Effect and mechanism of Qingre Huashi decoction on drug-resistant Helicobacter pylori

BACKGROUND Helicobacter pylori(HP),the most common pathogenic microorganism in stomach,can induce inflammatory reactions in the gastric mucosa,causing chronic gastritis and even gastric cancer.HP infection affects over 4.4 billion people globally,with a worldwide infection rate of up to 50%.The multidrug resistance of HP poses a serious challenge to eradication.It has been monstrated that compared to bismuth quadruple therapy,Qingre Huashi decoction(QHD)combined with triple therapy exhibits comparable eradication rates but with a lower incidence of adverse reactions;in addition,QHD directly inhibit and kill HP in vitro.METHODS In this study,12 HP strains were isolated in vitro after biopsy during gastroscopy of HP-infected patients.In vitro,the minimum inhibitory concentration(MIC)values for clinical HP strains and biofilm quantification were determined through the E-test method and crystal violet staining,respectively.The most robust biofilm-forming strain of HP was selected,and QHD was evaluated for its inhibitory and bactericidal effects on the strain with strong biofilm formation.This assessment was performed using agar dilution,E-test,killing dynamics,and transmission electron microscopy(TEM).The study also explored the impact of QHD on antibiotic resistance in these HP strains with strong biofilm formation.Crystalline violet method,scanning electron microscopy,laser confocal scanning microscopy,and(p)ppGpp chromatographic identification were employed to evaluate the effect of QHD on biofilm in strong biofilm-forming HP strains.The effect of QHD on biofilm and efflux pump-related gene expression was evaluated by quantitative polymerase chain reaction.Non-targeted metabolomics with UHPLC-MS/MS was used to identify potential metabolic pathways and biomarkers which were different between the NC and QHD groups.RESULTS HP could form biofilms of different degrees in vitro,and the intensity of formation was associated with the drug resistance of the strain.QHD had strong bacteriostatic and bactericidal effects on HP,with MICs of 32-64 mg/mL.QHD could inhibit the biofilm formation of the strong biofilm-forming HP strains,disrupt the biofilm structure,lower the accumulation of(p)ppGpp,decrease the expression of biofilm-related genes including LuxS,Spot,glup(HP1174),NapA,and CagE,and reduce the expression of efflux pump-related genes such as HP0605,HP0971,HP1327,and HP1489.Based on metabolomic analysis,QHD induced oxidative stress in HP,enhanced metabolism,and potentially inhibited relevant signaling pathways by upregulating adenosine monophosphate(AMP),thereby affecting HP growth,metabolism,and protein synthesis.CONCLUSION QHD exerts bacteriostatic and bactericidal effects on HP,and reduces HP drug resistance by inhibiting HP biofilm formation,destroying its biofilm structure,inhibiting the expression of biofilm-related genes and efflux pump-related genes,enhancing HP metabolism,and activating AMP in HP.

Efficacy of Pudilan Xiaoyan Oral Liquid in the treatment of pneumonia induced by drug-resistant Pseudomonas aeruginosa

Background:Pudilan Xiaoyan Oral Liquid(PDL)is a Chinese patent medicine with notable pharmacological properties,including anti-inflammatory and antibacterial effects.Drug-resistant Pseudomonas aeruginosa infection is a common and refractory bacterial infection in clinical practice.Due to its high drug resistance,it brings great challenges to treatment.This study aimed to assess the therapeutic efficacy of PDL in a murine model of pneumonia induced by drug-resistant Pseudomonas aeruginosa.Methods:Three different doses of PDL(11 mL/kg/d,5.5 mL/kg/d,2.75 mL/kg/d)were used to observe lung tissue pathology and inflammatory cytokine levels in pneumonia mouse models induced by multidrug-resistant Pseudomonas aeruginosa(MDR-PA).Additionally,the protective efficacy of PDL against mortality in infected mice was evaluated using a death model caused by MDR-PA.Finally sub-MIC concentration of levofloxacin was used to induce drug-resistant mice pneumonia model to evaluate the role of PDL in reversing drug resistance.Experimental data are expressed as mean±standard deviation.Statistical significance was determined by one-way analysis of variance followed by Tukey’s multiple-comparisons test.Results:Treatment effect of PDL on MDR-PA pneumonia:the medium and small doses of PDL can significantly reduce the lung index of multi-drug resistant bacteria infected pneumonia model mice(P<0.05),the lung index inhibition rates for these groups were 55.09%and 58.43%,and improve the degree of lung tissue lesions of mice;The expression of serum cytokines keratinocyte chemoattractant,tumor necrosis factor-αand monocyte chemoattractant protein-1 could be decreased in the three dosage groups of PDL(P<0.01).PDL treatment not only lowered the mortality but also extended the survival duration in mice infected with MDR-PA.It was found after sub-MIC concentration of levofloxacin induced resistance of Pseudomonas aeruginosa to pneumonia in mice.Compared with the model group,the lung index of mice in high and medium PDL doses was significantly reduced(P<0.05),with inhibition rates of 32.16%and 37.73%,respectively.Conclusion:PDL demonstrates protective effects against MDR-PA infection pneumonia,notably decreasing serum inflammatory factor levels.It shows promise in mitigating antibiotic resistance and offers potential for treating pneumonia resulting from Pseudomonas aeruginosa resistance.

SCN1A rs6732655A/T polymorphism:Diagnostic and therapeutic insights for drug-resistant epilepsy

BACKGROUND A significant subset of individuals with epilepsy fails to respond to currently available antiepileptic drugs,resulting in heightened mortality rates,psychosocial challenges,and a diminished quality of life.Genetic factors,particularly within the SCN1A gene,and the pro-inflammatory cytokine response is important in intricating the drug resistance in idiopathic epilepsy cases.In this extended study,we determined the correlation of rs6732655A/T single nucleotide polymorphism to understand the causative association of SCN1A gene with epilepsy drug resistance and inflammatory response.AIM To find the correlation of SCN1A gene rs6732655A/T polymorphism with the drug-resistant epilepsy and inflammatory response.METHODS The study enrolled 100 age and sex-matched patients of both drug-resistant and drug-responsive epilepsy cases.We analysed the rs6732655A/T polymorphism to study its association and causative role in drug-resistant epilepsy cases using restriction fragment length polymorphism technique.The diagnostic performance of interleukin(IL)-1β,IL-6,and high mobility group box 1(HMGB1)protein levels was evaluated in conjunction with genotypic outcome receiver operating characteristic analysis.RESULTS AT and AA genotypes of rs6732655 SCN1A gene polymorphism were associated with higher risk of drug resistance epilepsy.Serum biomarkers IL-6,IL1βand HMGB1 demonstrated diagnostic potential,with cutoff values of 4.63 pg/mL,59.52 pg/mL and 7.99 ng/mL,respectively,offering valuable tools for epilepsy management.Moreover,specific genotypes(AA and AT)were found to be linked to the elevated levels of IL-1βand IL-6 and potentially reflecting increased oxidative stress and neuro-inflammation in drug-resistant cases supporting the previous reported outcome of high inflammatory markers response in drug resistance epilepsy.CONCLUSION SCN1A genotypes AA and AT are linked to higher drug-resistant epilepsy risk.These findings underscore the potential influence of inflammation and genetics on epilepsy treatment resistance.

Incidence, risk factors and clinical outcome of multidrug-resistant organisms after heart transplantation

BACKGROUND Transplant recipients commonly harbor multidrug-resistant organisms(MDROs),as a result of frequent hospital admissions and increased exposure to antimi-crobials and invasive procedures.AIM To investigate the impact of patient demographic and clinical characteristics on MDRO acquisition,as well as the impact of MDRO acquisition on intensive care unit(ICU)and hospital length of stay,and on ICU mortality and 1-year mortality post heart transplantation.METHODS This retrospective cohort study analyzed 98 consecutive heart transplant patients over a ten-year period(2013-2022)in a single transplantation center.Data was collected regarding MDROs commonly encountered in critical care.RESULTS Among the 98 transplanted patients(70%male),about a third(32%)acquired or already harbored MDROs upon transplantation(MDRO group),while two thirds did not(MDRO-free group).The prevalent MDROs were Acinetobacter baumannii(14%),Pseudomonas aeruginosa(12%)and Klebsiella pneumoniae(11%).Compared to MDRO-free patients,the MDRO group was characterized by higher body mass index(P=0.002),higher rates of renal failure(P=0.017),primary graft dysfunction(10%vs 4.5%,P=0.001),surgical re-exploration(34%vs 14%,P=0.017),mechanical circulatory support(47%vs 26%P=0.037)and renal replacement therapy(28%vs 9%,P=0.014),as well as longer extracorporeal circulation time(median 210 vs 161 min,P=0.003).The median length of stay was longer in the MDRO group,namely ICU stay was 16 vs 9 d in the MDRO-free group(P=0.001),and hospital stay was 38 vs 28 d(P=0.006),while 1-year mortality was higher(28%vs 7.6%,log-rank-χ2:7.34).CONCLUSION Following heart transplantation,a predominance of Gram-negative MDROs was noted.MDRO acquisition was associated with higher complication rates,prolonged ICU and total hospital stay,and higher post-transplantation mortality.

Analysis of The Correlation Between inhA Gene Mutation and Resistance to Protionamide in Drug-Resistant Mycobacterium Tuberculosis

Objective: To investigate the characteristics of katG and inhA gene mutations in multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (preXDR-TB), and their correlation with resistance to protionamide (Pto). Methods: A total of 229 patients with MDR-TB and pre-XDR-TB diagnosed in the Eighth Affiliated Hospital of Xinjiang Medical University from January 2020 to February 2024 were selected to analyze the characteristics of katG and inhA mutations in MTB clinical isolates and their correlation with Pto resistance. Results: The mutation rate of katG (with or without inhA mutation) was 85.2%. The mutation rates in MDR-TB and pre-XDR-TB were 87.4% (125/143) and 81.4% (70/86), respectively. The mutation rate of inhA (including katG mutation) was 14.8% (34/229), which was 12.6% (18/143) and 18.6% (16/86) in MDR-TB and pre-XDR-MTB, respectively. There was no difference in mutation (P > 0.05). Conclusion: The total resistance rate to Pto in 229 strains was 8.7% (20/229), which was 8.4% (12/143) and 9.3% (8/86) in MDR-TB and pre-XDR-TB, respectively. Among the inhA mutant strains, 13 were resistant to the Pto phenotype, and the resistance rate was 65% (13/20). In MDR-TB and pre-XDR-TB strains resistant to Pto, inhA gene mutations occurred in 66.7% (6/9) and 63.6% (7/11), respectively. The resistance rates of MDR-MTB and pre-XDR-TB strains without inhA gene mutation to Pto were 2.4% (3/125) and 5.7% (4/70), respectively.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy.Prior research has illuminated reasons behind drug resistance,including increased drug efflux,alterations in drug targets,and abnormal activation of oncogenic pathways.However,there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment(TME).Recent studies on extracellular vesicles(EVs)have provided valuable insights.EVs are membrane-bound particles secreted by all cells,mediating cell-to-cell communication.They contain functional cargoes like DNA,RNA,lipids,proteins,and metabolites from mother cells,delivered to other cells.Notably,EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs.This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance,covering therapeutic approaches like chemo-therapy,targeted therapy,immunotherapy and even radiotherapy.Detecting Ev-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance.Additionally,targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance.We highlight the importance of conducting in-depth mechanistic research on EVs,their cargoes,and functional ap-proaches specifically focusing on EV subpopulations.These efforts will significantly advance the devel-opment of strategies to overcome drug resistance in anti-tumor therapy.

Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China

Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking.Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns.Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023–1.954;P=0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains.Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

The superiority of PMFs on reversing drug resistance of colon cancer and the effect on aerobic glycolysis-ROS-autophagy signaling axis

Background:Polymethoxylatedflavones(PMFs)are compounds present in citrus peels and other Rutaceae plants,which exhibit diverse biological activities,including robust antitumor and antioxidant effects.However,the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown.In the present study,we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs.Methods:MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo;the mRNA and protein levels of the target were detected by SDS-PAGE(sodium dodecyl sulfate-polyacrylamide gel electrophoresis),quantitative real-timefluorescence polymerase chain reaction(qRT-PCR)and Western blot protein immunoblotting(WB);An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo;The extracellular acidification rate(ECAR)and the oxygen consumption rate(OCR)were detected to assess the cellular oxygen consumption rate and glycolytic process.Results:HCT8/T cells demonstrated significant resistance to PTX,up-regulating the expression levels of ABCB1 mRNA,P-gp,LC3-I,and LC3-II protein,and increasing intracellular reactive oxygen species(ROS)content.PMFs mainly contain two active ingredients,nobiletin,and tangeretin,which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner.PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly.PMFs combined with PTX reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)in HCT8/T cells.Additionally,PMFs reduced intracellular ROS content,down-regulated the expression levels of autophagy-related proteins LC3-I,LC3-II,Beclin1,and ATG7,and significantly reduced the number of autophagosomes in HCT8/T cells.Conclusions:The present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis,which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.

Assessment of the Indirect Cost of Drug Resistant Tuberculosis Treatment to Patients in a High Burden, Low Income Setting in Mozambique

Introduction: Tuberculosis is closely linked to poverty, with patients facing significant indirect treatment costs. Treating drug-resistant tuberculosis further increases these expenses. Notably, there is a lack of published data on the indirect costs incurred by patients with drug-resistant tuberculosis in Mozambique. Objective: To assess the indirect costs, income reduction, and work productivity incurred by patients undergoing diagnosis and treatment for Drug-Resistant Tuberculosis (DRTB) in Mozambique during their TB treatment. Methods: As part of a comprehensive mixed-methods study conducted from January 2021 to April 2023, this research utilized a descriptive cross-sectional approach, incorporating both quantitative and qualitative methods. The primary goal was to evaluate the costs incurred by the national health system due to drug-resistant TB. Additionally, to explore the indirect costs experienced by patients and their families during treatment, semi-structured interviews were conducted with 27 individuals who had been undergoing treatment for over six months. Results: All survey participants unanimously reported a significant decline in labour productivity, with 70.3% experiencing a reduction in their monthly income. Before falling ill, the majority of respondents (33.3%) earned up to $76.92 monthly, representing the minimum earnings range, while 29.2% had a monthly income above $230.77, the maximum earnings range. Among those who experienced income loss, the majority (22.2%) reported a decrease of up to $76.92 per month, and 18.5% cited a loss exceeding $230.77 per month. Notably, patients with Drug-Resistant Tuberculosis (DRTB) have not incurred the direct costs of the disease, as these are covered by the government. Conclusion: The financial burden of treating Drug-Resistant Tuberculosis (DRTB), along with the income reduction it causes, is substantial. Implementing a patient-centred, multidisciplinary, and multisector approach, coupled with strong psychosocial support, can significantly reduce the catastrophic costs DRTB patients incur.

Suppression of P-gp induced multiple drug resistance in a drug resistant gastric cancer cell line by overexpression of Fas

AIM To observe the drug sensitizing effect andrelated mechanisms of fas gene transduction onhuman drug-resistant gastric cancer cellSGC7901/VCR(resistant to Vincristine).METHODS The cell cycle alteration wasobserved by FACS.The sensitivity of gastriccancer cells to apoptosis was determined by invitro apoptosis assay.The drug sensitization ofcells to several anti-tumor drugs was observedby MTT assay.Immunochemical method wasused to show expression of P-gp and Topo Ⅱ ingastric cancer cells.RESULTS Comparing to SGC7901 and pBK-SGC7901/VCR,fas-SGC7901/VCR showeddecreasing G2 cells and increasing S cells,theG2 phase fraction of pBK-SGC7901/VCR wasabout 3.0 times that of fas-SGC7901/VCR,but Sphase fraction of fas-SGC7901/VCR was about1.9 times that of pBK-SGC7901/VCR,indicatingS phase arrest of fas-SGC7901/VCR.FACS alsosuggested apoptosis of fas-SGC7901/VCR,fas-SGC7901/VCR was more sensitive to apoptosisinducing agent VM-26 than pBK-SGC7901/VCR.MTT assay showed increased sensitization offas-SGC7901/VCR to DDP,MMC and 5-FU,butsame sensitization to VCR according to pBK-SGC7901/VCR.SGC7901,pBK-SGC7901/ VCRand fas-SGC7901/VCR had positively stainedTopo Ⅱ equally.P-gp staining in pBK- SGC7901/VCR was stronger than in SG07901,but there was little staining of P-gp in fas.SGC7901/VCR.CONCLUSION fas gene transduction couldreverse the MDR of human drug-resistant gastriccancer cell SGC7901/VCR to a degree,possiblybecause of higher sensitization to apoptosis anddecreased expression of P-gp.

Transduction of Fas gene or Bcl-2 antisense RNA sensitizes cultured drug resistant gastric cancer cells to chemotherapeutic drugs

AIM To compare the expression level of Fas gene and Bcl-2 gene in gastric cancer cells SGC7901 and gastric cancer MDR (multidrug resistant) cells SGC7901/VCR, to transduce Fas cDNA and Bcl-2 antisense nucleic acid into SGC7901/VCR cells respectively, and to observe the expression of two genes in transfectants and non-transfectants as well as their drug sensitivity.METHODS Eukaryotic expression vector pBK-Fas cDNA and pDOR-anti Bcl-2 were constructed and transfected into SGC7901/VCR cells by lipofectamine, respectively. Northern blot and Western blot were used to detect the expression of mRNA and protein in SGC7901/VCR and SGC7901 cells and transfectants, and drug sensitivity of transfectants for VCR, CDDP and 5-FU was analyzed with MTT assay.RESULTS After gene transfection, 80 for Fas and 120 for antisense Bcl-2 drug-resistant clones were selected from 2×105 cells, transfection rate being 0.04% and 0.06%. Two clones of SGC7901 Fas/VCR cells and SGC7901 anti Bcl-2/VCR cells were randomly selected for further incubation. Hybridization results showed that the expression level of Fas mRNA and protein in SGC7901/VCR cells was much lower, but that of Bcl-2 mRNA and protein was higher than that in SGC7901 cells. The expression of Fas mRNA and protein in SGC7901 Fas/VCR cells was higher, and of Bcl-2 mRNA and protein was lower in SGC7901 anti Bcl-2/VCR cells than that in non-transfectants. MTT assay showed that transfectants were more sensitive to VCR, CDDP, 5-FU than non-transfectants.CONCLUSION Bcl-2 gene displayed high expression while Fas gene had low expression in drug resistant gastric cancer cells. Expression of Bcl-2 protein was effectively blocked in SGC7901 anti Bcl-2/VCR cells by gene transfection. In contrast, the expression of Fas mRNA and protein in SGC7901 Fas/VCR cells increased. Fas gene and Bcl-2 antisense nucleic acid transfection sensitized drug resistant gastric cancer cells to chemotherapeutic drugs. These results suggest cell apoptosis plays an important role in the mechanism of MDR, and enhancing apoptosis might reverse MDR.

Risk factors for hepatocellular carcinoma in patients with drug-resistant chronic hepatitis B

AIM:To investigate the risk factors and characteristics of hepatocellular carcinoma(HCC) in the patients with drug-resistant chronic hepatitis B(CHB).METHODS:A total of 432 patients with drug-resistant CHB were analyzed retrospectively from January 2004to December 2012. The patients were divided into two groups:the HCC group(n = 57) and the non-HCC group(n = 375). Two groups compared using logistic regression for various patients and viral characteristics in order to identify associated risk factors for HCC.Secondarily,patient and tumor characteristics of HCC patients with na ve CHB(N group,n = 117) were compared to the HCC group(R group,n = 57) to identify any difference in HCC characteristics between them.RESULTS:A significant difference was found for age,platelet count,alpha-fetoprotein(AFP),positivity of HBeAg,seroconversion rate of HBeAg,virologic response,the Child-Pugh score,presence of rtM204I,and the duration of antiviral treatment in non-HCC and HCC group. Cirrhosis,age(> 50 years),HBeAg(+),virologic non-responder status,and rtM204I mutants were independent risk factors for the development of HCC. The R group had lower serum C-reactive protein(CRP) and AFP levels,earlier stage tumors,and a shorter mean tumor surveillance period than the N group. However,the total follow-up duration was not significantly different between the two groups.CONCLUSION:13.2% of patients with drug-resistant CHB developed HCC. Age,cirrhosis,YIDD status,HBeAg status,and virologic response are associated with risk of HCC. Patients with drug-resistant CHB and these clinical factors may benefit from closer HCC surveillance.

Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.

Three-in-one DNA nanowheels for simultaneous tumor regression and drug resistance prevention in breast cancer model

Herein,we proposed novel three-in-one DNA nanowheels with simultaneous chemo and gene therapy to treat tumor,especially to prevent simultaneous drug resistance,which could be disassembled via a cascaded hybridization reactions triggered by the highly expressed microRNA in cancer cells for smart and efficient cancer therapy.Typically,with breast cancer as a model,microRNA 21 could trigger the self-disassembly of DNA nanowheel 1 via hybridization with a specially designed oligonucleotide(anti-microRNA 21)in DNA nanowheel 1,releasing another special oligonucleotide(Contact sequence)to trigger the self-disassembly of DNA nanowheel 2 with releasing of a special oligonucleotide(anti-Contact sequence)to trigger the self-disassembly of DNA nanowheel 1 cyclically,and thus the cascaded hybridization reactions with three-in-one anti-cancer functions could be generated based on three main therapeutic effects via releasing doxorubicin to inhibit macromolecular biosynthesis,antisense oligonucleotide of microRNA 21 to activate the apoptotic cell pathway and antisense oligonucleotide of MDR1 to prevent the drug resistance respectively.As expected,the proposed method showed improved therapeutic efficacy on the cancer cells with about 80%apoptosis ratio,especially on the drug resistant cancer cells with about 75%apoptosis ratio,compared with that in the conventional anti-cancer systems of about 70%on cancer cells and below 40%on drug resistant cancer cells,respectively.Most importantly,this strategy opened the door for generation of complex functional DNA-based structures for target triggering drugs releasing system combining with chemo-and genetherapy to generate tumor regression and prevent drug resistance with an optimized therapeutic efficacy,providing a new avenue for efficient cancer treatment,especially drug resistant cancers.

Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant Mycobacterium Tuberculosis Patients in Xinjiang

Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods:The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tuberculosis were amplified through fluorescence quantitative PCR,and the amplified products were sequenced and compared.Results:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51%(20/148),among which the inhA gene mutation rate among patients of Han,Uygur,and Kazakh ethnicity were 15.87%,13.21%,and 17.65%,respectively.There was no significant difference in the inhA mutation rate among nationalities(c^(2)=2.897,P>0.05).The mutation rate of the katG gene was 84.46%(125/148),among which the mutation rates of patients of Han,Uyghur,and Kazak ethnicities were 82.54%,84.91%,and 76.47%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There was no significant difference in the mutation rate of the katG gene among different ethnicities(c^(2)=3.772,P>0.05).The mutation rates of the inhA gene in southern Xinjiang,northern Xinjiang,and other provinces were 18.60%,9.28%,and 37.50%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)and between southern Xinjiang and other provinces(c^(2)=1.424,P>0.05).However,the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang(c^(2)=5.539,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.

Photostable and Biocompatible Fluorescent Silicon Nanoparticles for Imaging-Guided Co-Delivery of siRNA and Doxorubicin to Drug-Resistant Cancer Cells

The development of effective and safe vehicles to deliver small interfering RNA(siRNA) and chemotherapeutics remains a major challenge in RNA interference-based combination therapy with chemotherapeutics,which has emerged as a powerful platform to treat drug-resistant cancer cells.Herein,we describe the development of novel all-in-one fluorescent silicon nanoparticles(SiNPs)-based nanomedicine platform for imaging-guided co-delivery of siRNA and doxorubicin(DOX).This approach enhanced therapeutic efficacy in multidrug-resistant breast cancer cells(i.e.,MCF-7/ADR cells).Typically,the SiNP-based nanocarriers enhanced the stability of siRNA in a biological environment(i.e.,medium or RNase A) and imparted the responsive release behavior of siRNA,resulting in approximately 80% down-regulation of P-glycoprotein expression.Co-delivery of P-glycoprotein siRNA and DOX led to>35-fold decrease in the half maximal inhibitory concentration of DOX in comparison with free DOX,indicating the pronounced therapeutic efficiency of the resultant nanocomposites for drug-resistant breast cancer cells.The intracellular time-dependent release behaviors of siRNA and DOX were revealed through tracking the strong and stable fluorescence of SiNPs.These data provide valuable information for designing effective RNA interference-based co-delivery carriers.

The emergence of drug resistant HIV variants and novel anti-retroviral therapy

After its identification in 1980s,HIV has infected more than 30 million people worldwide.Inthe era of highly active anti-retroviral therapy,anti-retroviral drug resistance results frominsufficient anti-retroviral pressure,which may lead to treatment failure.Preliminary studiessupport the idea that anti-retroviral drug resistance has evolved largely as a result of low-adherence of patients to therapy and extensive use of anti-retroviral drugs in the developedworld;however,a highly heterogeneous horde of viral quasi-species are currently circulating indeveloping nations.Thus,the prioritizing of strategies adopted in such two worlds should be quitedifferent considering the varying anti-retroviral drug resistance prevalence.In this article,weexplore differences in anti-retroviral drug resistance patterns between developed and developingcountries,as they represent two distinct ecological niches of HIV from an evolutionary standpoint.

Prevalence and Risk Factors of Primary Drug-Resistant Tuberculosis in China

Objective To investigate the prevalence of primary drug-resistant tuberculosis（TB） and associated risk factors in China. We also explored factors contributing to the transmission of multidrug-resistant tuberculosis（MDR-TB）. Methods A total of 2794 representative, Mycobacterium tuberculosis isolates from treatment-naive patients were subjected to drug susceptibility testing, and risk factors for drug-resistant TB were analyzed. We also analyzed MDR-TB strain sublineages, drug-resistance-conferring mutations, and risk factors associated with clustered primary MDR strains. Results Among 2794 Mycobacterium tuberculosis isolates from treatment-naive patients, the prevalence of any resistance to first-line drugs was 33.2% and the prevalence of MDR-TB was 5.7%. We did not find any risk factors significantly associated with resistance to first-line drugs. The 93 primary MDR-TB isolates were classified into six sublineages, of which, 75（80.6%） isolates were the RD105-deleted Beijing lineage. The largest sublineage included 65（69.9%） isolates with concurrent deletions of RD105, RD207, and RD181. Twenty-nine（31.2%） primary MDR strains grouped in clusters; MDR isolates in clusters were more likely to have S531 L rpoB mutation. Conclusion This study indicates that primary drug-resistant TB and MDR-TB strains are prevalent in China, and multiple measures should be taken to address drug-resistant TB.

Multidrug-resistant organisms in intensive care units and logistic analysis of risk factors

BACKGROUND Intensive care unit(ICU)patients are critically ill and have low immunity.They will undergo various trauma medical procedures during diagnosis and treatment.The use of high-dose hormones and broad-spectrum antibiotics will increase the incidence of nosocomial infection in ICU patients.Therefore,it is necessary to explore the causes of nosocomial infection in ICU and provide basis for the prevention and control of nosocomial infection in ICU.AIM To explore major pathogens of nosocomial infection in ICUs,methods of detection and drug resistance trends.METHODS Risk factors of multidrug-resistant infection were analyzed to provide a basis for clinical rational use of antimicrobial drugs in the ICU.These findings were used to standardize rational use of antimicrobial agents.BD PhoenixTM100 automatic bacterial identification analyzer was used to for cell identification in specimens collected from the ICU between January 2016 and December 2019.Drug sensitivity tests were carried out and drug resistance trends were analyzed using the optical disc diffusion method.Odds ratios and corresponding 95%CI of independent variables were calculated using a logistic regression model.Backward elimination(trend=0.1)was used as an inclusion criterion for multivariate analysis.All data were analyzed using SPSS version 22.0,and P<0.05 was considered statistically significant.RESULTS We collected 2070 samples from ICU patients between January 2016 and December 2019.Sample types comprised sputum(1139 strains,55.02%),blood(521 strains,25.17%),and drainage fluid(117 strains,5.65%).A total of 1051 strains of major pathogens,including Acinetobacter baumannii,Escherichia coli(E.coli),Pseudomonas aeruginosa(P.aeruginosa),Klebsiella pneumoniae(K.pneumoniae)and Staphylococcus aureus,were detected,with a detection rate of 35.97%(378/1051).Most of these strains were resistant to antibiotics.Detection rate of E.coli was 21.79%(229/1051),and it was generally sensitive to many antimicrobial drugs.Detection rate of P.aeruginosa was 24.74%(260/1051),and showed low sensitivity to most antibiotics.Detection rate of K.pneumoniae was 9.42%(99/1051),which was generally resistant to multiple antimicrobial drugs and resistant forms.K.pneumoniae was resistant to imipenem for approximate 4 years,and showed a 19.9%(19/99)and 20.20%(20/99)rate of meropenem resistance.Logistic analysis showed that mechanical ventilation and ureteral intubation were risk factors for multidrug-resistant bacterial infections.CONCLUSION This study showed a high incidence of ICU infections.Mechanical ventilation and urine tube intubation were risk factors for infection with multidrug-resistant bacteria.

Activation of STAT3 signaling in human stomach adenocarcinoma drug-resistant cell line and its relationship with expression of vascular endothelial growth factor

AIM: To investigate the difference in activation of STAT3 signaling between two human stomach adenocarcinoma cell lines: 5-fluorouracil resistant cell line and its parental cell line, and to evaluate its relationship with the expression of vascular endothelial growth factor (VEGF). METHODS: Western blot and electrophoretic mobility shift assay (EMSA) were used to detect the expression of phospho-STAT3 protein and constitutive activation of STAT3 in two human stomach adenocarcinoma cell lines, 5-fluorouracil resistant cell line SGC7901/R and its parental cell line SGC7901, respectively. The mRNA expression of VEGF was analysed by semi-quantitative RT-PCR. The expressive intensity of VEGF protein was measured by immunocytochemistry. RESULTS: The expressions of phospho-STATS protein and constitutive activation of STAT3 between two human stomach adenocarcinoma cell lines were different. Compared with the parental cell line SGC7901, the STAT3DNA binding activity and the expressive intensity of phospho-STAT3 protein were lower in the drug-resistant cell line SGC7901/R. The expression levels of VEGF mRNA and its encoded protein were also decreased in drugresistant cell line. CONCLUSION: Over-expression of VEGF may be correlated with elevated STAT3 activation in parental cell line. Lower VEGF expression may be correlated with decreased STAT3 activation in resistant cell line, which may have resulted from negative feedback regulation of STAT signaling.