Kai Zhou

Bio: Kai Zhou is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Microglia & Programmed cell death. The author has an hindex of 13, co-authored 22 publications receiving 468 citations. Previous affiliations of Kai Zhou include Karolinska University Hospital & University of Gothenburg.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Abstract: Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

Uncovering sex differences of rodent microglia.

Abstract: There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.

Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum

Abstract: Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient’s quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.

Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia.

Abstract: // Wei Han 1,2,3 , Takashi Umekawa 3,4 , Kai Zhou 3 , Xing-Mei Zhang 5 , Makiko Ohshima 3 , Cecilia A Dominguez 3 , Robert A Harris 5 , Changlian Zhu 2,6 and Klas Blomgren 3,7 1 Department of Pediatrics, Henan Provincial Women’s and Children’s Hospital, Zhengzhou, PR China 2 Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China 3 Karolinska Institutet, Department of Women’s and Children’s Health, Stockholm, Sweden 4 Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Tsu, Japan 5 Karolinska Institutet, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden 6 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden 7 Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden Correspondence to: Klas Blomgren, email: // Changlian Zhu, email: // Keywords : irradiation, neurogenesis, neuroinflammation, microglia, monocyte, macrophage Received : August 11, 2016 Accepted : October 13, 2016 Published : October 26, 2016 Abstract The relative contribution of resident microglia and peripheral monocyte-derived macrophages in neuroinflammation after cranial irradiation is not known A single dose of 8 Gy was administered to postnatal day 10 (juvenile) or 90 (adult) CX3CR1 GFP/+ CCR2 RFP/+ mouse brains Microglia accumulated in the subgranular zone of the hippocampal granule cell layer, where progenitor cell death was prominent The peak was earlier (6 h vs 24 h) but less pronounced in adult brains The increase in juvenile, but not adult, brains was partly attributed to proliferation Microglia numbers then decreased over time to 39% (juvenile) and 58% (adult) of controls 30 days after irradiation, largely as a result of cell death CD68 was expressed in 90% of amoeboid microglia in juvenile hippocampi but only in 9% of adult ones Isolated hippocampal microglia revealed reduced CD206 and increased IL1-beta expression after irradiation, more pronounced in juvenile brains CCL2 and IL-1 beta increased after irradiation, more in juvenile hippocampi, and remained elevated at all time points In summary, microglia activation after irradiation was more pronounced, protracted and pro-inflammatory by nature in juvenile than in adult hippocampi Common to both ages was long-lasting inflammation and the absence of monocyte-derived macrophages

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Molecular definitions of autophagy and related processes

Abstract: Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles.

Abstract: Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics However, such efforts have not yet generated clinically viable interventions In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic

Life, death and autophagy.

Abstract: Autophagy influences cell survival through maintenance of cell bioenergetics and clearance of protein aggregates and damaged organelles Several lines of evidence indicate that autophagy is a multifaceted regulator of cell death, but controversy exists over whether autophagy alone can drive cell death under physiologically relevant circumstances Here, we review the role of autophagy in cell death and examine how autophagy interfaces with other forms of cell death including apoptosis and necrosis