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Shigella: Insights into the Clinical Features, Pathogenesis, Diagnosis, and Treatment Strategies
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Periyanaina Kesika, Bhagavathi Sundaram Sivamaruthi, Krishnaswamy Balamurugan
In the enterocytes, the intracellular Shigella release PAMPs, DAMPs, and effectors of the T3S system into the cytosol. The PAMPs such as PGN are recognized by NOD1 and further activate the NOD-RIP2 pathway, mitogen-activated protein kinases (MAPK), and NF-kB signaling.109 The effectors, such as IpgB1 and IpgB2, which act as invasin are secreted into the host epithelial cell by the T3S system of Shigella to induce membrane ruffling for the invasion of enterocytes by Shigella and induce Rho GTPase-dependent NF-kB and MAPK in the site of bacterial entry.110 During the disruption of the vacuolar membrane in epithelial cells caused by Shigella, the vacuolar membrane remnants are polyubiquitinated and further activate autophagy.109 The ubiquitinated host vacuolar membrane remnants are recognized as DAMPs by NLRs which in turn activate the massive inflammatory responses and cell death.109 NLRX1 is reported to specifically control reactive oxygen species (ROS) production. ROS are known to induce proinflammatory pathways like NF-kB and JNK pathway.111 NOD5 (NLRX1) promotes the formation of ROS after 45 minutes of Shigella infection and activates the NF-kB pathway.112
Exploratory studies with NX-13: oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1
Published in Drug and Chemical Toxicology, 2022
Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Marion Ehrich, Jyoti Chauhan, Josep Bassaganya-Riera
New classes of therapeutics are emerging for IBD, and autoimmune disease in general, targeting immunometabolism (Herrlinger et al. 2013, Leber et al. 2019a). These immunometabolic therapeutics control not only the over-expressed pro-inflammatory pathways but also the underlying metabolism of immune cells that enable their dysregulation and pathogenic activation. The discovery of new therapeutic targets that exploit this interaction through the dual-pronged regulation of both immunity and metabolism can result in the development of more effective therapeutics. One potential immunometabolic target is nucleotide-binding oligomerization domain, leucine rich repeat containing X1, NLRX1. NLRX1 is a unique NOD-like receptor (NLR) functioning as one of three regulatory NLRs and localized to the mitochondria. NLRX1 has been implicated in anti-viral signaling, sensing of dietary ligands and the gut microbiome and cancer in addition to autoimmune disease and inflammatory bowel disease (IBD). Beyond simple localization to the mitochondria and potential interactions with oxidative phosphorylation (OXPHOS) transcription, the loss of NLRX1 bias both CD4+ T cells and epithelial cells towards a metabolic profile associated with inflammation and increased disease severity and pathology in IBD (Leber et al. 2018, 2017).
The role of microRNA in cisplatin resistance or sensitivity
Published in Expert Opinion on Therapeutic Targets, 2020
Shanshan Wang, Ming-Yue Li, Yi Liu, Alexander C Vlantis, Jason YK Chan, Lingbin Xue, Bao-Guang Hu, Shucai Yang, Mo-Xian Chen, Shaoming Zhou, Wei Guo, Xianhai Zeng, Shuqi Qiu, C Andrew van Hasselt, Michael CF Tong, George G Chen
Hypoxia is widely known to be a key factor stimulating angiogenesis and contributes to chemotherapy resistance. It represents a common microenvironmental feature and a distinctive property of solid tumors, stemming from a lack in the supply of oxygen. Decreased oxygenation can result in various cellular responses that ultimately lead to either adaptation or cell death. Hypoxia selects cells with the low expression of p53 and consequently p53-induced apoptosis is reduced in hypoxic cells [40]. Cytoplasmic pattern recognition receptor nucleotide-binding domain and leucine-rich-repeat-containing family member ×1 (NLRX1) is tightly related to mitochondrial functions, reactive oxygen species (ROS) production, and autophagy. NLRX1 is able to potentiate the mitochondrial-derived ROS generation in response to cisplatin exposure in auditory HEI-OC1 cells. The inhibition of ROS generation has been shown to prevent the induction of autophagy and apoptosis in both HEI-OC1cells and cochlear explants treated with cisplatin [41]. Another factor associated with cisplatin resistance is P-glycoprotein (P-gp) that is also known as ahifs multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1). The downregulation of P-gp can reduce the cisplatin resistance whereas its upregulation promotes the resistance in several types of cancers including esophageal squamous cell carcinoma, leukemia, lung adenocarcinoma, oral cancer, ovarian cancer and steosarcoma [42,47]. Though cisplatin is not a direct substrate for P-gp, the decrease of P-gp, which can be caused by miR-130a downregulation [48], has been reported to modulate a number of molecules that reduce cell viability or/and promote apoptosis to increase the sensitivity of cancer cells to cisplatin treatment [45]. Firstly, the downregulation of P-gp can lead to the inhibition of NF-kB and MAPK-ERK pathways that may be induced by miR-205 [43,49]. Secondly, the downregulation of P-gp may activate c-June or/and caspase-3 to induce apoptosis [45]. Finally, the downregulation of P-gp can elicit the response to cisplatin probably via inhibiting the phosphorylation of AKT [44], and AKT is also a target of miR-125b [13].