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Objective To investigate the transcriptome differences of ovarian cancer cells after cisplatin(DDP)resistance,and to find potential antagonists based on this screening.Methods DDP-resistant cell line A2780-DDP was constructed with A2780 cells as the research object.Through transcriptome sequencing anal-ysis,the key factors of DDP resistance were found and verified by quantitative real-time PCR(qPCR)and Western blot experiments.Through the screening of small molecule inhibitors,CCK-8 cell viability assay was used to find potential antagonists.Results A2780-DDP were successfully constructed,and it was found that there was no difference in cell proliferation after drug resistance,but the ability of cell invasion and migration was enhanced.Through transcriptome sequencing analysis,it was found that ITGB7 and Akt may be the key genes of A2780-DDP,and qPCR and Western blot showed that they were highly expressed in A2780-DDP.CCK-8 results showed that triptolide(TPL)and Olaparib had good inhibitory effects in DDP-resistant cell lines.Conclusion The ITGB7/Akt pathway plays an important role in DDP resistance,and potential DDP re-sistance antagonists such as TPL can provide new ideas for the treatment of ovarian cancer.
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Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related death,following lung cancer,colorectal cancer and gastric cancer.Chemoresistance is currently the major challenge in clinical treatment of HCC patients,and it is also the primary cause of the poor prognosis and high recurrence rate of patients.There are multiple factors and complex mechanisms in the occurrence of HCC drug resistance.Recent research has shown that non-coding RNA(ncRNA)is closely related to HCC chemoresistance.By regulating the expression of target genes and protein translation,ncRNA affects the occurrence,metastasis,and prognosis of HCC and is expected to become a therapeutic biomarker and potential drug therapeutic target for HCC.Therefore,this study reviews several common ncRNAs,including long non-coding RNAs(LncRNAs),miRNAs and transferRNA(tRNAs),in the molecular mechanisms and research progress of HCC chemoresistance,providing new ideas for solving the problem of HCC chemoresistance.
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In recent years,the incidence of Elizabethkingia infection has increased significantly.Elizabethkingia can cause pneumonia,meningitis,and bacteremia,etc.The high rate of drug resistance leads to prolonged hospital stay and increased mortality,posing a heavy burden to patients and society.This paper reviews the epidemiology,pathogenesis and drug resistance of Elizabethkingia,with a view to providing a reference for the clinical diagnosis,treatment,prevention and control of Elizabethkingia infection.
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Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.
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Streptococcus pneumoniae(SP)is one of the common pathogens of respiratory tract infection in children, which can evolve into severe pneumonia and necrotizing pneumonia in case of severe infection.β-lactam antibiotics are the first-line treatment for SP.The resistance mechanism of SP to β-lactam antibiotics is mainly PBPs gene mutation, followed by mutations related to non-PBPs genes such as MurM, CpoA, TEM, CiaH/CiaR-TCSS and StkP-PhpP signal conjugations.Antibiotic selection pressure and vaccine-induced serotype substitution may influence SP resistance.Serotypes 19F and 19A have high resistance to β-lactam antibiotics, and promotion of PCV13 may be more beneficial than other SP vaccines in preventing SP infection in children.
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Objective:To investigate the mechanism of polymyxin resistance related to lipopolysaccharide modification in carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods:Plasmid-mediated drug resistance genes in seven CRKP strains were detected by conjugation assay and mcr gene detection. The expression of polymyxin resistance-related genes was measured using quantitative real-time PCR. The complete genomes of CRKP strains were sequenced. Silver staining and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were performed to analyze the changes in lipopolysaccharide (LPS). Results:The seven CRKP strains were negative for mcr genes and the results of conjugation assay were also negative. Moreover, no mobile genetic elements related to drug resistance were detected. Compared with wild-type strain, all seven CRKP strains that were resistant to polymyxin showed increased expression of pmrA, pmrB and pmrC genes at the transcriptional level; six showed increased expression of phoP/ phoQ genes; three showed decreased expression of crrA/ crrB genes; four showed decreased expression of mgrB gene. The missense mutation sites in drug-resistant strains were mainly in KPHS_09430, KPHS_35900, KPHS_39520 and KPHS_52420. IS Kpn14 insertion sequence was detected in CRKP-6 strain. MALDI-TOF-MS reveals the modification of natural lipid A with L-Ara4N in CRKP LPS. Conclusions:LPS modification induced by chromosome-mediated mutation in the two-component regulatory system was the main molecular mechanism of polymyxin resistance in CRKP isolates in this study. Effects of the mutation in the two-component system on polymyxin resistance varied in different strains.
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β-lactam antibiotics are a class of antibiotics widely used in clinical treatment. The antibacterial mechanism of them is to inhibit the cell wall synthesis of bacteria. However, the widespread of β-lactam resistance genes among bacteria has posed a great challenge to the use of β-lactam antibiotics. One of the main genes encoding β-lactamase is blaTEM, and 243 subtypes of it have been identified to date. Studying blaTEM gene is of great significance in antibiotic resistance research. This review focused on the discovery, structure, promoter, distribution, spread, antibacterial mechanism and research status of blaTEM gene, hoping to provide reference for further research on the subtypes of β-lactam resistance genes in bacteria.
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Klebsiella pneumoniae is one of the common pathogens causing hospital-acquired infection. With the wide use of carbapenem in recent years, carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged around the world. Carbapenemase production is the main cause of resistance to carbapenem antibiotics in Klebsiella pneumoniae. More than 70% of Klebsiella pneumoniae strains produce carbapenemase. Ceftazidime/avibactam (CAZ/AVI) can effectively treat CRKP infection, especially those caused by CRKP that can produce Klebsiella pneumoniae carbapenemase (KPC) or oxaclillinase (OXA)-48. However, it has been reported that CAZ/AVI-resistant CRKP strains have emerged. In this paper, the epidemiology, risk factors, resistance mechanism and treatment of CAZ/AVI-resistant CRKP were summarized to provide reference for clinical treatment.
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Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is highly aggressive, easy to relapse, and chemotherapy remains its mainstay treatment due to the lack of therapeutic targets. In recent years, many advances have been made in the development of immunotherapy for TNBC. This review summarizes the primary modalities of immunotherapy for TNBC, including immune checkpoint inhibitors, adoptive immune cell therapy, tumor vaccines and oncolytic virus. We present the latest research progress on each treatment from the perspective of clinical study and fundamental research, while introducing the potential predictive biomarkers and resistance mechanisms of immunotherapy for TNBC.
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Objectives:To investigate the distribution characteristics and mechanism of drug-resistant genes in carbapenem-resistant Klebsiella pneumoniae.Methods:A total of 58 strains of carbapenem-resistant Klebsiella pneumoniae isolated from clinical specimens at Weihai Central Hospital,Qingdao University, from January to December 2021 were collected. Their phenotypes were confirmed by modified Hodge test and modified carbapenem inactivation test. Polymerase chain reaction was used for amplification. Pulsed field gel electrophoresis clustering and multilocus sequence typing were performed to characterize the molecular epidemiology of the strains.Results:Carbapenem-resistant Klebsiella pneumoniae had a sensitivity rate of 51.7% to amikacin, a high (> 60%) resistance rate to antibiotics such as ciprofloxacin, levofloxacin, compound sulfamethoxazole, piperacillin/tazobactam, and a 100.0% resistance to cefazolin, ceftazidime, cefotetan, and cefepime. The modified Hodge test was positive in 46 (79.3%) of the 58 strains, and the modified carbapenem inactivation test was positive in 31 strains (53.5%). Polymerase chain reaction amplification and gene sequencing showed that 42 strains (72.41%) carried mainly the KPC-2 gene, 12 strains (20.7%) carried the IMP-4 gene, and 4 strains (6.9%) carried the NDM-1 gene. The 12 strains carrying the IMP-4 gene all carried the KPC-2 gene and were double positive for the modified Hodge test and the modified carbapenem inactivation test. Pulsed field gel electrophoresis clustering and multilocus sequence typing analysis showed that the KPC-2 producing strains were mainly ST11-B and ST395-A, the KPC-2- and IMP-4-producing strains were mainly ST345-M and ST11-B, and NDM-1-producing strains were ST263-F and ST15-C. Conclusion:Carbapenem-resistant Klebsiella pneumoniae is highly drug-resistant and carries a variety of carbapenemases, including the KPC-2 and IMP-4 genes.
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Polymyxin antibiotics,particularly polymyxin B and polymyxin E(colistin),are often considered a last line of defense against penicillin carbapenem-resistant Enterobacteriaceae(CRE),because of their favorable clinical antibacterial effects.However,the emergence and spread of plasmid-mediated colistin resistance genes(mcr),and their multiple isoforms,have posed a substantial threat to public health in recent years.The mcr-1 genes exhibit complexity in both host and transmis-sion routes,and diversity in both the genetic environment and ecological locus distribution.Herein,we discuss the prevalence,transmission routes,drug resistance and transmission mechanisms of mcr-1 positive isolates,on the basis of epidemiological studies of Enterobacteriaceae carrying mcr-1 worldwide.to provide a theoretical reference for researchers.
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Brucellosis is a zoonosis with worldwide distribution,which is caused by bacteria of the genus Brucella.The in-cidence of brucellosis has recently increased each year,and caused great losses in terms of public health,animal husbandry and the social economy.Doxycycline plus rifampicin or streptomycin,the preferred antibiotic regimen,plays a key role in brucello-sis treatment.Because of the use of antibacterial drugs,Brucella has developed antimicrobial resistance,thus challenging clini-cal treatment.This article reviews research progress in drug resistance of Brucella from cattle and sheep(mainly Brucella abortus and Brucella melitensis)and Brucella from humans(mainly Brucella melitensis)from 2013 to 2023,including the types of antibiotic resistance,the rates of antibiotic resistance and the possible mechanism of antibiotic resistance,to provide a comprehensive reference for clinical the treatment of brucellosis and study of the drug resistance mechanisms of Brucella.
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Stenotrophomonas maltophilia is a gram-negative bacillus which widely exists in natural and hospital environment, and it is also one of the common opportunistic pathogens in clinical settings. The virulence and pathogenicity of Stenotrophomonas maltophilia are weak, however, due to resistance to a variety of antibacterial drugs, it can cause bloodstream infections or pneumonia in immunocompromised or critically ill patients, leading to poor prognosis. Moreover, the inherent drug resistance and increasing acquired drug resistance may make the treatment of the first line antibiotics, like trimethoprim-sulfamethoxazole or quinolone ineffective. Therefore, it is important to understand the drug resistance mechanism and the main countermeasures for it. In this article, the research progress on drug resistance mechanism and treatment for Stenotrophomonas maltophilia are reviewed.
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Salmonella are important food-borne infectious bacteria causing gastroenteritis, enteric fever, bloodstream infection and focal extraintestinal infection and other salmonellosis.It is a major global public health problem.Antibiotics play an important role in the prevention and treatment of salmonellosis.With the emergence of resistance to traditional first-line drugs for the treatment of salmonellosis, azithromycin has become one of the commonly used antibiotics.However, studies have reported azithromycin resistant Salmonella strains, and azithromycin resistance in Salmonella is becoming more common and increasing year by year.Enhanced activity of active efflux pump, destruction of lactone ring structure, methylation of ribosome, carrying ICE_erm42 gene may be related mechanisms of drug resistance.The discovery, monitoring and in-depth study of azithromycin resistance in Salmonella play an important role in the rational use of antibiotics and delaying the trend of resistance.This article reviews the research progress on the epidemiology and related mechanisms of azithromycin resistance in Salmonella.
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The cultivation and production of cucumber are seriously affected by downy mildew caused by Pseudoperonospora cubensis. Downy mildew damages leaves, stems and inflorescences, and then reduces the yield and quality of cucumber. This review summarized the research advances in cucumber downy mildew, including pathogen detection and defense pathways, regulatory factors, mining of pathogens-resistant candidate genes, proteomic and genomic analysis, and development of QTL remarks. This review may facilitate clarifying the resistance mechanisms of cucumber to downy mildew.
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Cucumis sativus/genética , Oomicetos/genética , Peronospora , Enfermedades de las Plantas/genética , ProteómicaRESUMEN
With th e massive use of antibiotics ，Klebsiella pneumoniae has shown a trend of multiple drug resistance ， especially carbapenem-resistant K. pneumoniae ，which means that fewer and fewer antibiotics can be used to treat K. pneumoniae infection. Polymyxin has become the last line of defense for the treatment of carbapenem-resistant K. pneumoniae infection due to its unique antibacterial mechanism. However ，with the increase of its use ，the reports of drug-resistant K. pneumoniae strains at home and abroad are also on the rise ，seriously endangering the lives of patients . The author summarizes the resistance mechanism of K. pneumoniae to polymyxin ，and find that the resistance mechanism of K. pneumoniae to polymyxin mainly includes the structural modification of lipopolysaccharide in bacterial outer membrane ，the overexpression of capsular polysaccharide and the overexpression of multidrug efflux pump ，which can provide a basis for the rational use of the drug and the prevention and treatment of drug-resistant K. pneumoniae .
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Platinum anti-tumor drugs are currently the most widely used first-line chemotherapeutic drugs in clinical practice, and their curative effects are remarkable. However, the problems of platinum drug resistance in non-small cell lung cancer, breast cancer, ovarian cancer and others seriously limit effectiveness and clinical application of platinum drugs. The occurrence of platinum drug resistance is caused by many factors. At present, the resistance mechanism of platinum drugs mainly includes the following aspects: decreasing the accumulation of platinum in cells, increasing the inactivation of platinum in cells, repairing DNA damage and tumor cell apoptosis inactivation. This article reviews the drug resistance mechanism and coping strategy of platinum anti-tumor drugs, providing ideas for the development of platinum anti-tumor drugs and references for overcoming clinical platinum drug resistance.
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Extracellular vesicles (EV) are lipid bilayer vesicles with a diameter of 30-1000 nm secreted by cells or microorganisms, which are abundant in proteins, nucleic acids, lipids and other biological information molecules. Therefore, EV can be used as a carrier, transferring materials between cells. At present, in infectious diseases, EV derived from pathogenic microorganisms could be considered as a double-edged sword, which means it can not only play a negative role in the host′s infection immunity, bacteria′s pathogenicity and antibiotic resistance transmission, but also manifest the advantages in clinical diagnosis and treatment.
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Patients with oncogenic driver alterations of non-small cell lung cancer (NSCLC) can benefit from targeted therapy, but acquired resistance is inevitable ultimately. Epigenetic modifications, including DNA methylation, histone modifications, non-coding RNA-mediated regulate and chromatin remodeling, are important mechanisms of acquired resistance in targeted therapy of NSCLC. In recent years, studies have found that epigenetic modifications can effectively reverse drug resistance. Targeted therapy combined with epigenetic modifications may become a promising therapeutic strategy. Here, we review the progress of epigenetic mechanism in acquired resistance of targeted therapy in NSCLC, hoping to provide ideas for screening dominant population and overcoming resistance. .
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Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Metilación de ADN , Epigénesis Genética , Neoplasias Pulmonares/genéticaRESUMEN
Inhibition of immune checkpoints is at the forefront of immunotherapy for lung cancer. However, a high percentage of lung cancer patients do not respond to these immunotherpy or their responses are transient, indicating the existence of immune resistance. Emerging evidence suggested that the interactions between cancer cells and immune system were continuous and dynamic. Here, we review how a range of cancer-cell-autonomous characteristics, tumor-microenvironment factors, and host-related influences account for heterogenous responses. Furthermore, with the identification of new targets of immunotherapy and development of immune-based combination therapy, we elucidate the methods might useful to overcome resistance.