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Advances in Protein Chemistry and... 2024Acinetobacter baumannii is a gram-negative bacterium well known for its multidrug resistance and connection to nosocomial infections under ESKAPE pathogens. This... (Review)
Review
Acinetobacter baumannii is a gram-negative bacterium well known for its multidrug resistance and connection to nosocomial infections under ESKAPE pathogens. This opportunistic pathogen is ubiquitously associated with nosocomial infections, posing significant threats within healthcare environments. Its critical clinical symptoms, namely, meningitis, urinary tract infections, bloodstream infections, ventilator-associated pneumonia, and pneumonia, catalyze the imperative demand for innovative therapeutic interventions. The proposed research focuses on delineating the role of Zinc, a crucial metallo-binding protein and micronutrient integral to bacterial metabolism and virulence, to enhance understanding of the pathogenicity of A. baumannii. RNA sequencing and subsequent DESeq2 analytical methods were used to identify differential gene expressions influenced by zinc exposure. Exploiting the STRING database for functional enrichment analysis has demonstrated the complex molecular mechanisms underlying the enhancement of pathogenicity prompted by Zinc. Moreover, hub genes like gltB, ribD, AIL77834.1, sdhB, nuoI, acsA_1, acoC, accA, accD were predicted using the cytohubba tool in Cytoscape. This investigation underscores the pivotal role of Zinc in the virulence of A. baumannii elucidates the underlying molecular pathways responsible for its pathogenicity. The research further accentuates the need for innovative therapeutic strategies to combat A. baumannii infections, particularly those induced by multidrug-resistant strains.
Topics: Acinetobacter baumannii; Zinc; Drug Resistance, Multiple, Bacterial; Virulence; Humans; Gene Expression Profiling; Transcriptome; Acinetobacter Infections; Bacterial Proteins
PubMed: 38960471
DOI: 10.1016/bs.apcsb.2023.12.018 -
Translational Research : the Journal of... Jul 2024Pulmonary hypertension (PH) is a medical condition characterized by elevated pulmonary vascular resistance and pressure, resulting from different diseases. Due to their... (Review)
Review
Pulmonary hypertension (PH) is a medical condition characterized by elevated pulmonary vascular resistance and pressure, resulting from different diseases. Due to their high occurrence of PH, intricate hemodynamic classification, and frequently multifactorial cause and mechanism, individuals suffering from chronic kidney disease (CKD) are categorized as the fifth primary group of PH. Based on both domestic and international research, this article provides information on the epidemiology, risk factors, pathogenesis, and targeted drug treatment of PH associated with CKD.
PubMed: 38960282
DOI: 10.1016/j.trsl.2024.06.003 -
International Journal of Biological... Jul 2024Streptococcus pneumoniae is a leading cause of community-acquired pneumonia and is responsible for acute invasive and non-invasive infections. Fight against pneumococcus...
Streptococcus pneumoniae is a leading cause of community-acquired pneumonia and is responsible for acute invasive and non-invasive infections. Fight against pneumococcus is currently hampered by insufficient vaccine coverage and rising antimicrobial resistance, making the research necessary on novel drug targets. High-throughput mutagenesis has shown that acetyl-CoA carboxylase (ACC) is an essential enzyme in S. pneumoniae which converts acetyl-CoA to malonyl-CoA, a key step in fatty acid biosynthesis. ACC has four subunits; Biotin carboxyl carrier protein (BCCP), Biotin carboxylase (BC), Carboxyl transferase subunit α and β. Biotinylation of S. pneumoniae BCCP (SpBCCP) is required for the activation of ACC complex. In this study, we have biophysically characterized the apo- and holo- biotinylating domain of SpBCCP80. We have performed 2D and 3D NMR experiments to analyze the changes in amino acid residues upon biotinylation of SpBCCP80. Further, we used NMR backbone chemical shift assignment data for bioinformatical analyses to determine the secondary and tertiary structure of proteins. We observed major changes in AMKVM motif and thumb region of SpBCCP80 upon biotinylation. Overall, this work provides structural insight into the apo- to holo- conversion of SpBCCP80 which can be further used as a drug target against S. pneumoniae.
PubMed: 38960227
DOI: 10.1016/j.ijbiomac.2024.133580 -
Microbial Pathogenesis Jul 2024Neisseria gonorrheae, the causative agent of genitourinary infections, has been associated with asymptomatic or recurrent infections and has the potential to form...
Neisseria gonorrheae, the causative agent of genitourinary infections, has been associated with asymptomatic or recurrent infections and has the potential to form biofilms and induce inflammation and cell transformation. Herein, we aimed to use computational analysis to predict novel associations between chronic inflammation caused by gonorrhea infection and neoplastic transformation. Prioritization and gene enrichment strategies based on virulence and resistance genes utilizing essential genes from the DEG and PANTHER databases, respectively, were performed. Using the STRING database, protein‒protein interaction networks were constructed with 55 nodes of bacterial proteins and 72 nodes of proteins involved in the host immune response. MCODE and cytoHubba were used to identify 12 bacterial hub proteins (murA, murB, murC, murD, murE, purN, purL, thyA, uvrB, kdsB, lpxC, and ftsH) and 19 human hub proteins, of which TNF, STAT3 and AKT1 had high significance. The PPI networks are based on the connectivity degree (K), betweenness centrality (BC), and closeness centrality (CC) values. Hub genes are vital for cell survival and growth, and their significance as potential drug targets is discussed. This computational study provides a comprehensive understanding of inflammation and carcinogenesis pathways that are activated during gonorrhea infection.
PubMed: 38960215
DOI: 10.1016/j.micpath.2024.106770 -
Journal of Controlled Release :... Jul 2024Biofilms, particularly those formed by multiple bacterial species, pose significant economic and environmental challenges, especially in the context of medical implants....
Biofilms, particularly those formed by multiple bacterial species, pose significant economic and environmental challenges, especially in the context of medical implants. Addressing the urgent need for effective treatment strategies that do not exacerbate drug resistance, we developed a novel nanoformulation, Ce6&PMb@BPN, based on black phosphorus nanosheets (BPN) for targeted treatment of mixed-species biofilms formed by Acinetobacter baumannii (A. baumannii) and methicillin-resistant Staphylococcus aureus (MRSA).The formulation leverages polymyxin B (PMb) for bacterial targeting and chlorin e6 (Ce6) for photodynamic action. Upon near-infrared (NIR) irradiation, Ce6&PMb@BPN efficiently eliminates biofilms by combining chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), reducing biofilm biomass significantly within 30 min. In vivo studies on mice infected with mixed-species biofilm-coated catheters demonstrated the formulation's potent antibacterial and biofilm ablation effects. Moreover, comprehensive biosafety evaluations confirmed the excellent biocompatibility of Ce6&PMb@BPN. Taken together, this intelligently designed nanoformulation holds potential for effectively treating biofilm-associated infections, addressing the urgent need for strategies to combat antibiotic-resistant biofilms, particularly mixed-species biofilm, in medical settings.
PubMed: 38960150
DOI: 10.1016/j.jconrel.2024.06.068 -
European Journal of Medicinal Chemistry Jul 2024Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were...
Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 μg/mL to 0.5 μg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 μg/mL to 16.0 μg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.
PubMed: 38959728
DOI: 10.1016/j.ejmech.2024.116637 -
Translational Oncology Jul 2024To assess the consistency of liquid biopsy and histologic analysis for detecting epidermal growth factor receptor (EGFR) gene mutations in patients with advanced...
OBJECTIVE
To assess the consistency of liquid biopsy and histologic analysis for detecting epidermal growth factor receptor (EGFR) gene mutations in patients with advanced non-small cell lung cancer (NSCLC).
METHODS
The PubMed, Cochrane Library, and CNKI et al. databases were searched to collect studies comparing liquid biopsy and histopathologic specimens. The EGFR mutation status was extracted from the studies, and meta-analysis was carried out using Stata 12.0 software.
RESULTS
We included 22 studies of 3359 NSCLC patients. In the meta-analysis, eight papers with a sample size of size <150 had an OR of 45, indicating that liquid biopsy had high sensitivity for detecting EGFR mutations. In addition, seven papers with a sample size ≥150, with an OR of 70, reported that liquid biopsy was highly susceptible to detecting EGFR mutations. The pooled diagnostic effect size of 6 for literature that included the T790M mutation was smaller than that of 69 for literature that did not include the T790M mutation, and I >50 %, showing that literature that did not include the T790M mutation was more heterogeneous. The combined diagnostic effect size of 34 in the exon 19 group was smaller than that in the group with no exon 19, with an I>50 %. There was substantial heterogeneity in both the exon 19 group and the non-exon 19 group. The group with the L858R mutation had a greater diagnostic effect size of 28, lower I, and less heterogeneity than the group without the L858R mutation. The exon 21 group had a larger pooled diagnostic effect size of 66, a smaller I, and less heterogeneity than the group without exon 21.
CONCLUSION
Liquid biopsy and histologic analysis have high concordance for detecting EGFR mutations in NSCLC. Liquid biopsy can provide an alternative technology for individualized treatment and monitoring of minimal residual disease (MRD) in advanced NSCLC patients with EGFR tyrosine kinase inhibitor-sensitive and drug resistance (T790M) mutations.
PubMed: 38959710
DOI: 10.1016/j.tranon.2024.102022 -
Mutation Research Jun 2024Multiple myeloma cancer stem cells (MMSC) have been considered as the leading cause of multiple myeloma (MM) drug resistance and eventual relapse, microRNAs (miRNAs)...
BACKGROUND
Multiple myeloma cancer stem cells (MMSC) have been considered as the leading cause of multiple myeloma (MM) drug resistance and eventual relapse, microRNAs (miRNAs) collectively participate in the progression of MM. However, the pathogenesis of miR-138 in MMSC is still not fully understood.
OBJECTIVE
The intention of this study was to investigate the mechanism and role of miR-138 in multiple myeloma.
METHOD
Bone marrow samples and peripheral blood from patients and normal controls were collected. Use Magnet-based Cancer Stem Cell Isolation Kit to separate and extract MMSC. Real-time quantitative PCR (RT-qPCR) was carried out to determine mRNA level. Western blot was applied to detect protein levels. MTT and flow cytometry were conducted to examine the proliferation and apoptosis of MMSC. Finally, dual-luciferase reporter gene assays were performed to confirm that paired box 5 (PAX5) is a direct target for miR-138.
RESULTS
Compared with normal group, the expression of miR-138 in patients was significantly up-regulated, and the expression of miR-138 was in a negative correlation with PAX5. Additionally, downregulated miR-138 facilitated the apoptosis and inhibited the proliferation of MMSC in vitro and in vivo. Downregulated miR-138 moderated the expression of PAX5, Bcl-2, Bax, and Caspase-3. PAX5 was a direct target of miR-138.
CONCLUSION
Taken together, miR-138 plays a carcinogenic role in MM, and miR-138 adjusted the proliferation and apoptosis of MMSC by targeting PAX5. miR-138 has the probability of becoming a new medicinal target for the treatment of MM.
PubMed: 38959562
DOI: 10.1016/j.mrfmmm.2024.111869 -
International Immunopharmacology Jul 2024Cancer stem cells (CSCs) significantly interfere with immunotherapy, leading to challenges such as low response rates and acquired resistance. PD-L1 expression is... (Review)
Review
Cancer stem cells (CSCs) significantly interfere with immunotherapy, leading to challenges such as low response rates and acquired resistance. PD-L1 expression is associated with the CSC population's overexpression of CD44. Mounting evidence suggests that the breast cancer stem cell (BCSC) marker CD44 and the immune checkpoint PD-L1 contribute to treatment failure through their networks. Natural compounds can overcome therapy resistance in breast cancer by targeting mechanisms underlying resistance in BCSCs. This review provides an updated insight into the CD44 and PD-L1 networks of BCSCs in mediating metastasis and immune evasion. The review critically examines existing literature, providing a comprehensive understanding of the topic and emphasizing the impact of natural flavones on the signaling pathways of BCSCs. Additionally, the review discusses the potential of natural compounds in targeting CD44 and PD-L1 in breast cancer (BC). Natural compounds consistently show potential in targeting regulatory mechanisms of BCSCs, inducing loss of stemness, and promoting differentiation. They offer a promising approach for developing alternative therapeutic strategies to manage breast cancer.
PubMed: 38959542
DOI: 10.1016/j.intimp.2024.112613 -
Biochemical and Biophysical Research... Jun 2024Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are...
BACKGROUND AND OBJECTIVE
Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC.
METHODS
HT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 10 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells.
RESULTS
Compared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC.
CONCLUSION
The combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.
PubMed: 38959530
DOI: 10.1016/j.bbrc.2024.150262