Brain–gut axis after stroke

Stroke leads to inflammatory and immune response in the brain and immune organs. The gut or gastrointestinal tract is a major immune organ equipped with the largest pool of immune cells representing more than 70% of the entire immune system and the largest population of macrophages in the human body. The bidirectional communication between the brain and the gut is commonly known as brain–gut or gut–brain axis. Stroke often leads to gut dysmotility, gut microbiota dysbiosis, “leaky” gut, gut hemorrhage, and even gut-origin sepsis, which is often associated with poor prognosis. Emerging evidence suggests that gut inflammatory and immune response plays a key role in the pathophysiology of stroke and may become a key therapeutic target for its treatment. Ischemic brain tissue produces damage-associated molecular patterns to initiate innate and adaptive immune response both locally and systemically through the specialized pattern-recognition receptors (e.g., toll-like receptors). After stroke, innate immune cells including neutrophils, microglia or macrophages, mast cells, innate lymphocytes (IL-17 secreting γδ T-cell), and natural killer T-cell respond within hours, followed by the adaptive immune response through activation of T and B lymphocytes. Subpopulations of T-cells can help or worsen ischemic brain injury. Pro-inflammatory Th1, Th17, and γδ T-cells are often associated with increased inflammatory damage, whereas regulatory T-cells are known to suppress postischemic inflammation by increasing the secretion of anti-inflammatory cytokine IL-10. Although known to play a key role, research in the gut inflammatory and immune response after stroke is still in its initial stage. A better understanding of the gut inflammatory and immune response after stroke may be important for the development of effective stroke therapies. The present review will discuss recent advances in the studies of the brain–gut axis after stroke, the key issues to be solved, and the future directions

Autophagy and protein aggregation after brain ischemia

Autophagy is the main degradation pathway responsible for eliminating abnormal protein aggregates and damaged organelles prevalent in neurons after transient cerebral ischemia. This study investigated whether accumulation of protein aggregate-associated organelles in postischemic neurons is a consequence of changes in autophagy. Electron microscopic (EM) analysis indicated that both autophagosomes (AP) and autolysosomes (AL) are significantlly upregulated in hippocampal CA1 and DG neurons after ischemia. The LC3-II conjugate, a marker for APs assessed by Western blotting, was upregulated in postischemic brain tissues. Confocal microscopy showed that LC3 isoforms were located in living postischemic neurons. Treatment with chloriquine (CQ) resulted in accumulation of LC3-II in sham-operated rats, but did not further change the LC3-II levels in postischemic brain tissues. The results indicate that at least part of the accumulation of protein aggregate-associated organelles seen following ischemia is likely to be due to failure of the autophagy pathway. The resulting protein aggregation on subcellular organelle membranes could lead to multiple organelle damage and to delayed neuronal death after transient cerebral ischemia

Adjunctive Nutraceutical Therapies for COVID-19

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19), is a worldwide pandemic, as declared by the World Health Organization (WHO). It is a respiratory virus that infects people of all ages. Although it may present with mild to no symptoms in most patients, those who are older, immunocompromised, or with multiple comorbidities may present with severe and life-threatening infections. Throughout history, nutraceuticals, such as a variety of phytochemicals from medicinal plants and dietary supplements, have been used as adjunct therapies for many disease conditions, including viral infections. Appropriate use of these adjunct therapies with antiviral proprieties may be beneficial in the treatment and/or prophylaxis of COVID-19. In this review, we provide a comprehensive summary of nutraceuticals, such as vitamins C, D, E, zinc, melatonin, and other phytochemicals and function foods. These nutraceuticals may have potential therapeutic efficacies in fighting the threat of the SARS-CoV-2/COVID-19 pandemic

Protein kinase C is translocated to cell membranes during cerebral ischemia

The subcellular distribution of PKC(α) and PKC(γ) was studied in homogenates of cerebral cortex from rats subjected to 10 and 15 min of ischemia and 15 min of ischemia followed by 1 h, 6 h, 24 h, 48 h, and 7 days of reperfusion. During ischemia no significant changes in the levels of PKC (α) were seen. During the first hour of reperfusion, a transient 2.5-fold (P < 0.05) increase in PKC(α) levels was observed in the particulate fraction. In contrast, a three-fold increase of PKC(γ) in the particulate fraction concomitant with a 40% decrease in the cytosol was noted during ischemia. In the postischemic phase the levels in the cytosol decreased to 35% of control values at 2 days following ischemia, with a concomitant decrease in the particulate fraction to control levels. The redistribution of PKC to the cell membranes during and following ischemia could be due to ischemia induced receptor activation, increased levels of diacylglycerols, arachidonate and intracellular calcium, and may be of importance for the development of ischemic neuronal damage

Combining erythropoeitin and bone marrow stromal cell therapy after stroke

Both Erythropoietin (EPO) and bone marrow stromal cells (BMSCs) have been shown to improve outcome after stroke. EPO may improve outcome after stroke through its actions on blood progenitor cells, angiogenesis, or direct action in the CNS. BMSCs may improve outcome after stroke by regeneration, altering plasticity of viable cells, or prevention of cell death. Sorting out these potential modes of actions for EPO and BMSCs has been difficult using in vivo models of stroke. This study investigated neuroprotection afforded by EPO, BMSCs and the combination of these modalities in mouse hippocampal slice cultures after oxygen glucose deprivation (OGD). Significant neuroprotection was observed following post-injury treatment of slice cultures with BMSCs and neuroprotection was augmented by treating BMSCs with EPO. EPO alone did not protect neurons from OGD when given after injury, but was effective when given prior to OGD. The failure of EPO to protect when given after injury did not appear to result from its inability to activate EPO signaling pathways involving phosphorylation of Akt. This study supports the implication that BMSCs may rescue dying neurons after ischemia by providing trophic support. The data also show that EPO’s actions as a neuroprotective agent following stroke may be mediated by its actions on BMSCs

Cathepsin B knockout confers significant brain protection in the mouse model of stroke

BackgroundSignificant advances have been made in our understanding of the endolysosomal cycle. Disruption of this cycle leads to cell death. The objective of this study aims to investigate the role of disrupted endolysosomal cycle in brain ischemia-reperfusion injury.MethodsA total of 57 mice were randomly assigned into four experimental groups: (i) wildtype (wt) sham control; (ii) wt middle cerebral artery occlusion (MCAO); (iii) cathepsin B (CTSB) knockout (KO) sham control; and (iv) CTSB KO MCAO. Mice were subjected either to 0&nbsp;min (sham) or 40&nbsp;min of MCAO, followed by reperfusion for 1 or 7&nbsp;days. Physical and behavioral examinations were conducted in the 7-day reperfusion group for 7 consecutive days after MCAO. Confocal microscopy was used to assess the levels, redistributions, and co-localizations of key endolysosomal cycle-related proteins. Histopathology was examined by light microscopy.ResultsConfocal microscopy revealed a significant accumulation of CTSB in post-ischemic penumbral neurons relative to those in the sham group. In addition, N-ethylmaleimide sensitive factor ATPase (NSF) was irreversibly depleted in these neurons. Furthermore, CTSB-immunostained structures were enlarged and diffusely distributed in both the cytoplasm and extracellular space, indicating the release of CTSB from post-ischemic neurons. Compared to wt mice, CTSB KO mice showed a significant decrease in hippocampal injury area, a significant increase in the number of survival neurons in the striatal core area, and a significant improvement in physical and functional performance in post-MCAO mice.ConclusionBrain ischemia leads to a cascade of events leading to inactivation of NSF, disruption of the endolysosomal cycle, endolysosomal structural buildup and damage, and the release of CTSB, eventually resulting in brain ischemia reperfusion injury. CTSB KO in mice protected the brain from ischemia-reperfusion injury

Changes in autophagy after traumatic brain injury

Autophagy is the chief machinery for bulk degradation of superfluous or aberrant cytoplasmic components. This study used the rat moderate fluid percussion injury model to investigate whether the autophagy pathway plays a key role after traumatic brain injury (TBI). Induction of autophagy is manifested by accumulation of autophagosomes (APs), observable under transmission electron microscopy (EM). Two hallmarks of autophagy, i.e., the microtubule-associated protein light chain 3 (LC3)-II and the autophagy-related gene (ATG)12-ATG5 conjugates, were explored by biochemical and confocal microscopic analyses of brain tissues. Under EM, both APs and autolysosomes were markedly accumulated in neurons from 4 h onward after TBI. Western blot analysis showed that ATG12-ATG5 conjugate was markedly redistributed during 5 to 15 days in brain tissues after TBI. LC3-II conjugate was initially unchanged but was drastically upregulated from 24 h onward in the pre-AP-containing fraction after TBI. LC-3 immunostaining was mainly located in living neurons under confocal microscopy. These results clearly show that the autophagy pathway is persistently activated after TBI. Because the autophagy pathway is the chief machinery for bulk elimination of aberrant cell components, we propose that activation of this pathway serves as a protective mechanism for maintaining cellular homeostasis after TBI