From a Novel

Autophagy in ischemic stroke.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Guidelines for the use and interpretatoin of assays for monitoring autophagy

Advances in stroke pharmacology.

Bone metabolic disorders include osteolysis, osteoporosis, osteoarthritis and rheumatoid arthritis. Osteoblasts and osteoclasts are two major types of cells in bone constituting homeostasis. The imbalance between bone formation by osteoblasts and bone resorption by osteoclasts has been shown to have a direct contribution to the onset of these diseases. Recent evidence indicates that autophagy and mitophagy, the selective autophagy of mitochondria, may play a vital role in regulating the proliferation, differentiation and function of osteoblasts and osteoclasts. Several signaling pathways, including PINK1/Parkin, SIRT1, MAPK8/FOXO3, Beclin-1/BECN1, p62/SQSTM1, and mTOR pathways, have been implied in the regulation of autophagy and mitophagy in these cells. Here we review the current progress about the regulation of autophagy and mitophagy in osteoblasts and osteoclasts in these bone metabolic disorders, as well as the molecular signaling activated or deactivated during this process. Together, we hope to draw attention to the role of autophagy and mitophagy in bone metabolic disorders, and their potential as a new target for the treatment of bone metabolic diseases and the requirements of further mechanism studies.

/pdf/the-role-of-autophagy-and-mitophagy-in-bone-metabolic-3jx4qzu9om.pdf

The Role of Autophagy and Mitophagy in Bone Metabolic Disorders.

Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO2 during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PA...

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2016.1274596

PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window

Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion exhibits progressive white matter and cognitive impairments. However, its pathogenetic mechanisms are poorly understood. We investigated the role of interleukin-1β (IL-1β) and its receptor IL-1 receptor type 1 (IL-1R1) in an experimental SIVD model generated via right unilateral common carotid arteries occlusion (rUCCAO) in mice. We found that IL-1β expression was elevated in the corpus callosum at the early stages after rUCCAO. IL-1 receptor antagonist (IL-1Ra), when delivered at an early stage, as well as IL-1R1 knockout, rescued the downregulation of myelin basic protein (MBP) and improved remyelination at the later stage after rUCCAO. Our data suggest that the recruitment of OPCs, but not the proliferation or differentiation of OPCs, is the only compromised step of remyelination following chronic cerebral ischemia. IL-1Ra treatment and IL-1R1 knockout had no effect on the oligodendrocyte progenitor cell (OPC) proliferation, but did promote the recruitment of newly generated OPCs to the corpus callosum, which can be reversed by compensatory expression of IL-1R1 in the SVZ of IL-1R1 knockout mice. Further, we found that recruited OPCs contribute to oligodendrocyte regeneration and functional recovery. In transwell assays, IL-1β inhibited OPC migration through IL-1R1. Moreover, KdPT which can enter the brain to block IL-1R1 also showed comparable protection when intraperitoneally delivered. Our results suggest that IL-1β during the early stages following chronic cerebral hypoperfusion impedes OPC recruitment via IL-1R1, which inhibits white matter repair and functional recovery. IL-1R1 inhibitors may have potential uses in the treatment of SIVD.

Interleukin-1β impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits. 

Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

BACKGROUND
Interstitial lung disease (ILD) was a relatively common cause of drug-induced mortality. However, the safety profile of the whole TKIs induced ILD was largely unknown.


RESEARCH DESIGN AND METHODS
The reported cases of ILD associated with TKIs were downloaded from the FDA adverse event reporting system (FAERS) database between 1 January 2004 and 30 April 2022 to detect ILD signals by disproportionality analysis. Furthermore, the fatality rate and time to onset (TTO) of various TKIs were also calculated.


RESULTS
The median age of total 2999 reported cases was 67. The largest reported cases came from osimertinib (n = 736, 24.5%). However, gefitinib had the highest ROR of 12.47 (11.4, 13.64) and IC of 3.53 (3.23, 3.86), means the strongest association with ILD. Trametinib, vemurafenib, larotectinib, selpercatinib, and cabozantinib did not show ILD signal. The median age of dead cases was 72 (Q1:62, Q3:83), and 53.02% (n = 579) were female and 41.11% (n = 449) were male. MET group showed the highest fatality rate of 55.17% with the shortest median TTO of 21 days (Q1: 8.5, Q3: 35.5).


CONCLUSIONS
TKIs were significantly associated with ILD. More attention should be paid to female, older, MET group with shorter TTO, as their prognosis might be worse.

Tyrosine kinase inhibitors-associated interstitial lung disease used in non-small cell lung cancer: a pharmacovigilance analysis based on the FDA adverse event reporting system database.

Yiting Zhou

Papers

PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window

Interleukin-1β impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion.

Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

Tyrosine kinase inhibitors-associated interstitial lung disease used in non-small cell lung cancer: a pharmacovigilance analysis based on the FDA adverse event reporting system database.