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Frontiers in Cellular Neuroscience 2023Presynaptic plasticity is an activity-dependent change in the neurotransmitter release and plays a key role in dynamic modulation of synaptic strength. Particularly,... (Review)
Review
Presynaptic plasticity is an activity-dependent change in the neurotransmitter release and plays a key role in dynamic modulation of synaptic strength. Particularly, presynaptic potentiation mediated by cyclic adenosine monophosphate (cAMP) is widely seen across the animals and thought to contribute to learning and memory. Hippocampal mossy fiber-CA3 pyramidal cell synapses have been used as a model because of robust presynaptic potentiation in short- and long-term forms. Moreover, direct presynaptic recordings from large mossy fiber terminals allow one to dissect the potentiation mechanisms. Recently, super-resolution microscopy and flash-and-freeze electron microscopy have revealed the localizations of release site molecules and synaptic vesicles during the potentiation at a nanoscale, identifying the molecular mechanisms of the potentiation. Incorporating these growing knowledges, we try to present plausible mechanisms underlying the cAMP-mediated presynaptic potentiation.
PubMed: 37519634
DOI: 10.3389/fncel.2023.1237589 -
Cancer Letters Mar 2024Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Understanding the underlying mechanism driving CRC progression and identifying potential...
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Understanding the underlying mechanism driving CRC progression and identifying potential therapeutic drug targets are of utmost urgency. We previously utilized LC-MS-based proteomic profiling to identify proteins associated with postoperative progression in stage II/III CRC. Here, we revealed that proteasome subunit beta type-1 (PSMB1) is an independent predictor for postoperative progression in stage II/III CRC. Mechanistically, PSMB1 binds directly to onco-protein RAB34 and promotes its proteasome-dependent degradation, potentially leading to the inactivation of the MEK/ERK signaling pathway and inhibition of CRC progression. To further identify potential anticancer drugs, we screened a library of 2509 FDA-approved drugs using computer-aided drug design (CADD) and identified Kinetin as a potentiating agent for PSMB1. Functional assays confirmed that Kinetin enhanced the interaction between PSMB1 and RAB34, hence facilitated the degradation of RAB34 protein and decreased the MEK/ERK phosphorylation. Kinetin suppresses CRC progression in patient-derived xenograft (PDX) and liver metastasis models. Conclusively, our study identifies PSMB1 as a potential biomarker and therapeutic target for CRC, and Kinetin as an anticancer drug by enhancing proteasome-dependent onco-protein degradation.
Topics: Humans; Proteasome Endopeptidase Complex; Kinetin; Proteomics; Colorectal Neoplasms; Mitogen-Activated Protein Kinase Kinases; Cell Line, Tumor
PubMed: 38159835
DOI: 10.1016/j.canlet.2023.216600 -
International Journal of Medical... 2023Melanoma is a highly malignant tumor, which metastasizes and has poor prognosis in late-stage cancer patients. α-Mangostin possesses pharmacological properties,...
Melanoma is a highly malignant tumor, which metastasizes and has poor prognosis in late-stage cancer patients. α-Mangostin possesses pharmacological properties, including antioxidant, anti-infective, and anticarcinogenic activities. We investigated α-Mangostin effect on melanoma growth, migration, and invasion and its possible molecular mechanism. Melanoma cells growth inhibition was determined by the colorimetric 4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. Morphological changes of α-Mangostin-treated melanoma cells were evaluated by transmission electron microscopy and JC-1 staining. Cell apoptosis and cell cycle arrest were assessed by flow cytometry. The effect of α-Mangostin on tumor cells migration and invasion was observed by migration and invasion assay. Furthermore, the nude and C57BL/6 mouse subcutaneous melanoma models were used to evaluate the anti-tumor effect of α-Mangostin. Western blot and real time-PCR were performed to analyze the influence of α-Mangostin on some of the common signaling pathways in melanoma cell lines. Signaling pathways were further verified in dissected tumor tissues. α-Mangostin inhibited melanoma cells proliferation, migration, and invasion of melanoma cells, induced cell cycle arrest in G0/G1 phase, and caused mitochondrial swelling and membrane depolarization, whereas it effectively suppressed melanoma growth in xenografted mice. In addition, α-Mangostin potentiated the and anti-tumor effects of cisplatin both and . Mechanistically, α-Mangostin down-regulated expression of RAS protein and mRNA, as well as phosphorylation of PI3K in A375, B16F10, M14 and SK-MEL-2 cells. MITF protein and mRNA were inhibited only in M14 cells. α-Mangostin suppresses melanoma cells growth, migration and invasion, and synergistically enhances the anti-tumor effect of chemotherapy, whose mechanism may be mediated through inhibiting Ras, PI3K and MITF.
Topics: Animals; Mice; Cell Line, Tumor; Mice, Inbred C57BL; Melanoma; Cell Proliferation; Apoptosis; RNA, Messenger; Phosphatidylinositol 3-Kinases; Cell Movement
PubMed: 37575275
DOI: 10.7150/ijms.80940 -
Frontiers in Microbiology 2023Biochar is a carbonaceous by-product of lignocellulosic biomass developed by various thermochemical processes. Biochar can be transformed into "nano-biochar" by size... (Review)
Review
Biochar is a carbonaceous by-product of lignocellulosic biomass developed by various thermochemical processes. Biochar can be transformed into "nano-biochar" by size reduction to nano-meters level. Nano-biochar presents remarkable physico-chemical behavior in comparison to macro-biochar including; higher stability, unique nanostructure, higher catalytic ability, larger specific surface area, higher porosity, improved surface functionality, and surface active sites. Nano-biochar efficiently regulates the transport and absorption of vital micro-and macro-nutrients, in addition to toxic contaminants (heavy metals, pesticides, antibiotics). However an extensive understanding of the recent nano-biochar studies is essential for large scale implementations, including development, physico-chemical properties and targeted use. Nano-biochar toxicity on different organisms and its in-direct effect on humans is an important issue of concern and needs to be extensively evaluated for large scale applications. This review provides a detailed insight on nanobiochar research for (1) development methodologies, (2) compositions and properties, (3) characterization methods, (4) potentiality as emerging sorbent, photocatalyst, enzyme carrier for environmental application, and (5) environmental concerns.
PubMed: 37547682
DOI: 10.3389/fmicb.2023.1214870 -
NeuroImage Aug 2023Physical exercise, even stress-free very-light-intensity exercise such as yoga and very slow running, can have beneficial effects on executive function, possibly by...
Physical exercise, even stress-free very-light-intensity exercise such as yoga and very slow running, can have beneficial effects on executive function, possibly by potentiating prefrontal cortical activity. However, the exact mechanisms underlying this potentiation have not been identified. Evidence from studies using pupillometry demonstrates that pupil changes track the real-time dynamics of activity linked to arousal and attention, including neural circuits from the locus coeruleus to the cortex. This makes it possible to examine whether pupil-linked brain dynamics induced during very-light-intensity exercise mediate benefits to prefrontal executive function in healthy young adults. In this experiment, pupil diameter was measured during 10 min of very-light-intensity exercise (30% V˙o). A Stroop task was used to assess executive function before and after exercise. Prefrontal cortical activation during the task was assessed using multichannel functional near-infrared spectroscopy (fNIRS). We observed that very-light-intensity exercise significantly elicited pupil dilation, reduction of Stroop interference, and task-related left dorsolateral prefrontal cortex activation compared with the resting-control condition. The magnitude of change in pupil dilation predicted the magnitude of improvement in Stroop performance. In addition, causal mediation analysis showed that pupil dilation during very-light-intensity exercise robustly determined subsequent enhancement of Stroop performance. This finding supports our hypothesis that the pupil-linked mechanisms, which may be tied to locus coeruleus activation, are a potential mechanism by which very light exercise enhances prefrontal cortex activation and executive function. It also suggests that pupillometry may be a useful tool to interpret the beneficial impact of exercise on boosting cognition.
Topics: Young Adult; Humans; Pupil; Spectroscopy, Near-Infrared; Cognition; Executive Function; Exercise; Prefrontal Cortex
PubMed: 37353097
DOI: 10.1016/j.neuroimage.2023.120244 -
Antibiotics (Basel, Switzerland) Sep 2023The excessive use of antibiotics has led to the emergence of multidrug-resistant (MDR) pathogens in clinical settings and food-producing animals, posing significant... (Review)
Review
The excessive use of antibiotics has led to the emergence of multidrug-resistant (MDR) pathogens in clinical settings and food-producing animals, posing significant challenges to clinical management and food control. Over the past few decades, the discovery of antimicrobials has slowed down, leading to a lack of treatment options for clinical infectious diseases and foodborne illnesses. Given the increasing prevalence of antibiotic resistance and the limited availability of effective antibiotics, the discovery of novel antibiotic potentiators may prove useful for the treatment of bacterial infections. The application of antibiotics combined with antibiotic potentiators has demonstrated successful outcomes in bench-scale experiments and clinical settings. For instance, the use of efflux pump inhibitors (EPIs) in combination with antibiotics showed effective inhibition of MDR pathogens. Thus, this review aims to enable the possibility of using novel EPIs as potential adjuvants to effectively control MDR pathogens. Specifically, it provides a comprehensive summary of the advances in novel EPI discovery and the underlying mechanisms that restore antimicrobial activity. In addition, we also characterize plant-derived EPIs as novel potentiators. This review provides insights into current challenges and potential strategies for future advancements in fighting antibiotic resistance.
PubMed: 37760714
DOI: 10.3390/antibiotics12091417 -
The Journal of Neuroscience : the... Nov 2023In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared with novel stimuli. This stimulus-selective response plasticity...
In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared with novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer 4 (L4) by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDARs) and has been hypothesized to reflect potentiation of thalamocortical (TC) synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed in male and female mice, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knock-out (KO) of NMDAR in L6 principal neurons disrupts SRP. Current-source density (CSD) analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4, and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1. Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurologic and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials (VEPs), neuronal spiking activity, and oscillations in the local field potentials (LFPs) across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 (L6) of visual cortex.
Topics: Humans; Mice; Male; Female; Animals; Evoked Potentials, Visual; Learning; Neurons; Visual Cortex; Memory; Photic Stimulation
PubMed: 37714707
DOI: 10.1523/JNEUROSCI.0090-23.2023 -
Journal of Nanobiotechnology Dec 2023The present work was an endeavor to shed light on how mild photothermia possibly synergizes with immune checkpoint inhibition for tumor therapy. We established mild...
The present work was an endeavor to shed light on how mild photothermia possibly synergizes with immune checkpoint inhibition for tumor therapy. We established mild photothermal heating protocols to generate temperatures of 43 °C and 45 °C in both in vitro and in vivo mouse 4T1 triple-negative breast cancer (TNBC) models using polyglycerol-coated carbon nanohorns (CNH-PG) and 808 nm laser irradiation. Next, we found that 1) CNH-PG-mediated mild photothermia (CNH-PG-mPT) significantly increased expression of the immune checkpoint PD-L1 and type-1 macrophage (M1) markers in the TNBC tumors; 2) CNH-PG-mPT had a lower level of anti-tumor efficacy which was markedly potentiated by BMS-1, a PD-L1 blocker. These observations prompted us to explore the synergetic mechanisms of CNH-PG-mPT and BMS-1 in the context of tumor cell-macrophage interactions mediated by PD-L1 since tumor-associated macrophages (TAMs) are a major source of PD-L1 expression in tumors. In vitro, the study then identified two dimensions where BMS-1 potentiated CNH-PG-mPT. First, CNH-PG-mPT induced PD-L1 upregulation in the tumor cells and showed a low level of cytotoxicity which was potentiated by BMS-1. Second, CNH-PG-mPT skewed TAMs towards an M1-like anti-tumor phenotype with upregulated PD-L1, and BMS-1 bolstered the M1-like phenotype. The synergistic effects of BMS-1 and CNH-PG-mPT both on the tumor cells and TAMs were more pronounced when the two cell populations were in co-culture. Further in vivo study confirmed PD-L1 upregulation both in tumor cells and TAMs in the TNBC tumors following treatment of CNH-PG-mPT. Significantly, TAMs depletion largely abolished the anti-TNBC efficacy of CNH-PG-mPT alone and in synergy with BMS-1. Collectively, our findings reveal PD-L1 upregulation to be a key response of TNBC to mild photothermal stress, which plays a pro-survival role in the tumor cells while also acting as a brake on the M1-like activation of the TAMs. Blockade of mPT‑induced PD‑L1 achieves synergistic anti-TNBC efficacy by taking the intrinsic survival edge off the tumor cells on one hand and taking the brakes off the M1-like TAMs on the other. Our findings reveal a novel way (i.e. mild thermia plus PD-L1 blockade) to modulate the TAMs-tumor cell interaction to instigate a mutiny of the TAMs against their host tumor cells.
Topics: Humans; Animals; Mice; Triple Negative Breast Neoplasms; B7-H1 Antigen; Photothermal Therapy; Macrophages; Phenotype; Cell Line, Tumor
PubMed: 38082443
DOI: 10.1186/s12951-023-02240-3 -
Biomedicines Sep 2023This study aimed to evaluate the anti-arthritic activity of curcumin and meloxicam co-loaded PLGA nanoparticles in adjuvant-induced arthritic rats. PLGA nanoparticles...
This study aimed to evaluate the anti-arthritic activity of curcumin and meloxicam co-loaded PLGA nanoparticles in adjuvant-induced arthritic rats. PLGA nanoparticles encapsulating curcumin (nCur) and meloxicam (nMlx) alone and in combination (nCur/Mlx) were used to characterize zeta size and potential, polydispersity index, encapsulation efficiency (%), compound-polymer interactions (FT-IR analysis), and surface morphology (SEM imaging). In vivo, Complete Freund's adjuvant-induced arthritic rats were intraperitoneally (i.p.) administered with curcumin, meloxicam, curcumin plus meloxicam, nCur, nMlx, and nCur/Mlx for 28 consecutive days. Results showed that nCur, nMlx, and nCur/Mlx significantly ( ≤ 0.05) reduced paw swelling and arthritic score, restored body weight and the immune organ index (thymus and spleen), as well as attenuated serum inflammatory markers (RF, CRP, and PGE2) and oxidative stress parameters (MDA, SOD, and CAT) in adjuvant-induced arthritic rats compared to free compounds. In addition, mono- and dual-compound-loaded nanoparticles significantly ( ≤ 0.05) down-regulated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), up-regulated anti-inflammatory cytokines (IL-4, IL-10, and IFN-γ), and modulated OPG and RANKL expressions in paw tissue. The aforementioned results were further confirmed through radiological and histopathological examinations. Furthermore, the anti-arthritic effect of nCur/Mlx was notably ( ≤ 0.05) enhanced compared to nCur or nMlx alone. In conclusion, the co-nanoencapsulation of curcumin could potentiate the anti-arthritic activity of meloxicam and could provide a novel therapeutic approach for the formulation of nanocarrier pharmaceutical products for the management of arthritis.
PubMed: 37893036
DOI: 10.3390/biomedicines11102662 -
Biomolecules Aug 2023The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the...
The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against and erythromycin against . Compounds , , , , , , , , and exhibited strong growth inhibition of methicillin-resistant (MRSA) and , with minimum inhibitory concentrations (MIC) typically less than 0.2 µM. Four analogues, including a 5-bromo and three 5-methoxyls - also exhibited intrinsic activity towards . Antibiotic kill curve analysis of identified it to be a bactericide. While only one derivative was found to (weakly) enhance the action of erythromycin against , three examples, including , were found to be strong enhancers of the antibiotic action of doxycycline against . Collectively, these results highlight the promising potential of α,ω-disubstituted indole-3-acetamido polyamine conjugates as antimicrobials and antibiotic adjuvants.
Topics: Anti-Bacterial Agents; Doxycycline; Escherichia coli; Methicillin-Resistant Staphylococcus aureus; Anti-Infective Agents; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Erythromycin; Fatty Acids, Omega-3; Indoles; Polyamines; Pseudomonas aeruginosa
PubMed: 37627291
DOI: 10.3390/biom13081226