Exploring potential targets of HPV&BC based on network pharmacology and urine proteomics.

BACKGROUND: Bladder cancer (BC) caused by Human papillomavirus (HPV) infection remains a complex public health problem in developing countries. Although the HPV vaccine effectively prevents HPV infection, it does not benefit patients with BC who already have HPV. METHODS: Firstly, the differential genes of HPV-related BC patients were screened by transcriptomics, and then the prognostic and clinical characteristics of the differential genes were analyzed to screen out the valuable protein signatures. Furthermore, the compound components and targets of Astragali Radix (AR) were analyzed by network pharmacology, and the intersection targets of drug components and HPV_BC were screened out for pathway analysis. In addition, the binding ability of the compound to the Astragali-HPV_BC target was verified by molecular docking and virtual simulation. Finally, to identify potential targets in BC patients through urine proteomics and in vitro experiments. RESULTS: Eleven HPV_BC-related protein signatures were screened out, among which high expression of EGFR, CTNNB1, MYC, GSTM1, MMP9, CXCR4, NOTCH1, JUN, CXCL12, and KRT14 had a poor prognosis, while low expression of CASP3 had a poor prognosis. In the analysis of clinical characteristics, it was found that high-risk scores, EGFR, MMP9, CXCR4, JUN, and CXCL12 tended to have higher T stage, pathological stage, and grade. Pharmacological and molecular docking analysis identified a natural component of AR (Quercetin) and it corresponding core targets (EGFR). The OB of the natural component was 46.43, and the DL was 0.28, respectively. In addition, EGFR-Quercetin has high affinity. Urine proteomics and RT-PCR showed that EGFR was expressed explicitly in BC patients. Mechanism analysis revealed that AR component targets might affect HPV_BC patients through Proteoglycans in the cancer pathway. CONCLUSION: AR can target EGFR through its active component (Quercetin), and has a therapeutic effect on HPV_BC patients.

Tibetan medicine salidroside improves host anti-mycobacterial response by boosting inflammatory cytokine production in zebrafish.

The treatment for tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), has a prolonged cycle which can last up to a year. This is partially due to the lack of effective therapies. The development of novel anti-TB drugs from the perspective of host immune regulation can provide an important supplement for conventional treatment strategies. Salidroside (SAL), a bioactive component from the Tibetan medicine Rhodiola rosea, has been used in the treatment of TB, although its mechanism remains unclear. Here, the bacteriostatic effect of SAL in vivo was first demonstrated using a zebrafish-M. marinum infection model. To further investigate the underlying mechanism, we then examined the impact of SAL on immune cell recruitment during wound and infection. Increased macrophage and neutrophil infiltrations were found both in the vicinity of the wound and infection sites after SAL treatment compared with control, which might be due to the elevated chemokine expression levels after SAL treatment. SAL treatment alone was also demonstrated to improve the survival of infected zebrafish larvae, an effect that was amplified when combining SAL treatment with isoniazid or rifampicin. Interestingly, the reduced bacterial burden and improved survival rate under SAL treatment were compromised in tnfα-deficient embryos which suggests a requirement of Tnfα signaling on the anti-mycobacterial effects of SAL. In summary, this study provides not only the cellular and molecular mechanisms for the host anti-mycobacterial effects of the Tibetan medicine SAL but also proof of concept that combined application of SAL with traditional first-line anti-TB drugs could be a novel strategy to improve treatment efficacy.

The change of the state of cell membrane can enhance the synthesis of menaquinone in Escherichia coli.

Menaquinone (MK) was an attractive membrane-bound intracellular chemical. To enhance its production, we tried to find the relationship between its synthesis and the state of cell membrane in producing strain. Due to non-ionic surfactant-polyoxyethylene oleyl ether (POE) and plant oil-cedar wood oil (CWO) can typically increase extracellular secretion and intracellular synthesis of MK respectively, the effect of these two substances on cell morphology, physical properties of cell membrane was investigated. Finally, two engineering strains were constructed to verify whether the state of cell membrane can enhance MK synthesis. The result showed that the edge of cells was broken when POE added in the medium. Other physical properties such as total fatty acid content decreased by 40.7% and the ratio of saturated fatty acids to unsaturated fatty acids decreased from 1.58 ± 0.05 to 1.31 ± 0.04. Meanwhile, cell membrane leakage was enhanced from 7.14 to 64.31%. Different from POE group, cell membrane was intact in CWO group. Moreover, the ratio of saturated fatty acids to unsaturated fatty acids increased from 1.58 ± 0.05 to 1.78 ± 0.04 and the average lipid length decreased from 16.05 ± 0.08 to 15.99 ± 0.10. Two constructed strains, especially Escherichia coli DH5α FatB, exhibited strong MK secretion ability and the extracellular MK reached 10.71 ± 0.19 mg/L. An understanding of these functionary mechanisms could not only provide a new idea for the synthesis of MK, but also provide a reference to increase the yield of intracellular membrane-bound metabolites.

Assessment of echinocandin regimens by pharmacokinetic/pharmacodynamic analysis against Candida spp. in paediatric patients.

This study aimed to investigate the cumulative fraction of response of various echinocandin (caspofungin, micafungin and anidulafungin) dosing regimens against Candida spp. in paediatric patients with invasive fungal infections (IFIs). Monte Carlo simulations were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the ability of each echinocandin regimen in terms of fAUC/MIC (free drug area under the concentration-time curve/minimum inhibition concentration ratio) targets of caspofungin, micafungin and anidulafungin. Pharmacodynamic targets were attained in paediatric patients by both caspofungin regimens as well as by a high micafungin dosing regimens against Candida albicans and Candida glabrata. However, the results for anidulafungin suggested that the dosing regimens recommended were not optimal for paediatric patients. In addition, the predicted efficacy of all of the echinocandins against Candida parapsilosis was low. This is the first study to assess caspofungin, micafungin and anidulafungin therapy using Monte Carlo simulation. These results rationalise and optimise the dosage regimens of caspofungin, micafungin and anidulafungin against C. albicans, C. glabrata and C. parapsilosis for paediatric patients with IFIs.

A prospective randomized comparison of PEEK cage containing calcium sulphate or demineralized bone matrix with autograft in anterior cervical interbody fusion.

PURPOSE: A variety of bone substitutes have been successfully used to fill PEEK cages in cervical interbody fusion in order to avoid the complications related to bone harvesting from the donor site. However, no controlled study has previously been conducted to compare the effectiveness of PEEK interbody cages containing calcium sulphate/ demineralized bone matrix (CS/DBM) with autogenous cancellous bone for the treatment of cervical spondylosis. The objective of this prospective, randomized clinical study was to evaluate the effectiveness of implanting PEEK cages containing CS/DBM for the treatment of cervical radiculopathy and/or myelopathy. METHODS: Sixty-eight patients with cervical radiculopathy and/or myelopathy were randomly assigned to receive one- or two-level discectomy and fusion with PEEK interbody cages containing CS/DBM or autogenous iliac cancellous bone (AIB). The patients were followed up for two years postoperatively. The radiological and clinical outcomes were assessed during a two-year follow-up. RESULTS: The mean blood loss was 75 ± 18.5 ml in the CS/DBM group and 100 ± 19.6 ml (P < 0.01) in the AIB group. The fusion rate was 94.3 % in the CS/DBM group and 100 % in the AIB group at 12-month follow-up. The fusion rate was 100 % at final follow-up in both groups. No significant difference (P > 0.05) was found regarding improvement of JOA score and segmental lordosis as well as neck and arm pain at all time intervals between the two groups. The total complication rate was significantly higher (P < 0.05) in the AIB group than in the CS/DBM group, but there was no significant difference between the two groups (P > 0.05) when comparing the complications in the neck. CONCLUSIONS: In conclusion, the PEEK interbody fusion cage containing CS/DBM or AIB following one- or two-level discectomy had a similar outcome for cervical spondylotic radiculopathy and/or myelopathy. The rate of fusion and the recovery rate of JOA score between the two groups were the same. The filling of CS/DBM in the PEEK cage instead of AIB has the advantage of less operative blood loss and fewer complications at the donor site.