Efgartigimod versus intravenous immunoglobulin in the treatment of patients with impending myasthenic crisis.

Impending myasthenic crisis (IMC) is an emergent situation requiring aggressive management to prevent patients from developing myasthenic crisis (MC) in patients with myasthenia gravis (MG). Efgartigimod has been proved to be well tolerated and efficacious in MG patients. The present study aimed to compare the efficacy of efgartigimod and intravenous immunoglobulin (IVIg) in rescuing IMC.

TBK1 is involved in M-CSF-induced macrophage polarization through mediating the IRF5/IRF4 axis.

TANK binding kinase 1 (TBK1) is an important kinase that is involved in innate immunity and tumor development. Macrophage colony-stimulating factor (M-CSF) regulates the differentiation and function of macrophages towards the immunosuppressive M2 phenotype in the glioblastoma multiforme microenvironment. The role of TBK1 in macrophages, especially in regulating macrophage polarization in response to M-CSF stimulation, remains unclear.

Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.

Background: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.

Methods: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.

OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear.

Sodium formononetin-3'-sulphonate alleviates cerebral ischemia-reperfusion injury in rats via suppressing endoplasmic reticulum stress-mediated apoptosis.

Background: Sodium formononetin-3'-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia-reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis.

IRF5 knockdown reverses TDP-related phenotypes partially by increasing TBK1 expression.

Interferon-regulatory factor 5 (IRF5) participates in the regulation of apoptosis, affects the phenotype of inflammatory macrophages and plays an essential role in the inflammatory response. However, the role of IRF5 in the progression of amyotrophic lateral sclerosis (ALS) remains largely unknown. Here, we show that IRF5 mainly accumulated in the nucleus in cells expressing the truncated 25 k C-terminal fragments of TDP-43 (TDP-25, named TDP-25 cells hereafter).

Herbal medicine for amyotrophic lateral sclerosis: A systematic review and meta-analysis.

The effect of herbal medicine (HM) on amyotrophic lateral sclerosis (ALS) is controversial. Clinical trials investigating HMs continue; however, the use of HM is still questioned. We aimed to systematically review the literature pertaining to the effects and safety of HM in ALS.

Deletion of FGF9 in GABAergic neurons causes epilepsy.

Fibroblast growth factor 9 (FGF9) has long been assumed to modulate multiple biological processes, yet very little is known about the impact of FGF9 on neurodevelopment. Herein, we found that loss of Fgf9 in olig1 progenitor cells induced epilepsy in mice, with pathological changes in the cortex. Then depleting Fgf9 in different neural populations revealed that epilepsy was associated with GABAergic neurons.

Myeloid TBK1 Deficiency Induces Motor Deficits and Axon Degeneration Through Inflammatory Cell Infiltration.

Background: TANK-binding kinase1 (TBK1) haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear.

Methods: Myeloid Tbk1 knockout mice (Tbk1-LKO mice) were established and motor function and pathological analyses were also performed. The level of p-TBK1 was analyzed in the ALS animal model and in patient samples using flow cytometry.

Myeloid NEMO deficiency promotes tumor immunosuppression partly via MCP1-CCR2 axis.

Tumor-associated macrophages (TAM), which are found in the tumor microenvironment of solid tumors, not only mediate cancer immune evasion but also promote tumor growth. The transcription factor NF-κB, which is a crucial link between inflammation and tumors, can accelerate tumor occurrence and development. NEMO, the regulatory subunit of the IKK complex, plays a pivotal role in activating the NF-κB signaling pathway.

The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model.

The superoxide dismutase 1 (SOD1) mutation is one of the most notable causes of amyotrophic lateral sclerosis (ALS), and modifying the mutant SOD1 gene is the best approach for the treatment of patients with ALS linked to the mutations in this gene. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas9)/sgRNA delivered by the adeno-associated virus (AAV) system is a powerful tool for genome editing in the central nervous system (CNS). Here, we tested the capacity of the AAV-SaCas9-sgRNA system to modify mutant SOD1 in SOD1G93A transgenic mice and found that AAV9-SaCas9-sgRNA5 deleted the SOD1 gene, improved the lifespan of SOD1G93A mice by 54.

FGF9 knockout in GABAergic neurons induces apoptosis and inflammation via the Fas/caspase-3 pathway in the cerebellum of mice.

Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family and is widely expressed in the central nervous system (CNS). However, it is not clear how the working mechanism of FGF9 is involved in cerebellar development. To address this question, we deleted the Fgf9 gene specifically in GABAergic neurons or glutamatergic neurons, and demonstrated that Fgf9 ablation in GABAergic neurons rather than the glutamatergic neurons caused severe ataxia.

FGF9 alters the Wallerian degeneration process by inhibiting Schwann cell transformation and accelerating macrophage infiltration.

In vitro experiments have proved that Fibroblast Growth Factor 9 (FGF9) was decreased in Schwann cells (SCs) in which Wallerian degeneration (WD) occurred after nerve injury. We hypothesize that FGF9 downregulation in WD has some biological influence on Schwann cells (SCs) and macrophages - the two most important cell components involved in WD. In this study, we employed strategies to regulate FGF9 in sciatic nerve crush by generating a mouse model, wherein Fgf9 was specifically knocked-out in SCs, and an intraneural injection of human FGF9 protein administered to overexpress FGF9 independently.

Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice.

Haploinsufficiency of the protein kinase Tbk1 has shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the pathogenic mechanisms are unclear. Here we show that conditional neuronal deletion of Tbk1 in leads to cognitive and locomotor deficits in mice. Tbk1-NKO mice exhibited numerous neuropathological changes, including neurofibrillary tangles, abnormal dendrites, reduced dendritic spine density, and cortical synapse loss.

The role of insulin-like growth factor 1 in ALS cell and mouse models: A mitochondrial protector.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder, but little is known about the exact causes and pathophysiology of this disease. In transgenic mouse models of ALS, mitochondrial abnormalities develop during the disease and might contribute to the progression of ALS. Gene therapy was recently shown to induce beneficial effects.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis.

Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia.

Diallyl Trisulfide Protects Motor Neurons from the Neurotoxic Protein TDP-43 via Activating Lysosomal Degradation and the Antioxidant Response.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease for which only limited effective therapeutics are available. Currently, TAR DNA-binding protein 43 (TDP-43) is recognized as a pathological and biochemical marker for ALS. Increases in the levels of aggregated or mislocalized forms of TDP-43 might result in ALS pathology.

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro-inflammatory environment during injury.

Myelin sheath is critical for the proper functioning of the peripheral nervous system (PNS), which allows the effective conduction of nerve impulses. Fibroblast growth factor 9 (FGF9) is an autocrine and paracrine protein in the fibroblast growth factor family that regulates cell differentiation and proliferation. Fgf9 Schwann cell (SC) conditional knockout mice were developed to detect the role of FGF9 in the PNS.

scAAV9-VEGF-165 inhibits neuroinflammatory responses and invasion of macrophages into the peripheral nervous system of ALS transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to paralysis and death within 3-5 years. Although the vast majority of studies have focused on vulnerable neurons, growing evidence has shown that non-neuronal cells contribute to the pathogenesis and disease progression. Here, we showed that intrathecal injection of scAAV9-VEGF at 60 days of age significantly reduced the number of microglia and inhibited the neuroinflammatory response in the CNS.

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Background: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves.

Methods: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM).

Schwann Cell Plasticity is Regulated by a Weakened Intrinsic Antioxidant Defense System in Acute Peripheral Nerve Injury.

The biological effects of the transcription factor NF-E2-related factor 2 (Nrf2) in acute peripheral nervous system (PNS) injury have not been adequately elucidated. By analyzing the results of Nrf2 knockout and Nrf2 activation experiments, we found the following: (1) the antioxidant system was rapidly inactivated after acute PNS injury in a partly Nrf2-dependent manner, giving rise to a temporary state of oxidative stress, and then slowly and partially recovered following regeneration. (2) Nrf2 knockout promoted the reprogramming and proliferation of Schwann cells and inhibited myelination, as well as the redifferentiation of repair Schwann cells.

Systemic administration of scAAV9-IGF1 extends survival in SOD1 ALS mice via inhibiting p38 MAPK and the JNK-mediated apoptosis pathway.

Amyotrophic lateral sclerosis (ALS) is closely associated with a reduction of neurotrophic factors in the central nervous system (CNS). Insulin-like growth factor 1 (IGF1)-encoding vectors delivered via intramuscular and intraparenchymal spinal cord injections have conferred therapeutic benefits in ALS model mice, although the development of a noninvasive delivery route is still needed. Intravenous administration of adeno-associated virus (AAV) vectors has been used to induce expression of neurotrophic genes in the lumbar spinal cords of adult mice.

Intrathecal Injection of scAAV9-hIGF1 Prolongs the Survival of ALS Model Mice by Inhibiting the NF-kB Pathway.

Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons. Currently, there is no effective drug for ALS. Recent studies in ALS model mice have shown that insulin-like growth factor-1 (IGF1) may be a promising therapeutic drug.

Adeno-associated virus serotype 9 mediated vascular endothelial growth factor gene overexpression in mdx mice.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Vascular endothelial growth factor (VEGF) is a heparin-binding dimeric glycoprotein and principal angiogenic factor stimulating the migration, proliferation and expression of various genes in endothelial cells. Recently, VEGF was demonstrated to exhibit an antiapoptotic and direct myogenic effect, as well as to enhance muscle force restoration subsequent to traumatic injury.