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Journal of the American Chemical Society Oct 2023Coley's toxins, an early and enigmatic form of cancer (immuno)therapy, were based on preparations of . As part of a program to explore bacterial metabolites with...
Coley's toxins, an early and enigmatic form of cancer (immuno)therapy, were based on preparations of . As part of a program to explore bacterial metabolites with immunomodulatory potential, . metabolites were assayed in a cell-based immune assay, and a single membrane lipid, 18:1/18:0/18:1/18:0 cardiolipin, was identified. Its activity was profiled in additional cellular assays, which showed it to be an agonist of a TLR2-TLR1 signaling pathway with a 6 μM EC and robust TNF-α induction. A synthetic analog with switched acyl chains had no measurable activity in immune assays. The identification of a single immunogenic cardiolipin with a restricted structure-activity profile has implications for immune regulation, cancer immunotherapy, and poststreptococcal autoimmune diseases.
Topics: Humans; Streptococcus pyogenes; Cardiolipins; Neoplasms; Tumor Necrosis Factor-alpha
PubMed: 37738205
DOI: 10.1021/jacs.3c07727 -
JHEP Reports : Innovation in Hepatology Dec 2023Liver paracrine signaling from liver sinusoid endothelial cells to hepatocytes in response to mechanical stimuli is crucial in highly coordinated liver regeneration....
BACKGROUND & AIMS
Liver paracrine signaling from liver sinusoid endothelial cells to hepatocytes in response to mechanical stimuli is crucial in highly coordinated liver regeneration. Interstitial flow through the fenestrated endothelium inside the space of Disse potentiates the role of direct exposure of hepatocytes to fluid flow in the immediate regenerative responses after partial hepatectomy, but the underlying mechanisms remain unclear.
METHODS
Mouse liver perfusion was used to identify the effects of interstitial flow on hepatocyte proliferation . Isolated hepatocytes were further exposed to varied shear stresses directly . Knockdown and/or inhibition of mechanosensitive proteins were used to unravel the signaling pathways responsible for cell proliferation.
RESULTS
An increased interstitial flow was visualized and hepatocytes' regenerative response was demonstrated experimentally by perfusion of mouse livers. measurements also showed that fluid flow initiated hepatocyte proliferation in a duration- and amplitude-dependent manner. Mechanistically, flow enhanced β1 integrin expression and nuclear translocation of YAP (yes-associated protein), via the Hippo pathway, to stimulate hepatocytes to re-enter the cell cycle.
CONCLUSIONS
Hepatocyte proliferation was initiated after direct exposure to interstitial flow or shear stress , which provides new insights into the contributions of mechanical forces to liver regeneration.
IMPACT AND IMPLICATIONS
By using both liver perfusion and flow exposure tests, we identified the roles of interstitial flow in the space of Disse in stimulating hepatocytes to re-enter the cell cycle. We found an increase in shear flow-induced hepatocyte proliferation via β1 integrin-YAP mechanotransductive pathways. This serves as a useful model to potentiate hepatocyte expansion using mechanical forces.
PubMed: 37920845
DOI: 10.1016/j.jhepr.2023.100905 -
Cell Reports Dec 2023The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory...
The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory remains unclear. Here, we discover the crucial role of cholecystokinin (CCK) in heterosynaptic neuromodulation from the medial entorhinal cortex (MEC) to the hippocampus. Systematic knockout of the CCK gene impairs CA3-CA1 LTP and space-related performance. The MEC provides most of the CCK-positive neurons projecting to the hippocampal region, which potentiates CA3-CA1 long-term plasticity heterosynaptically in a frequency- and NMDA receptor (NMDAR)-dependent manner. Selective inhibition of MEC CCKergic neurons or downregulation of their CCK mRNA levels also impairs CA3-CA1 LTP formation and animals' performance in the water maze. This excitatory extrahippocampal projection releases CCK upon high-frequency excitation and is active during animal exploration. Our results reveal the critical role of entorhinal CCKergic projections in bridging intra- and extrahippocampal circuitry at electrophysiological and behavioral levels.
Topics: Cholecystokinin; Entorhinal Cortex; CA3 Region, Hippocampal; CA1 Region, Hippocampal; CA2 Region, Hippocampal; Synapses; Spatial Learning; Neuronal Plasticity; Animals; Mice; Mice, Knockout; Long-Term Potentiation
PubMed: 37979171
DOI: 10.1016/j.celrep.2023.113467 -
Neurobiology of Disease Sep 2023Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical...
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAR subunit composition, there was a redistribution of extrasynaptic GABARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
Topics: Mice; Animals; Diazepam; Alcoholism; Substance Withdrawal Syndrome; Receptors, GABA-A; Benzodiazepines; Brain; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37536384
DOI: 10.1016/j.nbd.2023.106248 -
Acta Pharmaceutica Sinica. B Aug 2023Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of...
Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.
PubMed: 37655331
DOI: 10.1016/j.apsb.2023.05.010 -
Vaccines Nov 2023Vaccination is a groundbreaking approach in preventing and controlling infectious diseases. However, the effectiveness of vaccines can be greatly enhanced by the... (Review)
Review
Vaccination is a groundbreaking approach in preventing and controlling infectious diseases. However, the effectiveness of vaccines can be greatly enhanced by the inclusion of adjuvants, which are substances that potentiate and modulate the immune response. This review is based on extensive searches in reputable databases such as Web of Science, PubMed, EMBASE, Scopus, and Google Scholar. The goal of this review is to provide a thorough analysis of the advances in the field of adjuvant research, to trace the evolution, and to understand the effects of the various adjuvants. Historically, alum was the pioneer in the field of adjuvants because it was the first to be approved for use in humans. It served as the foundation for subsequent research and innovation in the field. As science progressed, research shifted to identifying and exploiting the potential of newer adjuvants. One important area of interest is nano formulations. These advanced adjuvants have special properties that can be tailored to enhance the immune response to vaccines. The transition from traditional alum-based adjuvants to nano formulations is indicative of the dynamism and potential of vaccine research. Innovations in adjuvant research, particularly the development of nano formulations, are a promising step toward improving vaccine efficacy and safety. These advances have the potential to redefine the boundaries of vaccination and potentially expand the range of diseases that can be addressed with this approach. There is an optimistic view of the future in which improved vaccine formulations will contribute significantly to improving global health outcomes.
PubMed: 38006036
DOI: 10.3390/vaccines11111704 -
Proceedings of the National Academy of... Aug 2023Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks,...
Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a mouse model of EA1 and restored the neuromuscular transmission and climbing ability in (Kv1.1) mutant flies (). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.
Topics: Animals; Mice; Myokymia; Drosophila melanogaster; Ataxia; Drosophila; Kv1.2 Potassium Channel
PubMed: 37487086
DOI: 10.1073/pnas.2207978120 -
Sensors (Basel, Switzerland) Jun 2023Atomic clocks are highly precise timing devices used in numerous Positioning, Navigation, and Timing (PNT) applications on the ground and in outer space. In recent... (Review)
Review
Atomic clocks are highly precise timing devices used in numerous Positioning, Navigation, and Timing (PNT) applications on the ground and in outer space. In recent years, however, more precise timing solutions based on optical technology have been introduced as current technology capabilities advance. State-of-the-art optical clocks-predicted to be the next level of their predecessor atomic clocks-have achieved ultimate uncertainty of 1 × 10 and beyond, which exceeds the best atomic clock's performance by two orders of magnitude. Hence, the successful development of optical clocks has drawn significant attention in academia and industry to exploit many more opportunities. This paper first provides an overview of the emerging optical clock technology, its current development, and characteristics, followed by a clock stability analysis of some of the successfully developed optical clocks against current Global Navigation Satellite System (GNSS) satellite clocks to discuss the optical clock potentiality in GNSS positioning. The overlapping Allan Deviation (ADEV) method is applied to estimate the satellite clock stability from International GNSS Service (IGS) clock products, whereas the optical clock details are sourced from the existing literature. The findings are (a) the optical clocks are more stable than that of atomic clocks onboard GNSS satellites, though they may require further technological maturity to meet spacecraft payload requirements, and (b) in GNSS positioning, optical clocks could potentially offer less than a 1 mm range error (clock-related) in 30 s and at least 10 times better timing performance after 900 s in contrast to the Galileo satellite atomic clocks-which is determined in this study as the most stable GNSS atomic clock type used in satellite positioning.
Topics: Industry; Spacecraft; Technology; Uncertainty
PubMed: 37447847
DOI: 10.3390/s23135998 -
Biomedicines Feb 2024Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be... (Review)
Review
Endothelin-1 (ET-1) plays a physiological role as a potent vasoconstrictor. It is implicated in an array of diseases, and its signalling is often found to be overactivated within cancers. ET-1 has been found to potentiate hallmarks of cancer progression such as cell proliferation, invasion and metastasis, as well as angiogenesis. ET-1 has also been implicated in inducing the epithelial-mesenchymal transition (EMT) and promoting resistance to anticancer drugs. Many preclinical efforts have been made to target ET-1 expression within cancer, such as by using ET-1 receptor antagonists, many of which have been approved for treating pulmonary hypertension. Targeting ET-1 has been shown to improve the response to various other cancer therapeutics, highlighting the potential benefits targeting this peptide may exert. Drug repurposing is an attractive strategy, and exploration of this avenue may be promising for targeting ET-1 in cancer. There are many clinical trials which have been completed and are currently undergoing involving the repurposing of ET-1 receptor antagonists for cancer treatment. In this review, the pathways through which ET-1 potentiates cancer will be discussed, as well as where the opportunity for therapeutic intervention lies in relation to cancer.
PubMed: 38540124
DOI: 10.3390/biomedicines12030511 -
Inflammation and Regeneration Nov 2023Inflammatory bowel disease (IBD) is a multifactorial intractable intestinal disease. Focusing on only one facet of the pathogenesis of IBD is insufficient to fully... (Review)
Review
Inflammatory bowel disease (IBD) is a multifactorial intractable intestinal disease. Focusing on only one facet of the pathogenesis of IBD is insufficient to fully capture the complexity of the disease, and results in limited advance in clinical management. Therefore, it is critical to dissect the interactions amongst the multifarious contributors to the pathogenesis to comprehensively understand its pathology and subsequently improve clinical outcomes. In this context, the systemic interactions between organs, particularly the oral-gut axis mediated by host immune cells and resident microorganisms, have garnered significant attention in IBD research. More specifically, periodontal disease such as periodontitis has been implicated in augmenting intestinal inflammation beyond the confines of the oral cavity. There is mounting evidence suggesting that potentially harmful oral resident bacteria, termed pathobionts, and pro-inflammatory immune cells from the oral mucosa can migrate to the gastrointestinal tract, thereby potentiating intestinal inflammation. This article aims to provide a holistic overview of the causal relationship between periodontal disease and intestinal inflammation. Furthermore, we will discuss potential determinants that facilitate the translocation of oral pathobionts into the gut, a key event underpinning the oral-gut axis. Unraveling the complex dynamics of microbiota and immunity in the oral-gut continuum will lead to a better understanding of the pathophysiology inherent in both oral and intestinal diseases and the development of prospective therapeutic strategies.
PubMed: 37932859
DOI: 10.1186/s41232-023-00304-3