Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis.

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice.

Enhancement of LC3-associated efferocytosis for the alleviation of intestinal inflammation.

LC3-associated phagocytosis (LAP) is an instrumental machinery for the clearance of extracellular particles including apoptotic cells for the alleviation of inflammation. While pharmacological approaches to modulate LAP for inflammation regulation have been poorly explored, in our study we identified a novel compound, columbamine (COL), which can trigger LAP and enhance efferocytosis in an animal model of colitis to attenuate inflammation. We found that COL directly binds to and biasedly activates FPR2 (formyl peptide receptor 2) to promote efferocytosis and alleviate colitis.

Molecular Modulators and Receptors of Selective Autophagy: Disease Implication and Identification Strategies.

Autophagy is a highly conserved physiological process that maintains cellular homeostasis by recycling cellular contents. Selective autophagy is based on the specificity of cargo recognition and has been implicated in various human diseases, including neurodegenerative diseases and cancer. Selective autophagy receptors and modulators play key roles in this process.

Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation.

Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis.

Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models.

Impairment of autophagy maturation has been implicated in Alzheimer's disease (AD) pathogenesis. However, the mechanism for this impairment has not been elucidated, and whether enhancing autophagy maturation is a viable therapeutic strategy for AD has not been verified. We examined the autophagosome maturation process in AD cell and mouse models by immunoblotting.

Pharmacological insights into autophagy modulation in autoimmune diseases.

As a cellular bulk degradation and survival mechanism, autophagy is implicated in diverse biological processes. Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), indicating that autophagy dysregulation may be involved in the development of autoimmune diseases. A series of autophagy modulators have displayed protective effects on autoimmune disease models, highlighting the emerging role of autophagy modulators in treating autoimmune diseases.

Ferulic Acid in Animal Models of Alzheimer's Disease: A Systematic Review of Preclinical Studies.

Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence in the elderly. Many preclinical studies show that a natural product, ferulic acid (FA), displays neuroprotective effects in AD models. This review aims to systematically review and meta-analyze published pre-clinical researches about the effects, mechanism, and clinical prospects of FA in the treatment of AD.

Spinal sensory neurons project onto the hindbrain to stabilize posture and enhance locomotor speed.

In the spinal cord, cerebrospinal fluid-contacting neurons (CSF-cNs) are GABAergic interoceptive sensory neurons that detect spinal curvature via a functional coupling with the Reissner fiber. This mechanosensory system has recently been found to be involved in spine morphogenesis and postural control but the underlying mechanisms are not fully understood. In zebrafish, CSF-cNs project an ascending and ipsilateral axon reaching two to six segments away.

Evaluate the performance of four artificial intelligence-aided diagnostic systems in identifying and measuring four types of pulmonary nodules.

Purpose: This study aims to evaluate the performance of four artificial intelligence-aided diagnostic systems in identifying and measuring four types of pulmonary nodules.

Methods: Four types of nodules were implanted in a commercial lung phantom. The phantom was scanned with multislice spiral computed tomography, after which four systems (A, B, C, D) were used to identify the nodules and measure their volumes.

[Application of unrestrained conscious rats with acute inflammatory ankle pain to study of acupuncture analgesia].

Objective: To compare the analgesic effect of manual acupuncture(MA) stimulation of "Zusanli" (ST36) in rats with inflammatory pain under unrestrained conscious, restrained and general anesthesia conditions, so as to explore the applicability of unrestrained conscious model in the evaluation of acupuncture analgesia effect.

Methods: Male SD rats were divided into 5 groups: blank control (=9), pain model (=7), unrestrained conscious conditions+MA (=6), restrained conditions+MA (=6), and general anesthesia (GA)+MA(=6). The acute pain model was established by injection of complete Freund's adjuvant (CFA) into the left ankle joint 48 h ahead of acupuncture.

NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation.

NRBF2 is a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Our previous study has revealed its role in regulating ATG14-associated PtdIns3K activity for autophagosome initiation. In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation.

PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation.

NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation.

Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson's disease models.

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models.

Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis.

Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function.

iNOS Interacts with Autophagy Receptor p62 and is Degraded by Autophagy in Macrophages.

Nitric oxide (NO) is an important mediator of inflammation response and the production of NO has been linked to a variety of diseases, including tumors, inflammation and central nervous system diseases. In macrophages, a high level of NO is generated by iNOS during inflammatory responses triggered by cytokines or pathogens. Autophagy, a cellular bulk degradation process via lysosome, has been implicated in many disease conditions including inflammation.

Neuroprotective effects of berberine in animal models of Alzheimer's disease: a systematic review of pre-clinical studies.

Background: Berberine is an isoquinoline alkaloid extracted from various Berberis species which is widely used in East Asia for a wide range of symptoms. Recently, neuroprotective effects of berberine in Alzheimer's disease (AD) animal models are being extensively reported. So far, no clinical trial has been carried out on the neuroprotective effects of berberine.

Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation.

Background: Parkinson's disease (PD) is an age-dependent progressive movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Accumulation of -synuclein (-syn) positive protein aggregates in the substantia nigra is a pathological hallmark of PD, indicating that protein turnover defect is implicated in PD pathogenesis.

Purpose: This study aims to identify neuroprotective compounds which can alleviate the accumulation of -syn in neuronal cells and dissect the underlying mechanisms.

High content screening for drug discovery from traditional Chinese medicine.

Traditional Chinese medicine (TCM) represents the crystallization of Chinese wisdom and civilization. It has been valued as the renewable source for the discovery of novel drugs, owing to its long-term proved efficacy in human diseases and abundant biologically active components pools. To dissect the mystery of TCM, modern technologies such as omics approaches (proteomics, genomics, metabolomics) and drug screening technologies (high through-put screening, high content screening and virtual screening) have been widely applied to either identify the drug target of TCM or identify the active component with certain bio-activity.

Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the ubiquitin-proteasome system has been linked to its accumulation. In this work, we developed a tetracycline-inducible expression system, with simultaneous induced expression of α-syn-EGFP and a bright red fluorescent protein marker (mCherry) to screen for potential compounds for degrading α-syn.

Selective autophagy: The new player in the fight against neurodegenerative diseases?

Autophagy is the lysosome-mediated bulk degradation of cellular components for material recycling to maintain cellular homeostasis. Autophagy was initially regarded as a nonselective process, however, recent evidence indicates that this process can in fact be highly selective, especially for targeting and degrading organelles, invading pathogens and protein aggregates. Recent studies have revealed an intrinsic connection between selective autophagy and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity.

Autophagy is a cellular bulk degradation pathway implicated in various diseases. Inhibition of autophagy has been regarded as a new therapeutic strategy for cancer treatment, especially in combination with chemotherapy. In our study, we identified two natural compounds, dauricine (DAC) and daurisoline (DAS), as two potent autophagy blockers through a high-content screening.

PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum.

Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum.

NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models.

Alzheimer disease (AD) is the most common neurodegenerative disease characterized by the deposition of amyloid plaque in the brain. The autophagy-associated PIK3C3-containing phosphatidylinositol 3-kinase (PtdIns3K) complex has been shown to interfere with APP metabolism and amyloid beta peptide (Aβ) homeostasis via poorly understood mechanisms. Here we report that NRBF2 (nuclear receptor binding factor 2), a key component and regulator of the PtdIns3K, is involved in APP-CTFs homeostasis in AD cell models.