Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review provides an overview of our current knowledge of MAP4K4 structure and expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling pathways and, in the future, will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. SIGNIFICANCE STATEMENT: Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 biology within the context of metabolic dysfunction and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver and metabolic diseases.

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease.

BACKGROUND: Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. METHODS: Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. RESULTS: There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. CONCLUSIONS: These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease.

Background: Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Methods: Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. Results: There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally-and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions: These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

Anxiolytic and Antidepressant Effects of Maerua angolensis DC. Stem Bark Extract in Mice.

INTRODUCTION: The stem bark extract of Maerua angolensis DC. (Capparaceae) is used as a traditional remedy for management of anxiety, psychosis, and epilepsy. AIM OF THE STUDY: We therefore aimed at evaluating the anxiolytic and antidepressant potential of the plant in mice models. METHODS: The dried stem bark was extracted with petroleum ether/ethyl acetate (50:50) mixture to obtain the extract, MAE. We employed Irwin's test to identify the preliminary behavioral and autonomic effects. Subsequently, MAE was administered per os to male mice and subsequently assessed, 1 h later, for anxiety parameters in the elevated plus maze (EPM) and the regular Suok tests. The forced swim (FST) and tail suspension (TST) tests were employed to assess the antidepressant potential of the extract (100-1000 mg kg-1). RESULTS: In our preliminary assay, MAE (100-5000 mg/kg) exhibited analgesic effects and a reduction in fear response in the Irwin's test. The spontaneous locomotor activity was reduced at 1000 mg/kg. Additionally, MAE (1000 mg/kg) increased the latency to PTZ-induced convulsions, and duration to sleep in the pentobarbitone induced sleeping time assay. MAE (1000 mg/kg), similar to diazepam, in the anxiolytic assay, increased the percentage time spent in the open arms while decreasing protected head dips and unprotected stretch attend postures in the EPM. Correspondingly, there was a reduction in anxiety-induced immobility and freezing in the Suok test (300 mg/kg) without loss of sensorimotor coordination. Additionally, there was a significant reduction in immobility duration in the FST (300 mg/kg) and TST (1000 mg/kg). CONCLUSION: The petroleum ether/ethyl acetate fractions of Maerua angolensis stem bark possess anxiolytic and acute antidepressant effects in mice.

Antipleuritic and Vascular Permeability Inhibition of the Ethyl Acetate-Petroleum Ether Stem Bark Extract of Maerua angolensis DC (Capparaceae) in Murine.

Maerua angolensis has been used traditionally in the management of pain, arthritis, and rheumatism in Ghana and Nigeria but no scientific evidence is currently available to give credence to its folkloric use. The aim of this study was therefore to evaluate the anti-inflammatory effects of a stem bark extract of Maerua angolensis DC (MAE) in acute inflammatory models. The effects of MAE (30-300 mg kg-1) on neutrophil infiltration, exudate volume, and endogenous antioxidant enzymes in lung tissues and lung morphology were evaluated with the carrageenan induced pleurisy model in Sprague Dawley rats. The effects of MAE (30-300 mg kg-1) on vascular permeability were also evaluated in the acetic acid induced vascular permeability in ICR mice. MAE significantly reduced neutrophil infiltration, exudate volume, and lung tissue damage in carrageenan induced pleurisy. MAE increased the activities of antioxidant enzymes glutathione, superoxide dismutase, and catalase in lung tissues. The extract was also able to reduce myeloperoxidase activity and lipid peroxidation in lung tissues in carrageenan induced rat pleurisy. Vascular permeability was also attenuated by the extract with marked reduction of Evans blue dye leakage in acetic acid induced permeability assay. The results indicated that Maerua angolensis is effective in ameliorating inflammation induced by carrageenan and acetic acid. It also has the potential of increasing the activity of endogenous antioxidant enzymes.

Maerua angolensis DC. (Capparaceae) Stem Bark Extract Protects against Pentylenetetrazole-Induced Oxidative Stress and Seizures in Rats.

INTRODUCTION: The stem bark of Maerua angolensis DC. (Capparaceae) is traditionally used for management of epilepsy. Our aim was to evaluate the antiseizure potential and identify possible mechanisms by which the effects are registered. METHODS: The petroleum ether/ethyl acetate extract (100-1000 mg kg-1) was administered per os to male Sprague-Dawley rats after pretreatment with flumazenil (0.3 mg kg-1) or L-arginine (150 mg kg-1) or sildenafil (5 mg kg-1) and they subsequently received a subcutaneous injection of pentylenetetrazole (65 mg kg-1). Rats were observed for latency to and duration of myoclonic seizures and additionally the level of protection against oxidant markers and products was assessed in vitro and in vivo. RESULTS: The extract (300 and 1000 mg kg-1, p.o.) significantly delayed the onset and decreased the duration and frequency of PTZ-induced convulsions. The anticonvulsant effect of MAE (300 mg kg-1, p.o.) was reversed by pretreatment with flumazenil, L-arginine, or sildenafil. Also, MAE (300 mg kg-1) treatment reversed significantly PTZ-induced oxidative stress in rat brain tissue. CONCLUSION: The petroleum ether/ethyl acetate fraction exhibits antiseizure activity by affecting GABAergic and nitric oxide-cGMP pathways. In addition, the extract protects against the generation of free radicals and the oxidative products of the PTZ-induced seizures.