Cancer is a leading cause of death and poor quality of life globally. Even though several strategies are devised to reduce deaths, reduce chronic pain and improve the quality of life, there remains a shortfall in the adequacies of these cancer therapies. Among the cardinal steps towards ensuring optimal cancer treatment are early detection of cancer cells and drug application with high specificity to reduce toxicities. Due to increased systemic toxicities and refractoriness with conventional cancer diagnostic and therapeutic tools, other strategies including nanotechnology are being employed to improve diagnosis and mitigate disease severity. Over the years, immunotherapeutic agents based on nanotechnology have been used for several cancer types to reduce the invasiveness of cancerous cells while sparing healthy cells at the target site. Nanomaterials including carbon nanotubes, polymeric micelles and liposomes have been used in cancer drug design where they have shown considerable pharmacokinetic and pharmacodynamic benefits in cancer diagnosis and treatment. In this review, we outline the commonly used nanomaterials which are employed in cancer diagnosis and therapy. We have highlighted the suitability of these nanomaterials for cancer management based on their physicochemical and biological properties. We further reviewed the challenges that are associated with the various nanomaterials which limit their uses and hamper their translatability into the clinical setting in certain cancer types.
Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.
Introduction: Ischemic stroke-induced inflammation and inflammasome-dependent pyroptotic neural death cause serious neurological injury. Nano-sized plasma exosomes have exhibited therapeutic potential against ischemia and reperfusion injury by ameliorating inflammation. To enhance its therapeutic potential in patients with ischemic injury, we isolated exosomes from melatonin-treated rat plasma and assessed the neurological protective effect in a rat model of focal cerebral ischemia. Methods: Basal plasma exosomes and melatonin-treated plasma exosomes were isolated and intravenously injected into a rat model of focal cerebral ischemia. Neurological recovery was evaluated by determining the modified neurological severity score (mNSS), infarct volume, and brain water content. Pyroptosis in the ischemic cortex was detected through dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) release, and gasdermin D (GSDMD) cleavage. NLRP3 inflammasome assembly and global inflammatory cytokine secretion were detected by enzyme-linked immunosorbent assay (ELISA) and Western blot assay. In immunized Sprague-Dawley rats, microglia pyroptosis was determined through a positive percentage of IBA1 + and caspase-1 (p20) + cells. Finally, the microRNA (miRNA) profiles in melatonin-treated plasma exosomes were analyzed by exosome miRNA microarray analysis. Results: Melatonin treatment enhanced plasma exosome therapeutic effects against ischemia-induced inflammatory responses and inflammasome-mediated pyroptosis. In addition, we confirmed that ischemic stroke-induced pyroptotic cell death occurred in the microglia and neuron, while the administration of melatonin-treated exosomes further effectively decreased the infarct volume and improved recovery of function via regulation of the TLR4/NF-κB signaling pathway. Finally, the altered miRNA profiles in the melatonin-treated plasma exosomes demonstrated the regulatory mechanisms involved in neurological recovery after ischemic injury.
Ischemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D (GSDMD) is a newly discovered key molecule of cell pyroptosis, but its biological function and precise role in ischemic stroke are still unclear. The present study investigates the cleavage activity of GSDMD, localization of pyroptotic cells, and global neuroinflammation in gsdmd−/− mice after I/R. The level of cell pyroptosis around the infarcted area was significantly increased in the acute phase of cerebral I/R injury. The ablation of GSDMD reduced the infraction volume and improved neurological function against cerebral I/R injury. Furthermore, we confirmed I/R injury induced cell pyroptosis mainly in microglia. Knockdown of GSDMD effectively inhibited the secretion of mature IL-1β and IL-18 from microglia cells but did not affect the expression of caspase-1/11 in vitro and in vivo. In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke.
Introduction To investigate the protective effect of VX‐765 on human umbilical mesenchymal stem cells (HUMSCs) in stroke and its mechanism. Materials and methods Mouse models of ischemic stroke were established using the distal middle cerebral artery occlusion (dMCAO) method. The dMCAO mice were accordingly transplanted with HUMSCs, VX‐765‐treated HUMSCs, or VX‐765 + MHY185‐treated HUMSCs. The HUMSCs were inserted with green fluorescent protein (GFP) for measurement of transplantation efficiency which was determined by immunofluorescence assay. Oxygen‐glucose deprivation (OGD) was applied to mimic ischemic environment in vitro experiments, and the HUMSCs herein were transfected with AMPK inhibitor Compound C or autophagy inhibitor 3‐MA. MTT assay was used to test the toxicity of VX‐765. TUNEL staining and ELISA were applied to measure the levels of apoptosis and inflammatory cytokines (IL‐1β, IL‐6, and IL‐10), respectively. The expressions of autophagy‐associated proteins, AMPK, and mTOR were detected by Western blotting. TTC staining was applied to reveal the infarct lesions in the brain of dMCAO mice. Results The pro‐inflammatory cytokines, TUNEL‐positive cells, and p‐mTOR were decreased while the anti‐inflammatory cytokine, autophagy‐related proteins, and p‐AMPK were increased in HUMSCs treated with VX‐765 under OGD condition. Different expression patterns were found with the above factors after transfection of 3‐MA or Compound C. The pro‐inflammatory cytokines, TUNEL‐positive cells, and infarct sections were decreased while the anti‐inflammatory cytokine and autophagy‐related proteins were increased in dMCAO mice transplanted with VX‐765‐treated HUMSCs compared to those transplanted with HUMSCs only. The autophagy was inhibited while p‐mTOR was up‐regulated after transfection of MHY. Conclusion VX‐765 protects HUMSCs against stroke‐induced apoptosis and inflammatory responses by activating autophagy via the AMPK/mTOR signaling pathway in vivo and in vitro.
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