC1 and TUBB3 higher expression have reduced chemosensitivity, and lower expression have increased sensitivity. The purpose of this study was to explore the sensitivity of tumor cell lines with acquired resistance to geiftinib caused byEGFR-T790M mutation to cisplatin, gemcitabine, pemetrexed, vinorelbine, paclitaxel and docetaxel.Methods:MTT assay was used to detect the IC50 values of cisplatin, gemcitabine, vinorelbine, paclitaxel and docetaxel, pemetrexed to PC9 and PC9/GR cells, and to explore the chemosensitivity of lung adenocarcinoma cells to these chemotherapy drugs; Luminex method was used respectively to detect the expression levels of ERCC1 mRNA, TUBB3 mRNA, TS mRNA, and RRM1 mRNA in PC9 and PC9/GR cells. Western blot was used to detect the protein expression levels of ERCC1, TUBB3, TS and RRM1 in PC9 and PC9/GR cells.Results: The IC50 values of cisplatin, gemcitabine and pemetrexed to PC9/GR cells were signiifcantly higher than those to PC9 cells (P<0.05), while the IC50 values of vinorelbine, paclitaxe and docetaxel to PC9/GR cells were signiifcantly decreased (P<0.05). Luminex method showed the expressions of ERCC1 mRNA, TS mRNA and RRM1 mRNA in PC9/GR cells were signiifcantly increased than those in PC9 cells (P<0.05), while the expression of TUBB3 mRNA was signiifcantly decreased (P<0.05). Western blot method showed the expressions of TUBB3, TS and RRM1 protein in PC9/GR cells were signiifcantly increased than those in PC9 cells (P<0.05), while TUBB3 protein expression in PC9/GR cells was signiifcantly decreased (P<0.05). Western blot method analysis result showed that the expressions of TUBB3, TS and RRM1 protein in PC9/GR cells were significantly increased than those in PC9 cells (P<0.05), while TUBB3 protein expression in PC9/GR cells was signiifcantly decreased (P<0.05). Conclusion:The chemosensitivity of lung adenocarcinoma with EGFR-T790M mutation is changed. It has decreased sensitivity to cisplatin, gemcitabine, pemetrexed and increased sensitivity to vinorelbine, paclitaxel and docetaxel. The reason of the change of chemosensitivity of geiftinib-resistant lung adenocarcinoma cell maybe related to the changes of ERCC1 mRNA, RRM1 mRNA and TS mRNA and their protein expressions.

Gene mutation (e.g. substitution, insertion and deletion) and related phenotype information are important biomedical knowledge. Many biomedical databases (e.g. OMIM) incorporate such data. However, few studies have examined the quality of this data. In the current study, we examined the quality of protein single-point mutations in the OMIM and identified whether the corresponding reference sequences align with the mutation positions. Our results show that close to 20% of mutation data cannot be mapped to a single reference sequence. The failed mappings are caused by position conflict, site shifting (peptide, N-terminal methionine) and other types of data error. We propose a preliminary model to resolve such inconsistency in the OMIM database.
Amino Acid Sequence ; Consensus Sequence ; Databases, Genetic ; Molecular Sequence Data ; Point Mutation ; Sequence Alignment