Biology subjects

Ke, B.

Publications and source records attributed to Ke, B..

8 recordsLinked to original sources

bioRxiv2026

A Novel Hydrogen Polysulfide Donor Alleviates Neuropathic Pain by Enhancing A-Type Potassium Currents via LIMK1-Cofilin Mediated Interaction between Filamin A and Kv4.2

Hydrogen persulfide (H2S2) is an important endogenous signaling molecule, holding significant therapeutic potential across diverse disease models due to its potent antioxidant and redox-regulating properties. Herein, we report the synthesis, characterization, and in vivo evaluation of an esterase responsive H2S2 donor, HPD1. It reduced mechanical and cold allodynia at 14 mg/kg (i.p.) in chronic constriction injury and paclitaxel-induced neuropathic pain models. Moreover, HPD1 exhibited negligible systemic toxicity and behavioral side effects even at 28 mg/kg. Electrophysiological tests showed that HPD1 suppressed PTX-induced hyperexcitability in dorsal root ganglion (DRG) neurons by specifically potentiating A-type potassium currents (IA). Mechanistically, we demonstrate that HPD1 activates LIMK1, which inactivates cofilin and stabilizes F-actin, thereby promoting the interaction between the actin-binding protein Filamin A and Kv4.2. Furthermore, both the HPD1-induced increase in Filamin A-Kv4.2 co-localization and the subsequent restoration of IA density in DRG neurons, as well as the analgesic effect of HPD1 were dampened by pharmacological inhibition of LIMK1 with BMS-5. This work has developed a new generation of H2S2 donors, demonstrated the analgesic efficacy of HPD1, and uncovered the novel LIMK1-cofilin-Filamin A-Kv4.2 dependent mechanism that restores IA, thus providing a reliable therapeutic strategy for neuropathic pain based on H2S2 donors.

pharmacology and toxicology↗

bioRxiv2026

Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Pharmacological control of emergence from general anesthesia remains strikingly limited. Clinically available antagonists are largely drug-class specific, leaving recovery dependent on anesthetic clearance rather than to an actively programmable switch in brain state. Through phenotypic screening of a structurally diverse natural-product library, we identified BN3 (L-(-)-camphor) as a broad-spectrum emergence agent. BN3 robustly shortened recovery from propofol anesthesia across species--from mice and rats to rabbits, dogs, and rhesus monkeys--and remained effective after continuous infusion. In rodents, BN3 also accelerated emergence from mechanistically distinct anesthetics, including etomidate, remimazolam, sodium {gamma} - hydroxybutyrate, midazolam, ketamine, sodium pentobarbital, and isoflurane. EEG recordings revealed a rapid cortical shift from slow-wave dominance to a wake-like high-frequency spectrum. Mechanistically, BN3 preferentially recruited ventral tegmental area (VTA) glutamatergic neurons: chemogenetic silencing abolished the BN3-evoked EEG spectral shift and strongly attenuated behavioral acceleration of emergence, whereas optogenetic activation of these neurons was sufficient to promote recovery. BN3 increased glutamate release in the nucleus accumbens and medial prefrontal cortex, and projection-specific inhibition of VTA[->]NAc or VTA[->]mPFC outputs blunted BN3-induced emergence. These findings define a VTA-centered glutamatergic arousal circuit that can be pharmacologically recruited as a common gateway for anesthetic-independent emergence.

neuroscience↗

bioRxiv2026

TRPV4 Inhibition by a Natural Product Mediates Analgesia

The transient receptor potential vanilloid 4 (TRPV4) channel, a polymodal calcium-permeable cation channel, is activated by diverse stimuli, including hyposmolarity, moderate heat, mechanical stress, and acidic pH. TRPV4 plays a critical role in the onset and progression of pain and is implicated in multiple pathological conditions, positioning it as an attractive therapeutic target. However, the development of TRPV4-targeted therapeutics has been hindered by limited mechanistic understanding of its inhibition. Here, the natural product (R)-1-(3-ethylphenyl)ethane-1,2-diol (AH001) is identified as a potent, subtype-selective TRPV4 inhibitor. A potential gating mechanism of TRPV4 inhibition is proposed through a combination of structural analyses and site-directed mutagenesis. Electrophysiological studies and cryo-electron microscopy (cryo-EM) further reveal that AH001s glucuronide metabolite, AHP, retains robust TRPV4 inhibitory activity, providing a critical structural basis for rational optimization of AH001 as a lead compound. Notably, AH001 demonstrated significant efficacy in reducing neuronal hyperexcitability in dorsal root ganglia (DRGs) and produced pronounced analgesic effects across multiple pain models, highlighting its therapeutic potential in pain relief. This study offers critical structural and mechanistic insights into TRPV4 inhibition and lays the groundwork for the structure-based design of TRPV4-targeted therapeutics.

biochemistry↗

bioRxiv2024

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

neuroscience↗

bioRxiv2023

Spatial transcriptomics and single-nucleus RNA sequencing reveal a transcriptomic atlas of adult human spinal cord

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the mouse adult spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.

neuroscience↗

bioRxiv2023

The Diversity of NLRs in Brassica rapa Pan-genome

The species Brassica rapa is mainly cultivated as a vegetable crop with high economic value. But infectious diseases, such as soft rot disease and clubroot disease can cause severe yield losses. Introducing resistance genes through breeding is an efficient and sustainable way to reduce the susceptibility and improve the yield of crops. Nucleotide-Binding Leucine-Rich Repeat (NLR) genes are the main types of resistance genes. They can recognize pathogen effectors and initiate downstream immune response. However, the intraspecific diversity of NLR genes in Brassica rapa has remained unknown. Based on domain similarity search and machine learning pipeline, we identified 2188 NLRs in 17 accessions of Brassica rapa genomes, which constitute the species-wide pan-NLRome in Brassica rapa. The diversity of the four types of NLR genes are significantly different in the aspects of chromosome location, number stability, integrated domains (IDs), evolutionary trajectory, and positive selection sites. Phylogenetic analyses show TNL-type NLRs whose N terminus contain Toll/interleukin-1 receptor (TIR) domain experienced accession-specific expansion. Moreover, the expanded TNL-type NLRs carry more positively selected amino acid residues which are mainly located on the protein surface based on their 3D structures. These evidences might imply their important biological function in perceiving pathogen effectors. Taken together, our study provides better insights into the diversity and variation of NLR genes in Brassica rapa pangemone, which can facilitate the biofunction assigning, cloning, and subsequent application in breeding programs.

genomics↗

bioRxiv2021

The adenosine analogue prodrug ATV006 is orally bioavailable and has potent preclinical efficacy against SARS-CoV-2 and its variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5-hydroxyl-isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.

microbiology↗

bioRxiv2021

Single-shot rAAV5-based Vaccine Provides Long-term Protective Immunity against SARS-CoV-2 and Its Variants

The COVID-19 pandemic and the SARS-CoV-2 with its variants have posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against the SARS-CoV-2 variants. Therefore, novel vaccines to match current mutated viral lineages with long-term protective immunity are urgently in demand. In the current study, we for the first time designed a recombinant Adeno-Associated Virus 5 (rAAV5)-based vaccine named as rAAV-COVID-19 vaccine (Covacinplus) by using RBD-plus of spike protein with both the single-stranded and the self-complementary AAV5 delivering vectors (ssAAV5 and scAAAV5), which provides excellent protection from SARS-CoV-2 infection. A single dose vaccination induced the strong immune response against SARS-CoV-2. The induced neutralizing antibodies (NAs) titers were maintained at a high peak level of over 1:1024 even after more than one year of injection and accompanied with functional T-cells responses in mice. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines exhibited high levels of serum NAs against current circulating variants including variants Alpha, Beta, Gamma and Delta. SARS-CoV-2 virus challenge test showed that ssAAV5-RBD-plus vaccine protected both young and old age mice from SARS-CoV-2 infection in the upper and the lower respiratory tracts. Moreover, whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genome of the vaccinated mice after one year vaccination, demonstrating excellent safety of the vaccine. Taken together, this study suggests that rAAV5-based vaccine is powerful against SARS-CoV-2 and its variants with long-term protective immunity and excellent safety, which has great potential for development into prophylactic vaccination in human to end this global pandemic.

immunology↗