Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.10.15.464493

Propionate ameliorates diabetes-induced neurological dysfunction through regulating the PI3K-AKT-eNOS signaling pathway

Wu, Q.·Dong, J.·Cheng, Y.·Jiang, G.
View original source ↗Export metadata ↓

Abstract

A large body of research has established diabetes-related cognitive deterioration, sometimes known as "diabetic encephalopathy." Current evidence supports that oxidative stress, neuronal apoptosis, and cerebral microcirculation weakness are associated with cognition deficits induced by diabetes. The present study explores the effect of propionate on neurological deficits, cerebral blood flow, and oxidative stress in diabetic mice. Propionate can markedly improve neurological function, which is correlated with its capabilities of stimulating nitric oxide (NO) production, increasing cerebral microcirculation, suppressing oxidative stress and reducing neuron loss in the hippocampus. In addition, the results of Western Blotting indicated that the brain-protective function of propionate in streptozocin (STZ)-induced insulin-dependent diabetes mellitus (IDDM) mice is related to phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase (Akt)/endothelial nitric oxide synthase(eNOS) signaling pathway. In a diabetic mouse model, propionate reduces cerebral microcirculation, hippocampus apoptosis, and neurological impairment. Thus, propionate, now employed as a food preservative, may also help slow diabetes-induced cognitive loss. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/464493v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@81fa09org.highwire.dtl.DTLVardef@1469451org.highwire.dtl.DTLVardef@b37fa1org.highwire.dtl.DTLVardef@8037e7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPropionate ameliorates diabetic-induced depression-like behavior, spatial learning and memory deficits. C_LIO_LIPropionate increases cerebral microcirculation by enhancing NO production in diabetic mice. C_LIO_LIPropionate suppresses oxidative stress and reduces neuron loss in the hippocampus. C_LIO_LIThe brain-protective function of propionate is related to PI3K/Akt/eNOS signaling pathway. C_LI

Source connections

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wu, Q., Dong, J., Cheng, Y., Jiang, G.. 2021-10-16. Propionate ameliorates diabetes-induced neurological dysfunction through regulating the PI3K-AKT-eNOS signaling pathway. https://doi.org/10.1101/2021.10.15.464493

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Electrically Enhanced Intraperitoneal Drug Delivery Resolved by Fluorescence Lifetime Imaging Microscopy

Intraperitoneal delivery of nanoparticles (NPs) holds promise in the treatment of peritoneal metastases (PM), and the use of electric fields may enhance their tissue penetration. Evaluating NP delivery requires evidence of intracellular payload release, which is challenging in autofluorescent tissues. Here, we combined electromotive drug administration (EMDA) with cationic RL-100 NPs co-loaded with doxorubicin (DOX) and a near-infrared aza-BODIPY tracer, reporting carrier-associated distribution, while phasor fluorescence lifetime imaging microscopy (FLIM) characterized the molecular environment of DOX. In colorectal carcinoma, NP-delivered DOX progressed from cytoplasmic puncta to nuclear accumulation, while carrier-associated fluorescence remained cytoplasmic, supporting intracellular release. EMDA enhanced NP penetration in ex vivo human peritoneum and healthy rat peritoneum. In a syngeneic rat model of colorectal PM, both free and NP-delivered DOX remained detectable to approximately 1200 um after EMDA, compared with < 200 um after passive delivery. NP-delivered DOX remained detectable 24 h after EMDA. Whole-animal and ex vivo imaging showed the highest carrier-associated signals in tumor nodules and tumor-bearing omentum. These findings support electrically enhanced intraperitoneal delivery and a dual-reporter approach to evaluate carrier distribution, drug penetration, and intracellular release, with potential applications in other autofluorescent tissues. Together, these capabilities provide a preclinical basis for investigating NP-assisted delivery.

pharmacology and toxicology↗
bioRxiv2026

A mechanistic classification of GNAO1 mutations links Gβ γ sequestration to hyperkinetic disease and treatment response

Go is the most prevalent G protein subunit in the brain and is critical for signal transduction through G protein-coupled receptors. Mutations in the gene encoding Go (GNAO1) cause a rare neurodevelopmental disorder with involuntary movements (NEDIM) and, in some patients, developmental and epileptic encephalopathy (DEE). Here, we integrate human genetic analysis with cellular assays to define mechanistic classes of GNAO1 mutations and in vivo approaches to evaluate therapeutic strategies. We grouped variants into two functional categories: those predicted to sequester G{beta}{gamma} and those with reduced Go expression and therefore increased G{beta}{gamma} signaling. Analysis of patient data revealed that mutations predicted to impair G{beta}{gamma} release are significantly associated with NEDIM. Using the GNAO1R209H/+ mouse as a model of NEDIM, we evaluated two small molecules: caffeine, a nonselective adenosine receptor antagonist, and gallein, a selective modulator of G{beta}{gamma}-effector interactions. Both compounds significantly reduced hyperlocomotion in the open field test. Whole-cell patch-clamp electrophysiology revealed sex- and cell type-specific hyperexcitability in spiny projection neurons within the dorsolateral striatum of GNAO1R209H/+ mice. Together, these findings implicate dysfunction of dorsolateral striatal pathways in GNAO1-related disorder and suggest that mechanistic understanding of disease variants can guide targeted therapeutic strategies.

pharmacology and toxicology↗
bioRxiv2026

Screening and evaluation of medicine food homology herbal combinations for ameliorating chemotherapy induced ovarian aging under an integrated multi-strategy framework

Abstract Background: Ovarian aging poses a serious threat to women's reproductive health. Medicine food homology (MFH) herbs, owing to their favorable safety profile and suitability for long-term use, have become important interventional resources. However, conventional formula screening relies largely on empirical statistics and lacks mechanistic evidence and a systematic screening strategy. Methods: In this study, we integrated single cell transcriptomic analysis, human use evidence mining, UPLC/Q TOF MS chemical profiling and pretrained protein molecular representation models to establish a multi strategy framework for the discovery of MFH herbal combinations. Single cell transcriptomic datasets related to ovarian aging from the GEO database were analyzed to identify key pathological processes and candidate targets. High-frequency MFH herbs were selected by mining classical prescriptions and clinical literature. By comparing six protein molecular pretrained representation combinations, ESM T5 was identified for compound target affinity prediction and validated by molecular dynamics simulation and surface plasmon resonance (SPR) assays, ultimately identifying the Astragalus ginseng (Huangqi Renshen) herb pair (HXF) as the core candidate. Functional expression validation of key targets was performed, and the efficacy of HXF and the expression of related molecules were verified in a D gal induced KGN granulosa cell senescence model and a cyclophosphamide-induced rat model of diminished ovarian function. Results: Single cell analysis revealed that ovarian aging was characterized by impaired steroidogenesis, enhanced MDK NCL communication between granulosa cells and immune cells, and extracellular matrix remodeling, with CYP19A1, SERPINE1 and MDK as key targets. By further integrating human-use evidence mining and UPLC/Q TOF MS compound annotation, an MFH compound library comprising 712 molecules was established. ESM T5 prediction, molecular dynamics (MD) simulation and SPR assays confirmed that multiple constituents of Astragalus and ginseng exhibited favorable binding activity toward key targets. At the cellular level, knockdown of MDK or SERPINE1 attenuated the senescence phenotype, whereas knockdown of CYP19A1 aggravated it. In vitro and in vivo experiments demonstrated that Astragalus ginseng ameliorated granulosa cell senescence and diminished ovarian function in rats, restored CYP19A1 related steroidogenesis, downregulated inflammation- and matrix remodeling related molecules such as SERPINE1 and IL18, and reduced MDK NCL colocalization signals. Conclusion: This study established a multi-strategy screening framework integrating disease mechanism decoding, human use evidence constraints and pretrained model prediction, and identified Astragalus ginseng as a candidate herb pair for ameliorating ovarian aging. Its effects may be associated with promoting steroidogenesis, suppressing SERPINE1/IL18 related inflammation and matrix remodeling, and modulating MDK NCL signaling. These findings provide a strategic reference for the mechanism oriented discovery of MFH herbal combinations.

pharmacology and toxicology↗