Pore-Forming Toxins During Bacterial Infection: Molecular Mechanisms and Potential Therapeutic Targets

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

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NMPA-approved traditional Chinese medicine-Pingwei Pill: new indication for colistin recovery against MCR-positive bacteria infection

Chinese Medicine ◽

10.1186/s13020-021-00518-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Qiushuang Sheng ◽

Runbao Du ◽

Cunhui Ma ◽

Yonglin Zhou ◽

Xue Shen ◽

...

Keyword(s):

Molecular Docking ◽

Bacterial Infection ◽

Molecular Mechanisms ◽

Topological Analysis ◽

Network Pharmacology ◽

Synergistic Activity ◽

Colistin Resistance ◽

Western Blot Assay ◽

Gram Negative

Abstract Background The wide spread of plasmid-mediated colistin resistance by mobile colistin resistance (MCR) in Enterobacteriaceae severely limits the clinical application of colistin as a last-line drug against bacterial infection. The identification of colistin potentiator from natural plants or their compound preparation as antibiotic adjuncts is a new promising strategy to meet this challenge. Methods Herein, the synergistic activity, as well as the potential mechanism, of Pingwei pill plus antibiotics against MCR-positive Gram-negative pathogens was examined using checkerboard assay, time-killing curves, combined disk test, western blot assay, and microscope analysis. Additionally, the Salmonella sp. HYM2 infection models of mouse and chick were employed to examine the in vivo efficacy of Pingwei pill in combination with colistin against bacteria infection. Finally, network pharmacology and molecular docking assay were used to predicate other actions of Pingwei pill for Salmonella infection. Results Our results revealed that Pingwei Pill synergistically potentiated the antibacterial activity of colistin against MCR-1-positive bacteria by accelerating the damage and permeability of the bacterial outer membrane with an FIC (Fractional Inhibitory Concentration) index less than 0.5. The treatment of Pingwei Pill neither inhibited bacterial growth nor affected MCR production. Notably, Pingwei Pill in combination with colistin significantly prolonged the median survival in mouse and chick models of infection using the Salmonella sp. strain HYM2, decreased bacteria burden and organ index of infected animal, alleviated pathological damage of cecum, which suggest that Pingwei Pill recovered the therapeutic performance of colistin for MCR-1- positive Salmonella infection in mice and the naturally infected host chick. Pharmacological network topological analysis, molecular docking, bacterial adhesion, and invasion pathway verification assays were performed to identify the other molecular mechanisms of Pingwei Pill as a colistin potentiator against Gram-negative bacteria infection. Conclusion Taken together, NMPA (National Medical Products Administration)-approved Pingwei Pill is a promising adjuvant with colistin for MCR-positive bacterial infection with a shortened R&D (research and development) cycle and affordable R&D cost and risk.

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Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.768918 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ying Liu ◽

Xiang Ao ◽

Guoqiang Ji ◽

Yuan Zhang ◽

Wanpeng Yu ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Life Quality ◽

Therapeutic Targets ◽

Chemotherapeutic Agents ◽

Response To Chemotherapy ◽

Novel Biomarkers ◽

Related Proteins

Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.

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Long noncoding RNA FAM225A promotes the malignant progression of gastric cancer through the miR-326/PADI2 axis

Cell Death Discovery ◽

10.1038/s41420-021-00809-1 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Xiang Ma ◽

Gang Wang ◽

Hao Fan ◽

Zengliang Li ◽

Wangwang Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

In Vitro Assays ◽

Advanced Tumor Stage ◽

Advanced Tumor ◽

Mechanistic Investigation

AbstractGastric cancer (GC) is a global health problem and further studies of its molecular mechanisms are needed to identify effective therapeutic targets. Although some long noncoding RNAs (lncRNAs) have been found to be involved in the progression of GC, the molecular mechanisms of many GC-related lncRNAs remain unclear. In this study, a series of in vivo and in vitro assays were performed to study the relationship between FAM225A and GC, which showed that FAM225A levels were correlated with poor prognosis in GC. Higher FAM225A expression tended to be correlated with a more profound lymphatic metastasis rate, larger tumor size, and more advanced tumor stage. FAM225A also promoted gastric cell proliferation, invasion, and migration. Further mechanistic investigation showed that FAM225A acted as a miR-326 sponge to upregulate its direct target PADI2 in GC. Overall, our findings indicated that FAM225A promoted GC development and progression via a competitive endogenous RNA network of FAM225A/miR-326/PADI2 in GC, providing insight into possible therapeutic targets and prognosis of GC.

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Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury

Hereditas ◽

10.1186/s41065-021-00176-y ◽

2021 ◽

Vol 158 (1) ◽

Author(s):

Yun Tang ◽

Xiaobo Yang ◽

Huaqing Shu ◽

Yuan Yu ◽

Shangwen Pan ◽

...

Keyword(s):

Gene Expression ◽

Septic Shock ◽

Acute Kidney Injury ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

Kidney Injury ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Blood Samples ◽

Potential Biomarkers

Abstract Background Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI). Methods Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI. Results We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future. Conclusions Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

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The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4044606 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yanan Jiang ◽

Xiuyun Shen ◽

Moyondafoluwa Blessing Fasae ◽

Fengnan Zhi ◽

Lu Chai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Circadian Rhythm ◽

Circadian Rhythms ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

Pathogenic Mechanism ◽

Research Progress ◽

Biological Processes ◽

And Function ◽

Novel Therapeutic

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

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Cellular and molecular mechanisms of vascular injury in diabetes — Part II: Cellular mechanisms and therapeutic targets

Vascular Pharmacology ◽

10.1016/j.vph.2011.03.007 ◽

2011 ◽

Vol 54 (3-6) ◽

pp. 75-79 ◽

Cited By ~ 39

Author(s):

Rosalinda Madonna ◽

Raffaele De Caterina

Keyword(s):

Vascular Injury ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

Cellular Mechanisms

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Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽

10.3390/cells9010114 ◽

2020 ◽

Vol 9 (1) ◽

pp. 114

Author(s):

Lisa Linck-Paulus ◽

Claus Hellerbrand ◽

Anja K. Bosserhoff ◽

Peter Dietrich

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Therapeutic Targets ◽

Genetic Alterations ◽

Therapeutic Strategies ◽

The Future ◽

Associated Proteins ◽

Cancer Types ◽

Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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